Evidence of FDA, CFSAN, and NIH Food & Formula Adulteration & Misbranding- And Noncompliance with Food Safety Modernization Act, (FSMA)


Overwhelming evidence as revealed in the letter below proves the worst FDA- fetal, infant, and child food and formula crime in U.S. history-  Part 2.


October 9, 2016


Dear FDA, CFSAN, and NIH,

As CFSAN Dr. Hanson had requested, I previously sent to you Part 1 that details nearly ONE THOUSAND of your NIH Pubmed published studies, (many published by your own FDA and NIH researchers) that for decades consistently conclude a variety of destructive physiological, reproductive, and neurological adverse effects can be irreversibly caused to fetus, infants, and children exposed to fluctuating dosage levels of an assortment of developmental soy plant-poisons. 

I recently received your brief email reply to Part 1, stating, “We take the safety of infant formula very seriously,” however this note is void of any FDA, CFSAN, or NIH signature.  Clearly not one of you will sign this fabricated statement that attempts to cover-up your acknowledgement of this ongoing, bottomless pit of overwhelming numbers of NIH Pubmed studies, published by hundreds of renowned U.S., and worldwide soy phyto-toxic researchers who ALL study conclude a large variety of horrific, in fact deleterious body and brain soy phyto-poisonous effects are caused to exposed fetus, infants, and children.   
   
Many of you at the FDA, CFSAN, and NIH also personally confirm throughout testimonials that you do have desperate concern (in detail below) about fetal, infant, and child exposure to fluctuating dosage levels of multiple developmental  phyto-poisons in soy.  In spite of your acknowledgment of potential health-destructive developmental soy phyto-poisonous effects, you choose NOT to allow with lawful public disclosure, but to recklessly increase the U.S. marketing of soy foods and infant formulas, while without valid evidence that fetal, infant, and child contamination from dosages of multiple soy phyto-poisons are safe. 

Your own FDA Poisonous Plant Database recognizes soybean, “Genistein, and Daidzein,” as extremely dangerous developmental soy phyto-estrogenic hormone disruptors placed into baby formulas and foods.  As you are also fully aware, estrogenic hormone disruptors are without question highest level fetal, infant, and child poisons. Your acknowledgement of developmental exposure to these soybean phyto-poisonous hormone disruptors are withheld from lawful public disclosure, as evidence of your failure to comply with the Food Safety Modernization Act.  The FSMA demands that the “U.S. food supply is safe by shifting the focus of U.S. federal regulators from responding to contamination to preventing it.” 

You also know, but the U.S. public does not, that there are unknown numbers of infants and children, as well as pregnant women, who dangerously metabolize soy estrogenic hormone disruptor daidzein to equol, an additional established  developmentally contaminating soybean estrogenic hormone disruptor.  And soy, glycitein is a FORTH developmentally toxic estrogenic hormone disruptor, ALL of which are FDA, CFSAN, and NIH withheld from lawful public disclosure. 

You are also aware that expectant mothers consuming soy products create a highly toxic estrogenic hormone disruptor gestational environment, as developing fetus are NOT able to detoxify these contaminating soy phyto-poisonous hormone disruptors.  It is of greatest concern that while all living people are already exposed to a variety of environmental poisons, the addition of several soy phyto-estrogenic hormone disruptors in the diet of pregnant women, infants, and children, are overwhelmingly published study concluded to increase explosive adverse physiological, reproductive, and neurological fuel to this health destructive developmental fire. 

NO other developmentally poisonous estrogenic hormone disruptor: pesticides, alcohol, BPA, formaldehyde, pollution, etc., are deliberately fetal exposed, or directly fed into the mouths of infants and children, (as a murderous felony), other than your exception of several soy phyto-poisonous estrogenic hormone disruptors, while your law abiding WARNING labels remain FDA, CFSAN, and NIH withheld from public disclosure. 

You also acknowledge that years ago in 1999 your Federal Register confirms, “GRAS status of soy did not include a thorough evaluation of the safety of potentially harmful components, e.g. lysioalanine, nitrites, trypsin inhibitors, phytates, and isoflavones,” [soy estrogenic hormone disruptors]. 

Each, and ALL of these fluctuating dosage levels of multiple established soybean phyto-poisons are FDA, CFSAN, and NIH acknowledged as overtly harmful and destructive to the most vulnerable body and brain of fetus, infants, and children, while you continue to unlawfully refuse to post public disclosure as an equal opportunity for adverse developmental health knowledge for all. 

While sacrificing this public health threat, proven to result in serious and irreversible adverse developmental health consequences, it is your choice to allow adulterated and misbranded soy phyto-poisons to be popularly U.S. marketed as falsely safe, while at the same time asserting non-compliance to the Food Safety Modernization Act, (FSMA), and multiple food, health, and child safety laws. 

It is true, as you acknowledge that in addition to illegally U.S. marketed unknown  levels of fluctuating dosage levels of several contaminating soy phyto-poisonous isoflavone estrogenic hormone disruptors, each soybean plant also contains unknown fluctuating dosage levels of multiple additional fetal, infant, and child soy phyto-poisons to include as your Federal Register confirms; phytic acid- that blocks critical mineral absorption, inhibitors of several essential developmental enzymes, a host of toxic heavy metals, and a variety of “natural” environmental plant-poisons, ALL of which you, the FDA, CFSAN and NIH clearly acknowledge as capable of causing severe, irreversible, and potentially fatal physiological, reproductive, and neurological developmental effects, while you withhold all of this critical health knowledge from public disclosure.

Why do you, the FDA, CFSAN, and NIH continue to choose to silently and illegally conceal decades-worth of ongoing, nearly a THOUSAND NIH Pubmed published study evidence, (many your own FDA and NIH studies) as well as your own testimonials, (view below) that repeatedly and overwhelmingly confirm your acknowledgement of excessively harmful and health-destructive soy phyto-poisonous contamination of fetus, infants, and children from lawful public disclosure? 

Based upon the above, you, the FDA, CFSAN, and NIH are NOT in compliance with  food, health, and child safety laws such as: the U. S. Food Safety Modernization Act, or Protection of Children from Environmental Health Risks and Safety Risks, as well as the U.S. Infant Formula Act, while knowingly and willingly falsifying the public impression that soy (phyto-poisons) are fetal, infant, and child safe, of which developmental body and brain safety has NEVER been established. 

As you are also aware, according to nearly a THOUSAND NIH Pubmed published study conclusions, as well as your testimonials, it remains unproven thus unknown if any ONE most delicate developing fetus, infant, or child will be able to normally survive this overwhelmingly conclusive physiological, reproductive, or neurological chemical assault caused by developmental exposure to an explosive cornucopia of fluctuating dosage levels of numerous soybean phyto-poisons. 

Without compliance to FSMA and several U.S. laws, the FDA, CFSAN, and NIH continue to illegally choose to pretend safety of what you acknowledge as an ongoing U.S. undocumented, and undisclosed fetal, infant, and child body- and brain-contaminating soy phyto-poisoning experiment, while without fair and lawful public disclosure. 

Your very own NIEHS renowned scientists, (of whom you may personally know), who specialize in developmental soy phyto-poisonous research: Drs. Sheehan, Doerge, Newbold, Chang, Patisual, Jefferson, and many more, have continued for decades (since the 1970’s) and to this day, to repeatedly report to you, the FDA, CFSAN, and NIH, of their in-depth high risk study conclusions always resulting in soy phyto-poisonous adverse developmental body and brain effects, of which it is your ongoing choice to illegally remain publicly mute to NIEHS, and other mass numbers of NIH Pubmed published study evidence.   

Particularly related, your aware of this long history of highly respected NIEHS soybean researchers of whom for decades consistently confirm a pernicious soy phyto-poisonous assault upon developing fetus, infants, and children, while as most current, you again choose to ignore a recent published NIEHS report  confirming, “Soy Infant Formula” on their highly toxic list of “Environmental Agents.”  This NIEHS published toxic list reveals the following as established environmental poisons: “Air Pollution, Allergens, Arsenic, Dioxins, Endocrine Disruptors, Formaldehyde, Lead, Mercury, Mold, Pesticides, Radon, Soy Infant Formula, Styrene, and Water Pollution.”  http://www.niehs.nih.gov/health/topics/agents/index.cfm

Which one of the NIEHS environmental poisons listed above will you place into your baby’s mouth several times day and night?  Probably none, and surely NOT soy infant formulas, because you are able to acknowledge a long history of NIEHS (and worldwide) researchers who consistently report any one of several soy phyto-poisons can cause adverse developmental body and brain effects.  At this same time, it is again your illegal choice to conceal an ongoing massive soy phyto-poisonous chemical assault that largely targets and attacks the health and wellbeing of the body and brain of developing fetus, infants, and children, while unlawfully withheld from a trusting and innocent American public.  NO lawful public disclosure, and NO effort to responsibly protect fetal, infant, and child health! 

As nothing less than unthinkable betrayal, it is an alarming public health crisis that more than a million loving parents contaminate their most precious fetus, babies, and children, without the chance to know that you, the FDA, CFSAN, and NIH illegally withhold your massive file of overwhelming published study evidence, (and your concurring testimonials), that for decades repeatedly confirms a large variety of torturous soy phyto-poisonous adverse physiological, reproductive, and neurological developmental effects are caused to once healthy child. 

As confirmation of adulterated and misbranded, it is untold to a trusting U.S. public that you have no evidence proving which one, or “if” one fetus, baby, or child may be able to survive contaminating exposure from fluctuating dosage levels of several soy phyto-poisons, while you, the FDA, CFSAN, and NIH illegally choose to refuse compliance with your food, health, and child safety laws, including the FSMA. 

While without true evidence of safety, and relative to your acknowledgement that the vast majority of ALL baby foods and formulas now marketed in the U.S.A. contain fluctuating dosage levels of several soy phyto-poisons, you are aware that soy-contaminated baby formulas also contain highest levels of additional established developmental poisons: GMO soy, corn syrup, and sugar.  And again without lawful public disclosure! 

NEVER are marketed developmentally contaminating soy phyto-poisons FDA, CFSAN, or NIH established as safe.  And NOT proven as necessary or beneficial. A non-existing risk to benefit ratio also proves NO known reason to market soy phyto-poisonous infant formulas to babies, and/or to expose babies and children to soy phyto-poisonous foods.  And NOT to contaminate fetus, due to maternal consumption of soy phyto-posions!  To date, your ongoing choice to market adulterated and misbranded fluctuating dosage levels of multiple soy phyto-poisons is evidence of your painful secretive choice to knowingly, willingly, and silently gamble on fetal, baby, and child body and brain health, as comparable to an act of biochemical terror. 

Without argument, as soy phyto-poisons have become increasingly U.S. marketed so goes the increasing, in fact epidemic level of several severe and irreversible children’s body and brain disorders and diseases.  This is not coincidence, but a soy phyto-poisonous contaminating cause- as can be expected!
 
As fact, soy phyto-poisons are confirmed hundreds of times throughout your NIH Pubmed published studies, to cause any number of deleterious fetal, infant, and child physiological, reproductive, and neurological effects of which are repeatedly renowned researcher published study concluded to cause: multiple cancers (with greatest risks reported as the cause of leukemia, pancreatic cancers, and reproductive cancers), cancer metastasis, thyroid and liver diseases, immune system toxicity, diabetes, obesity, adverse development, allergic reactions, asphyxiation, asthma, severe gastrointestinal disorders and diseases, reproductive disorders and diseases, gender chaos, female and male homosexuality, severe and irreversible brain and behavioral disorders to include- Autism, ADHD, seizures, and more. 

As fact, it is impossible for the FDA, CFSAN, or NIH to prove that any one physiological, reproductive, or neurological disorder or disease is NOT caused by fetal, infant, and/or child exposure to fluctuating dosage levels of several soy phyto-poisons, as decades of NIH Pubmed published studies continue for decades to confirm. 
 
As can be expected, there is also NO study evidence able to predict which once healthy fetus, infants, or children, (if any one), will be able to survive exposure(s) to the fluctuating dosage levels of several soybean phyto-poisons, as an in-depth history of ongoing NIH Pubmed studies repeatedly confirm. 

Without FDA, CFSAN, or NIH valid evidence of developmental safety from exposure to soy phyto-poisons, it is established that: babies suffer, children suffer, and entire families suffer long-term hardships. Due to developmental exposure to soy phyto-poisons, required lifelong medical treatment costs are also study concluded to cause outrageous monetary hardships. 

In accordance with the Food Safety and Modernization Act, and several more food, health, and child safety laws, when will the FDA, CFSAN, and NIH choose to post truthful and lawful public warning labels for a trusting and innocent American public, as equal as your own acknowledgement of overwhelming mass evidence concluding severe and irreversible adverse developmental soy phyto-poisoning? 

LOOK at the following: Including your own FDA, CFSAN, and NIH TESTIMONIALS that confirm your ongoing acknowledgement of adverse developmental soy phyto-poisoning as the cause of unrelenting adverse developmental soy phyto-poisonous contamination, while your lawful U.S. public disclosure remains brutally withheld from trusting and innocent American people:

- CFSAN Janice Oliver states, “FDA acknowledges that concerns have been voiced about possible effects of isoflavones in soy infant formula on sexual development, neurobehavioral development, immune function and thyroid disease.” 

-CFSAN Michael Shelby confirms “yes,” to the question does soy infant formula contain estrogenic hormone disruptors? 

-NIEHS Dr. Sheehan states, “…closer study in experimental animals and human populations exposed to phytoestrogen containing products, and particularly soy-based foods is necessary.  Among human exposure, infant soy formula exposure appears to provide the highest of all phytoestrogen dosages and this occurred during development, often the most sensitive life-stage for induction of toxicity.”

-NIEHS Drs. Sheehan and Doerge 1999 letter to the FDA, “…there is abundant evidence that isoflavones found in soy…demonstrate toxicity in estrogen sensitive tissues and in the thyroid.  ...malformations and serious functional deficits in experimental animal and humans.  …no dose is without risk.”

-2010, NIEHS Drs. Patisual and Jefferson, “A possibility of increasing concern is that phytoestrogen may interfere with organizational role of estrogen in the developing brain and reproductive system.  …manipulation of estrogen during specific critical windows of development throughout gestation and early infancy leads to a myriad of adverse health outcomes including malformations in the ovary, uterus, mammary gland, and prostate, early puberty, reduced fertility, disrupted brain organization and reproductive tract cancers.  ….potentially making development one of the most susceptible periods for phytoestrogen and endocrine disrupting chemical exposure over the lifespan.  The isoflavone phytoestrogens genistein and daidzein...raising concern that these compounds pose an underappreciated threat to infant development.”

-2015, NIEHS Ian Thomas, “…our scientists study things in the environment that could potentially make people sick.  …like formaldehyde, and pesticides, or natural agents like mold and arsenic.  This also includes the study of soy.”

-2010, NTP NIEHS Birnbaum, “Soy-based infant formulas …contain high levels of the estrogenic isoflavone genistein leading to concern that neonatal genistein exposure could cause …adverse effects on reproductive and other organs.  …neonatal animal model raises concerns …and could potentially impact the development of human infants fed soy formula.”

-USDA Ag-Magazine- “Soy-based infant formulas …contain soy protein isolate.  …soy based formula involves isoflavones.  Critics suggest that isoflavones in soy formula might disrupt or impair development in infants.”

-Arkansas Children’s Nutritional Center confirms, “…some reasons to be concerned about possible drawbacks of soy proteins.”

- New Zealand, Dr. Fitzpatrick- “I am particularly concerned about the very high doses of isoflavones that infants fed soy infant formula receive….”

-UNICEF UK Louisa Barkla reports, “Soya formula contains high levels of a chemical called phytoestrogen which may have negative effects on babies.…”

-Renown soy researcher, Dr. Kenneth Setchell states, “To deny that soy isoflavones have biological effects would be absurd given a wealth of evidence from in vitro and in vivo cellular and molecular studies.”

-Dr. Lindy Woodard confirms, “I am deeply concerned….  I personally know of the dangers of soy infant formula …observed for myself that babies are not healthy on soy formula.” 

- 2010, American Academy of Pediatrics President Judith Palfrey states, “Concerns have been raised in relation to the safety of phytoestrogens and isoflavones, including their potential negative effects on sexual developmental and reproduction, neurobehavioral development, immune function and thyroid function.  ...a number of new studies have been published related to human exposure, reproductive toxicity, and developmental toxicity for soy infant formula.” 

-2015, NIH NIEHS report, “The safety of soy infant formula has been debated because it typically contains a class of compounds called isoflavones.  These isoflavones are referred to as phytoestrogens …because of their ability to act like the hormone estrogen in the body.  …it is recognized that infants go through developmental stages that are sensitive to estrogens.  In some cases, the health effects resulting from a soy-based diet may not be apparent until years later.  Animal studies indicate health effects of possible concern….  Also, infants go through developmental stages that are sensitive to estrogens.  Numerous studies in laboratory animals exposed to the isoflavones found in soy infant formula, including genistein show adverse effects on development.”

-2015- NIH National Center for Complimentary and Integrative Health confirms, “Side Effects and Cautions- the Safety of long-term use of soy isoflavones has not been established.”

-World Health Organization (WHO) report- “Endocrine Disrupting Chemicals- [soy] phytoestrogens.”  Of which WHO concludes- “Major concern.”

-2015- NTP Senior Scientist- John Bucher states, “The larger issue of just how significant exposures to potential (soy) endocrine disruptors are to public health is still a subject of intensive research.  To date it appears that exposure to the developing fetus are more potentially harmful than those after birth.”

-2002, UK Scientific Advisory Committee on Nutrition concludes, “There is cause for concern about the use of soy-based formula.”

-2010- NIH NIMH Susan Daniels states, “Dr. Insel is aware of the endocrine disrupting properties of soy….  Soy may indeed be one of many environmental factors that contributes to various disorders and deserves further study.”

-2002- WHO also confirms, “In this document, EDCs (Endocrine Disrupting Chemicals) have been defined as ‘exogenous substances that alter function(s) of the endocrine system and consequently cause adverse health effects….’  The diversity of chemicals includes natural and synthetic hormones, [soy] phytoestrogens, pesticides, and a variety of industrial chemicals and by-products.  The ubiquitous presence of natural hormones and plant estrogens poses difficult analytical issues because these natural EDCs may be more potent than environmental EDCs.  ...and developmental immunotoxicity studies link compounds such as DES and the phytoestrogen [soy] genistein to postnatal immune disorders.” 

-2000 EPA confirms, “However, an increase of soy consumption in the North American diet has resulted in increased exposure to dietary estrogen mimics by reproductive-aged women, raising concern regarding possible effects on the fetus and neonate.  …environmental endocrine disrupting chemicals [e.g., soy phytoestrogens] have caused a variety of adverse biological effects in wildlife species, domestic animals and humans….  Nevertheless, it is known that the normal endocrine functions of all organ systems are regulated by endocrine factors.  Small disturbances in endocrine function, especially during certain stages of the life cycle such as development, pregnancy, and lactation, can lead to profound and lasting [adverse] effects.” 

-1999 Federal Register confirms- " (Soy) trypsin inhibitors have potential effects of pancreatic function...deleterious effects on pancreas...are responsible for hyperplasia and nodules seen in animal studies.  ...high levels of trypsin inhibitors in humans can evoke this mecanism."

-2009 NTP Director Linda Birnbaum says, "Soy formula use is common and there is public health concern about its effects on infants and young children.  Soy-fed infants have much higher exposure to endocrine (disruptor) -active compounds in their diets...."

-Office of Environmental Health Hazard Assessment reports- "Soy formula may contain 200-300 micrograms of manganese, (toxic levels) compared to 6 micrograms in breast milk.  ...manganese exposure in childhood are associated with impaired neurodevelopment."

-EPA confirms- "Manganese concentrations were higher in soy formulas....  autism was associated with highest manganese concentrations.  Exposure to high manganese exposure can be detrimental to health."

-2003 USDA states, "Methanol extracts were prepared from soybeans....  ... a source of phytoestrogens with high levels of estrogenic activity." 

1998- the EPA Children's Environmental Health Yearbook- "Representing... actions to protect children from environmental hazards.  ...threats...and describes EPA's efforts to combat these hazards.  This work illustrates the commitment by EPA employees to safeguarding children against environmental hazards.  This research will characterize the toxic effects of environmental substances (4-tert-octylphenol, nonylphenol, bisphenol A, [soy] phytoestrogens) on steroid receptors;  address differences in age, gender and target tissue sensitivities; identify pathways through which toxics alter steroid receptor function; and demonstrate how such changes relate to altered fertility.  Phytoestrogens are naturally occurring nonsteroidal plant chemicals with estrogen-mimetic properties.  ...Endocrine disruptors as contaminates of concern."  

-June 2015, "EPA- Endocrine Disruptor Screening Program (EDSP) Estrogen Receptor Bioactivity" list includes soy phytoestrogenic endocrine disruptors "Genistein" and "Daidzein" on the first page (highest level) of their 30 page endocrine disruptor report, along side of Bisphenol A and B, Tamoxifen (pharma drug), as well as additional estrogens used in birth control pills.

 An endless supply of U. S. Health Official testimonials repeatedly confirm adverse fetal, infant, and child soy phyto-poisonous effects...adverse endocrine disruptor effects, while always illegally FDA, CFSAN, and NIH withheld from public disclosure!

With unproven soy phyto-poisonous safety, and your ongoing testimonials concluding dire concern that soy phyto-poisons cause fetal, infant, and child deleterious body and brain effects, how many more of your own FDA, CFSAN, NIH, and additional professional testimonials are you waiting for before you will abide by Food Safety Modernization Act, and several other U.S. food, health, and child safety laws, that require public disclosure of your acknowledged toxic truth?

How many more, than your collection of nearly ONE THOUSAND NIH Pubmed published studies ALL consistently confirming multiple soybean phyto-poisons are the concluded cause of any variety of severe, irreversible, and potentially fatal adverse developmental body and brain effects, are you waiting for before you will require lawful FSMA public WARNING labels? 

You must be familiar with your FDA MedWatch and CFSAN CARES reports that to this date are mercilessly overflowing with devastating parental reports of soy phyto-poisoning of their babies, their children.  Unnecessary and avoidable developmental soy phyto-poisoning adverse health nightmares are caused by continual FDA, CFSAN, and NIH failure to comply with U.S. laws that require you to publicly disclosure your acknowledgement of developmental contamination caused by fluctuating dosage levels of multiple soy phyto-poisons.   

As no other country in the world, you, the U.S. FDA, CFSAN, and NIH continue to illegally allow the increasing omnipresent marketing of soy phyto-poisons placed into baby formulas and foods sold throughout U.S. grocery store shelves. It is long past due to STOP pretending (unproven) safety of fetal, infant, and child soy phyto-poisoning- and disclose lawful contaminating truth as public.

BOTTOM LINE- In accordance to multiple U.S. food, health, and child safety laws, a trusting and innocent American public have waited long enough, and deserve an immediate right-to-know, as equally known by you- about the decades-worth of massive numbers of NIH Pubmed published study evidence, as well as your own testimonials, ALL confirming that fetal, infant, and child exposure to fluctuating dosage levels of soy phyto-poisons are an AVOIDABLE high risk cause of developmental body and brain destruction.

Below are additional NIH PUBMED STUDIES to add to your near one THOUSAND you already have in your files: As you acknowledge, never-ending  study evidence consistently concludes exposure to soy phyto-poisons cause any variety of extremely dangerous and permanently destructive fetal, infant, and child physiological, reproductive, and neurological effects, yet you continue to illegally choose to withhold lawful public disclosure.  You also ignore your own testimonials.  You ignore innumerable parental adverse health reports, while illegally allowing the omnipresent U.S. marketing of adulterated and misbranded fluctuating dosage levels of several developmental soy phyto-poisons in foods and formulas without lawful WARNING labels, and without compliance with U.S. food, health, and child safety laws, including the Food Safety Modernization Act. 

- Food Chem Toxicol. 2011 Oct;49(10):2681-8. doi: 10.1016/j.fct.2011.07.039. Epub 2011 Jul 23.
Estrogens in the daily diet: in vitro anaylysis indicates that estrogenic activity is omnipresent in foodstuff and infant formula.  
Behr M, Oehlmann J, Wagner M

Food is a main source of exposure to endocrine active compounds, many of which have been linked to adverse health effects. Phytoestrogens, especially from soy, are the major dietary source of estrogenicity. Soy-based products contained potent estrogenicity of 100-1500ng estradiol equivalents per kilogram (EEQ/kg). The estrogenicity in soy-free products was far lower (10-40ng EEQ/kg). We also detected significant estrogenic activity in three infant formulas (14-22ng EEQ/kg). Furthermore, we found soy lecithin to be strongly estrogenic. It might, therefore, be a major contributor to total estrogenicity... 

-U.S. Environmental Protection Agency (EPA) report- Updated 10-29-2015 - 1998 Progress Report: Developmental Effects of Dietary Soy phytoestrogens-
Naturally occurring compounds may disrupt or mimic hormone action. However, an increase of soy consumption in the North American diet has resulted in increased exposure to dietary estrogen mimics by reproductive-aged women, raising concern regarding possible (adverse) effects on fetus and neonate.  ...known to alter normal sexual dimorphic development and lead to defeminization/masculinization of females, and demasculinization /feminization of males.  Previous studies have shown adverse effects on sexual dimorphic development in rat pups treated parenterally with (soy) phytoestrogen genistein ...during the prenatal and neonatal intervals.   ...exposure of human fetus and/or nursing baby to these (soy) isoflavones has the potential to (adversely) influence immediate and future reproductive development.


- Proc Nutr Soc. 2016 Jul 8:1-15. [Epub ahead of print]
Endocrine disruption by dietary phyto-oestrogens: impact on dimorphic sexual systems and behaviours.
Patisaul HB1.
Author information
Abstract
A wide range of health benefits have been ascribed to soya intake including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms. Because it is a hormonally active diet, however, soya can also be endocrine disrupting, suggesting that intake has the potential to cause adverse health effects in certain circumstances, particularly when exposure occurs during development. Consequently, the question of whether or not soya phyto-oestrogens are beneficial or harmful to human health is neither straightforward nor universally applicable to all groups. Possible benefits and risks depend on age, health status, and even the presence or absence of specific gut microflora. As global consumption increases, greater awareness and consideration of the endocrine-disrupting properties of soya by nutrition specialists and other health practitioners is needed. Consumption by infants and small children is of particular concern because their hormone-sensitive organs, including the brain and reproductive system, are still undergoing sexual differentiation and maturation. Thus, their susceptibility to the endocrine-disrupting activities of soya phyto-oestrogens may be especially high. As oestrogen receptor partial agonists with molecular and cellular properties similar to anthropogenic endocrine disruptors such as bisphenol A, the soya phyto-oestrogens provide an interesting model for how attitudes about what is 'synthetic' v. what is 'natural,' shapes understanding and perception of what it means for a compound to be endocrine disrupting and/or potentially harmful. This review describes the endocrine-disrupting properties of soya phyto-oestrogens with a focus on neuroendocrine development and behaviour.
KEYWORDS:
AVP vasopressin; AVPV anterior ventral periventricular nucleus; EDC endocrine-disrupting compounds; ER oestrogen receptor; HPG hypothalamic–pituitary–gonadal; OT oxytocin; PVN paraventricular nucleus; SDN-POA sexually dimorphic nucleus of the preoptic area; Brain; ERα; ERβ; Endocrine disruption; Equol; Genistein; Hypothalamus; Isoflavones; Oestrogen; Soya
PMID:
27389644
DOI:
10.1017/S0029665116000677
[PubMed - as supplied by publisher]



-    Gen Comp Endocrinol. 2014 Jul 1;203:158-73. doi: 10.1016/j.ygcen.2014.02.005. Epub 2014 Feb 13.
Current concepts in neuroendocrine disruption.
León-Olea M1, Martyniuk CJ2, Orlando EF3, Ottinger MA4, Rosenfeld CS5, Wolstenholme JT6, Trudeau VL7.
Author information
Abstract
In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, [soy] phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and feeding in fish. There is growing evidence for the association between environmental contaminant exposures and diseases with strong neuroendocrine components, for example decreased fecundity, neurodegeneration, and cardiac disease. It is critical to consider the timing of exposures of neuroendocrine disruptors because embryonic stages of central nervous system development are exquisitely sensitive to adverse effects. There is also evidence for epigenetic and transgenerational neuroendocrine disrupting effects of some pollutants. We must now consider the impacts of neuroendocrine disruptors on reproduction, development, growth and behaviors, and the population consequences for evolutionary change in an increasingly contaminated world. This review examines the evidence to date that various so-called neuroendocrine disruptors can induce such effects often at environmentally-relevant concentrations.
Copyright © 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
Bisphenol A; Growth; Organochlorine pesticides; Pharmaceuticals; Polychlorinated biphenyls; Reproduction
PMID:
24530523
PMCID:
PMC4133337
DOI:
10.1016/j.ygcen.2014.02.005
[PubMed - indexed for MEDLINE]
Free PMC Article


-     Asian-Australas J Anim Sci. 2015 Nov;28(11):1573-82. doi: 10.5713/ajas.15.0185.
Effect of Soyabean Isoflavones Exposure on Onset of Puberty, Serum Hormone Concentration and Gene Expression in Hypothalamus, Pituitary Gland and Ovary of Female Bama Miniature Pigs.
Fan J1, Zhang B2, Li L3, Xiao C4, Oladele OA5, Jiang G3, Ding H1, Wang S3, Xing Y1, Xiao D2, Yin Y3.
Author information
Abstract
This study was to investigate the effect of soyabean isoflavones (SIF) on onset of puberty, serum hormone concentration, and gene expression in hypothalamus, pituitary and ovary of female Bama miniature pigs. Fifty five, 35-days old pigs were randomly assigned into 5 treatment groups consisting of 11 pigs per treatment. Results showed that dietary supplementation of varying dosage (0, 250, 500, and 1,250 mg/kg) of SIF induced puberty delay of the pigs with the age of puberty of pigs fed basal diet supplemented with 1,250 mg/kg SIF was significantly higher (p<0.05) compared to control. Supplementation of SIF or estradiol valerate (EV) reduced (p<0.05) serum gonadotrophin releasing hormone and luteinizing hormone concentration, but increased follicle-stimulating hormone concentration in pigs at 4 months of age. The expression of KiSS-1 metastasis-suppressor (KISS1), steroidogenic acute regulatory protein (StAR) and 3-beta-hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase (3β-HSD) was reduced (p<0.01) in SIF-supplemented groups. Expression of gonadotropin-releasing hormone receptor in the pituitary of miniature pigs was reduced (p<0.05) compared to the control when exposed to 250, 1,250 mg/kg SIF and EV. Pigs on 250 mg/kg SIF and EV also showed reduced (p<0.05) expression of cytochrome P450 19A1 compared to the control. Our results indicated that dietary supplementation of SIF induced puberty delay, which may be due to down-regulation of key genes that play vital roles in the synthesis of steroid hormones.
KEYWORDS:
Bama Miniature Pigs; Puberty; Puberty Delay; Soybean Isoflavones
PMID:
26580281
PMCID:
PMC4647097
DOI:
10.5713/ajas.15.0185
[PubMed]
Free PMC Article



-      Reprod Toxicol. 2011 Apr;31(3):272-9. doi: 10.1016/j.reprotox.2010.10.001. Epub 2010 Oct 15.
Circulating levels of genistein in the neonate, apart from dose and route, predict future adverse female reproductive outcomes.
Jefferson WN1, Williams CJ.
Author information
Abstract
Developmental exposure to estrogenic compounds can disrupt sexual differentiation and adult reproductive function in many animals including humans. Phytoestrogens (plant estrogens) in the diet comprise a significant source of estrogenic exposure to humans, particularly in infants who are fed soy-based infant formula. Animal models have been developed to test the effects of phytoestrogen exposure on the developing fetus and neonate. Here we review studies quantifying the amount of phytoestrogen exposure in human adults and infants and discuss the few available epidemiological studies that have addressed long-term consequences of developmental phytoestrogen exposure. We then describe in detail rodent models of developmental exposure to the most prevalent phytoestrogen in soy products, genistein, and the effects of this exposure on female reproductive function. These models have used various dosing strategies to mimic the phytoestrogen levels in human populations. Serum circulating levels of genistein following each of the models and their correlation to reproductive outcomes are also discussed. Taken together, the studies clearly demonstrate that environmentally relevant doses of genistein have significant negative impacts on ovarian differentiation, estrous cyclicity, and fertility in the rodent model. Additional studies of reproductive function in human populations exposed to high levels of phytoestrogens during development are warranted.
Published by Elsevier Inc.
PMID:
20955782
PMCID:
PMC3192433
DOI:
10.1016/j.reprotox.2010.10.001
[PubMed - indexed for MEDLINE]
Free PMC Article


-        Int J Endocrinol. 2013;2013:650984. doi: 10.1155/2013/650984. Epub 2013 Apr 23.
Diverse effects of phytoestrogens on the reproductive performance: cow as a model.
Wocławek-Potocka I1, Mannelli C, Boruszewska D, Kowalczyk-Zieba I, Waśniewski T, Skarżyński DJ.
Author information
Abstract
Phytoestrogens, polyphenolic compounds derived from plants, are more and more common constituents of human and animal diets. In most of the cases, these chemicals are much less potent than endogenous estrogens but exert their biological effects via similar mechanisms of action. The most common source of phytoestrogen exposure to humans as well as ruminants is soybean-derived foods that are rich in the isoflavones genistein and daidzein being metabolized in the digestive tract to even more potent metabolites-para-ethyl-phenol and equol. Phytoestrogens have recently come into considerable interest due to the increasing information on their adverse effects in human and animal reproduction, increasing the number of people substituting animal proteins with plant-derived proteins. Finally, the soybean becomes the main source of protein in animal fodder because of an absolute prohibition of bone meal use for animal feeding in 1995 in Europe. The review describes how exposure of soybean-derived phytoestrogens can have adverse effects on reproductive performance in female adults.
PMID:
23710176
PMCID:
PMC3655573
DOI:
10.1155/2013/650984
[PubMed]
Free PMC Article


-  Am J Clin Nutr. 2010 Feb;91(2):440-8. doi: 10.3945/ajcn.2009.28282. Epub 2009 Dec 9.
Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database.
Ward HA1, Kuhnle GG, Mulligan AA, Lentjes MA, Luben RN, Khaw KT.
Author information
Abstract
BACKGROUND:
The characterization of phytoestrogen intake and cancer risk has been hindered by the absence of accurate dietary phytoestrogen values.
OBJECTIVE:
We examined the risk of breast, colorectal, and prostate cancers relative to phytoestrogen intake on the basis of a comprehensive database.
DESIGN:
Demographic and anthropometric characteristics, a medical history, and 7-d records of diet were collected prospectively from participants (aged 40-79 y) in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Five hundred nine food items were analyzed by liquid chromatography-mass spectrometry/mass spectrometry, and (13)C(3)-labeled internal standards were analyzed for isoflavones (genistein, daidzein, glycitein, biochanin A, and formononetin), lignans (secoisolariciresinol and matairesinol), and enterolignans from gut microbial metabolism in animal food sources (equol and enterolactone). From the direct analysis, values for 10,708 foods were calculated. Odds ratios (ORs) for breast (244 cases, 941 controls), colorectal (221 cases, 886 controls), and prostate (204 cases, 812 controls) cancers were calculated relative to phytoestrogen intake.
RESULTS:
Phytoestrogen intake was not associated with breast cancer among women or colorectal cancer among men. Among women, colorectal cancer risk was inversely associated with enterolactone (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for secoisolariciresinol (OR: 1.60; 95% CI: 0.96, 2.69). A positive trend between enterolignan intake and prostate cancer risk (OR: 1.27; 95% CI: 0.97, 1.66) was attenuated after adjustment for dairy intake (OR: 1.19; 95% CI: 0.77, 1.82).
CONCLUSION:
Dietary phytoestrogens may contribute to the risk of colorectal cancer among women and prostate cancer among men.
PMID:
20007303
DOI:
10.3945/ajcn.2009.28282
[PubMed - indexed for MEDLINE]
Free full text



-       Toxicol Sci. 2014 Mar;138(1):21-35. doi: 10.1093/toxsci/kft271. Epub 2013 Nov 27.
Coexposure to phytoestrogens and bisphenol a mimics estrogenic effects in an additive manner.
Katchy A1, Pinto C, Jonsson P, Nguyen-Vu T, Pandelova M, Riu A, Schramm KW, Samarov D, Gustafsson JÅ, Bondesson M, Williams C.
Author information
Abstract
Endocrine-disrupting chemicals (EDC) are abundant in our environment. A number of EDCs, including bisphenol A (BPA) can bind to the estrogen receptors (ER), ERα and ERβ, and may contribute to estrogen-linked diseases such as breast cancer. Early exposure is of particular concern; many EDCs cross the placenta and infants have measurable levels of, eg, BPA. In addition, infants are frequently fed soy-based formula (SF) that contains phytoestrogens. Effects of combined exposure to xeno- and phytoestrogens are poorly studied. Here, we extensively compared to what extent BPA, genistein, and an extract of infant SF mimic estrogen-induced gene transcription and cell proliferation. We investigated ligand-specific effects on ER activation in HeLa-ERα and ERβ reporter cells; on proliferation, genome-wide gene regulation and non-ER-mediated effects in MCF7 breast cancer cells; and how coexposure influenced these effects. The biological relevance was explored using enrichment analyses of differentially regulated genes and clustering with clinical breast cancer profiles. We demonstrate that coexposure to BPA and genistein, or SF, results in increased functional and transcriptional estrogenic effects. Using statistical modeling, we determine that BPA and phytoestrogens act in an additive manner. The proliferative and transcriptional effects of the tested compounds mimic those of 17β-estradiol, and are abolished by cotreatment with an ER antagonist. Gene expression profiles induced by each compound clustered with poor prognosis breast cancer, indicating that exposure may adversely affect breast cancer prognosis. This study accentuates that coexposure to BPA and soy-based phytoestrogens results in additive estrogenic effects, and may contribute to estrogen-linked diseases, including breast cancer.
KEYWORDS:
bisphenol A; concentration addition.; estrogen receptor; phytoestrogens; proliferation; transcriptional activation
PMID:
24284790
PMCID:
PMC3930363
DOI:
10.1093/toxsci/kft271
[PubMed - indexed for MEDLINE]
Free PMC Article



-          Toxicol Lett. 2016 Jun 24;253:17-26. doi: 10.1016/j.toxlet.2016.04.017. Epub 2016 Apr 22.
In Utero exposure to genistein enhanced intranasal house dust mite allergen-induced respiratory sensitization in young adult B6C3F1 mice.
Guo TL1, Meng AH2.
Author information
Abstract
Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental immunotoxic effects are increasing. To understand how in utero GEN exposure may modulate postnatal respiratory sensitization, we conducted a time course study using a common household allergen (house dust mites: HDM; 10μg/mouse) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20mg/kg bw). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly doses of HDM extracts, and they were euthanized at day 3 following the final HDM exposure at four different time points (postnatal day (PND) 80, 120, 160, and 200). In utero GEN combined with postnatal HDM exposures (GEN+HDM) increased total IgE production in both young female and male B6C3F1 offspring (e.g., PND 80 in females and PND 120 in males). Increased antigen-specific IgG1, IgG2a and IgG2b levels were also observed at various time points in both female and male offspring. In addition, increases in macrophage number in bronchoalveolar lavage fluid of both female and male GEN+HDM offspring at PND 80 and PND 120, respectively, were observed when compared to the vehicle group. For T cells, an increase over the vehicle in female GEN+HDM offspring was observed at PND 80. Due to similar patterns of increases, it seems likely that GEN+HDM-induced increases in total IgE and macrophages are related. Overall, in utero GEN plus later-life HDM exposures exert increases in total IgE and HDM-specific IgG production as well as macrophage recruitments to the lung in young adult mice.
Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
KEYWORDS:
Asthma; Genistein; House dust mites; IgE; In utero exposure
PMID:
27113705
PMCID:
PMC4866898
[Available on 2017-06-24]
DOI:
10.1016/j.toxlet.2016.04.017
[PubMed - in process]




-        Food Chem Toxicol. 2013 Sep;59:129-36. doi: 10.1016/j.fct.2013.05.057. Epub 2013 Jun 10.
Glyphosate induces human breast cancer cells growth via estrogen receptors.
Thongprakaisang S1, Thiantanawat A, Rangkadilok N, Suriyo T, Satayavivad J.
Author information
Abstract
Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10⁻¹² to 10⁻⁶M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERα and β expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study.
Copyright © 2013 Elsevier Ltd. All rights reserved.
KEYWORDS:
Estrogenic effect; Genistein; Glyphosate; Human breast cancer; T47D; T47D-KBluc
PMID:
23756170
DOI:
10.1016/j.fct.2013.05.057
[PubMed - indexed for MEDLINE]



-      Gen Comp Endocrinol. 2013 Oct 1;192:89-94. doi: 10.1016/j.ygcen.2013.06.023. Epub 2013 Jul 10.
Luteinizing hormone receptor (lhcgr) as a marker gene for characterizing estrogenic endocrine-disrupting chemicals in zebrafish ovarian follicle cells.

Liu KC1, Wu RS, Ge W.
Author information

Abstract

The adverse effects of endocrine-disrupting chemicals (EDCs) have been well documented; however, the action mechanisms of many EDCs remain elusive and controversial. Furthermore, the highly diversified chemical structures and low environmental concentrations of EDCs present a major challenge to their chemical detection. Clearly, there is an urgent need for simple and reliable bioassays to detect EDCs in the environment and unravel their action mechanisms. We have recently identified luteinizing hormone receptor (lhcgr) as a robust estradiol (E2)-responsive gene in cultured zebrafish ovarian follicle cells. The expression of lhcgr exhibited a distinct biphasic response to E2 over a 24-h time-course treatment, making this a unique system for characterizing estrogenic EDCs. This study was undertaken to validate this platform by testing a wide range of EDCs, including 17α-ethinylestradiol (EE2), diethylstilbestrol (DES), bisphenol A (BPA), genistein (GEN), 1,1,1-trichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethane (o,p'-DDT), vinclozolin (VIN), bis(2-ethylhexyl) phthalate (DEHP), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47). Diethylstilbestrol (DES), EE2 and o,p'-DDT mimicked E2 and induced a biphasic expression of lhcgr while BPA and GEN stimulated a monophasic expression in the 24-h time-course. In contrast, BDE-47, DEHP and VIN had no effect, whereas TCDD decreased lhcgr expression. Dose-response experiment showed that E2, EE2 and DES had the highest potency, which was followed by GEN, BPA and o,p'-DDT. The effects of estrogenic EDCs were further confirmed by their potentiation of hCG-induced activin βA2 subunit (inhbab) expression. In conclusion, the present study showed that the expression of lhcgr in cultured zebrafish follicle cells and its biphasic response to estrogens provide a unique in vitro platform for screening and categorizing estrogenic substances and deciphering their action mechanisms.
Copyright © 2013 Elsevier Inc. All rights reserved.
KEYWORDS:

EDCs; Follicle cells; Lhcgr; Ovary; Zebrafish  PMID:23851042  DOI:10.1016/j.ygcen.2013.06.023



-         Environ Int. 2013 Sep;59:161-7. doi: 10.1016/j.envint.2013.06.009. Epub 2013 Jun 29.
Urinary phytoestrogen levels related to idiopathic male infertility in Chinese men.
Xia Y1, Chen M, Zhu P, Lu C, Fu G, Zhou X, Chen D, Wang H, Hang B, Wang S, Zhou Z, Sha J, Wang X.
Author information
Abstract
Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC-MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend=0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend<0.05), while these exposures had stronger association with the infertile men with abnormal sperm number per ejaculum. These findings provide the evidence that PE exposures are related to male reproductive function and raise a public health concern because that exposure to PEs is ubiquitous in China.
Copyright © 2013 Elsevier Ltd. All rights reserved.
KEYWORDS:
BMI; CI; COU; CR; CV; DAI; EQU; Exposure; GEN; Human urine; LODs; Male infertility; NAR; ORs; PEs; Phytoestrogens; SEC; Semen quality; UPLC–MS/MS; WHO; World Health Organization; body mass index; coefficients of variation; confidence interval; coumestrol; creatinine; daidzein; equol; genistein; limits of detection; naringenin; odds ratios; phytoestrogens; secoisolariciresinol; ultra high performance liquid chromatography–tandem mass spectrometry
PMID:
23820060
DOI:
10.1016/j.envint.2013.06.009
[PubMed - indexed for MEDLINE]



-          Food Chem Toxicol. 2013 Oct;60:497-505. doi: 10.1016/j.fct.2013.08.006. Epub 2013 Aug 12.
Individual and combined developmental toxicity assessment of bisphenol A and genistein using the embryonic stem cell test in vitro.
Kong D1, Xing L, Liu R, Jiang J, Wang W, Shang L, Wei X, Hao W.
Author information
Abstract
The potential developmental toxicity of environmental estrogenic endocrine disruptors have become a great concern in recent years. In this study, two typical environmental oestrogen, namely, bisphenol A (BPA) and genistein (GEN) were investigated for potential embryotoxicity using the embryonic stem cell test model. Afterwards, a 4×4 full factorial design and the estimated marginal means plot were performed to assess the combined effects of these two compounds. According to the linear discriminant functions and classification criteria, bisphenol A and genistein were classified as weakly embryotoxic and strongly embryotoxic respectively. As for combined effects, the overall interaction between BPA and GEN on embryonic stem cells (ESCs) differentiation was synergistic at low dosages, however, on ESCs and 3T3 cell proliferation, the predominate action was additive. Considering the actual daily intake of these chemicals, it is concluded that BPA alone might not have adverse reproductive or developmental effects on human being. However, given that BPA and GEN do have synergistic effect at low concentration, they may disturb normal embryo development together, which could result in birth defect and behavioral alterations later in life.
Copyright © 2013 Elsevier Ltd. All rights reserved.
KEYWORDS:
5-FU; 5-Fluorouracil; Bisphenol A; Combined effect; EBs; ECETOC; ECVAM; EEDs; EEs; ER; ES; EST; Embronic stem cell test; Embryotoxicity; European Center for the Validation of Alternative Methods; European Centre for Ecotoxicology and Toxicology of Chemicals; GEN; Genistein; LB; LIF; LOAEL; MB; MM; NEAA; NOAEL; NTP; National Toxicology Program; PG; WEC; embryonic bodies; embryonic stem cell test; embryonic stem cells; environmental endocrine disruptors; environmental estrogens; estrogen receptors; genistein; leukaemia inhibitory factor; limb bud; lowest observed adverse-effect level; micromass culture; midbrain; no-observed adverse-effect level; none essential amino acid; penicillin G sodium; whole embryo culture
PMID:
23948354
DOI:
10.1016/j.fct.2013.08.006
[PubMed - indexed for MEDLINE]



-        Biol Res. 2013;46(2):139-46. doi: 10.4067/S0716-97602013000200004.
Disruption of reproductive development in male rat offspring following gestational and lactational exposure to di-(2-ethylhexyl) phthalate and genistein.
Zhang LD1, Deng Q, Wang ZM, Gao M, Wang L, Chong T, Li HC.
Author information
Abstract
Studies of developmental effects of mixtures of endocrine disrupters on the male reproductive system are of great concern. In this study, the reproductive effects of the co-administration of di-2-(ethylhexyl) phthalate (DEHP) and genistein (GEN) during pregnancy and lactation were studied in male rat offspring. Pregnant Sprague-Dawley rats were gavaged from gestation day 3 to postnatal day 21 with vehicle control, DEHP 250 mg/kg body weight (bwyday, GEN 50 mg/kg bwday, GEN 400 mg/kg bwday, and two combinations of the two compounds (DEHP 250 mg/kg bwday + GEN 50 mg/kg bwday, DEHP 250 mg/kg bwday + GEN 400 mg/kg bwday). The outcomes studied were general morphometry (weight, AGD), testicular histology, testosterone levels, and expression at the mRNA level of genes involved in steroidogenesis. Organ coefficient, AGD / body weight1/3 י, serum testosterone concentration and genes involved in steroidogenic pathway expression when exposed to DEHP (250mg/kg bwday), GEN(50mg/kg bwday) or GEN(400mg/kg bwday) alone were not significantly different from the control group. When exposed to (DEHP 250mg/kg bwday +GEN 50mg/kg bwday) together during pregnancy and lactation, serum testosterone concentration, epididymis coefficient and Cypal17a1,Scarb1 m RNA expression significantly decreased compared to the control and GEN(50mg/kg bwday). When exposed to (DEHP 250mg/kg bwday +GEN 400mg/kg bwday) together during pregnancy and lactation, AGD / body weight1/3 י, serum testosterone concentration, testis and epididymis coefficient and Star, Cypal17a1 mRNA expression appeared significantly decreased compared to the control and DEHP/GEN single exposure, together with developmental impairment of seminiferous tubules and seminiferous epithelium. Overall, co-administration of DEHP and GEN during gestation and lactation seem to acts in a cumulative manner to induce the most significant alterations in the neonate, especially with GEN at high dose, although the effect of the DEHP-GEN mixture on adult offspring should be observed further.
PMID:
23959011
DOI:
10.4067/S0716-97602013000200004
[PubMed - indexed for MEDLINE]
Free full text


-          Nutrients. 2016 Jun 10;8(6). pii: E361. doi: 10.3390/nu8060361.
Isoflavones: Anti-Inflammatory Benefit and Possible Caveats.
Yu J1, Bi X2, Yu B3, Chen D4.
Author information
Abstract
Inflammation, a biological response of body tissues to harmful stimuli, is also known to be involved in a host of diseases, such as obesity, atherosclerosis, rheumatoid arthritis, and even cancer. Isoflavones are a class of flavonoids that exhibit antioxidant, anticancer, antimicrobial, and anti-inflammatory properties. Increasing evidence has highlighted the potential for isoflavones to prevent the chronic diseases in which inflammation plays a key role, though the underlying mechanisms remain unclear. Recently, some studies have raised concerns about isoflavones induced negative effects like carcinogenesis, thymic involution, and immunosuppression. Therefore, this review aims to...unravel the underlying mechanisms, and present the potential (isoflavone) health risks.
KEYWORDS:
anti-inflammation; flavonoids; health risks; isoflavones
PMID:
27294954
PMCID:
PMC4924202
DOI:
10.3390/nu8060361
[PubMed - in process]
Free PMC Article



-          Rev Assoc Med Bras (1992). 2011 Sep-Oct;57(5):534-9.
Effects of high-dose isoflavones on rat uterus.
[Article in English, Portuguese]
Carbonel AA1, Simões RS, Santos RH, Baracat MC, Simões Mde J, Baracat EC, Soares Júnior JM.
Author information
Abstract
OBJECTIVE:
To evaluate the effects of high-dose isoflavones on the uterus of castrated adult rats.
METHODS:
Adult, ovariectomized virgin rats (n = 40) were treated by gavage during 30 consecutive days with vehicle (propylene glycol, group GCtrl) or different doses of genistein: 42 (group GES42), 125 (GES125), or 250 (GES250) µg/g body weight per day. Animals were killed, weighed, vaginal and uterine samples were taken for cytologic evaluation, and serum levels of 17 β-estradiol and progesterone were determined. The middle third of the uterine horns was dissected, fixed in 10% formaldehyde and processed for paraffin inclusion; 5-µm thick sections were obtained and stained with HE for further histological study under light microscopy. The endometrial morphology and area, number and area of glands, and number of eosinophils in the lamina propria were analyzed. ANOVA and the Tukey-Kramer test were used for statistical analyses.
RESULTS:
Uterine weight, endometrial glandular area, and number of glands and eosinophils were all higher in GES250 > G125 than in the other groups (GES250 > GES125 > GES42 = GCtrl; p < 0.05). Morphological data showed signs of endometrial proliferation upon treatment with genistein, especially in animals in GES125 and GES250 compared to other groups. In all animals in GES250, signs of uterine squamous metaplasia were observed.
CONCLUSION:
A short treatment period with high daily doses of isoflavones can promote endometrial squamous metaplasia in ovariectomized rats.
PMID:
22012287
[PubMed - indexed for MEDLINE]
Free full text


-          Reprod Toxicol. 2014 Apr;44:85-92. doi: 10.1016/j.reprotox.2013.12.003. Epub 2013 Dec 21.
Postweaning dietary genistein exposure advances puberty without significantly affecting early pregnancy in C57BL/6J female mice.
Li R1, Zhao F2, Diao H3, Xiao S4, Ye X5.
Author information
Abstract
An epidemiological study indicates higher plasma level of genistein in girls with earlier puberty. This study tests the hypothesis in C57BL/6J mice that postweaning (peripubertal) dietary genistein exposure could result in earlier puberty in females assessed by vaginal opening, estrous cyclicity, corpus luteum and mammary gland development. Newly weaned female mice were fed with 0, 5, 100, or 500 ppm genistein diets. Decreased age at vaginal opening, increased length on estrus stage, and accelerated mammary gland development were detected in 100 and 500 ppm genistein-treated groups. Increased presence of corpus luteum was found in 5 ppm genistein-treated group at 6 weeks old only. Increased expression of epithelial-specific genes but not that of ERα or ERβ was detected in 500 ppm genistein-treated mammary glands at 5 weeks old. No significant adverse effect on embryo implantation was observed. These data demonstrate causal effect of dietary genistein on earlier puberty in female mice.
Copyright © 2013 Elsevier Inc. All rights reserved.
KEYWORDS:
Corpus luteum; Embryo implantation; Estrous cyclicity; Genistein; Mammary gland; Postweaning; Puberty; Vaginal opening
PMID:
24365114
PMCID:
PMC4004695
DOI:
10.1016/j.reprotox.2013.12.003
[PubMed - indexed for MEDLINE]
Free PMC Article

-  Environmental Protection Agency (EPA) - ORD Research Plan for Endocrine Disruptors- 
It has been suggested that humans...have suffered adverse health consequences reulsting from exposure to environmental chemicals that interact with the endocrine system.  To date, these problems have been identified primarily in wildlife species with relatively hisgh exposures to specific compounds, including: organochlorines, sucha s DDT, and it metabolites, PCBs, and dioxins, or ...on plants with high levels of phtyoestrogens (Kavlock et al., 1996).  Nevertheless, it is known that the normal functions of all organ systems are regulated by endocrine factors.  Small disturbances in endocrine function, especially during certain stages of the life cycle such as development, pregnancy, and lactation, can lead to profound and lasting effects. 


-          J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):217-23. doi: 10.1016/j.jsbmb.2014.04.013. Epub 2014 May 9.
Steroids and endocrine disruptors--History, recent state of art and open questions.
Hampl R1, Kubátová J2, Stárka L2.
Author information
Abstract
This introductory chapter provides an overview of the levels and sites at which endocrine disruptors (EDs) affect steroid actions. In contrast to the special issue of Journal of Steroid Biochemistry and Molecular Biology published three years ago and devoted to EDs as such, this paper focuses on steroids. We tried to point to more recent findings and opened questions. EDs interfere with steroid biosynthesis and metabolism either as inhibitors of relevant enzymes, or at the level of their expression. Particular attention was paid to enzymes metabolizing steroid hormones to biologically active products in target cells, such as aromatase, 5α-reductase and 3β-, 11β- and 17β-hydroxysteroid dehydrogenases. An important target for EDs is also steroid acute regulatory protein (StAR), responsible for steroid precursor trafficking to mitochondria. EDs influence receptor-mediated steroid actions at both genomic and non-genomic levels. The remarkable differences in response to various steroid-receptor ligands led to a more detailed investigation of events following steroid/disruptor binding to the receptors and to the mapping of the signaling cascades and nuclear factors involved. A virtual screening of a large array of EDs with steroid receptors, known as in silico methods (≡computer simulation), is another promising approach for studying quantitative structure activity relationships and docking. New data may be expected on the effect of EDs on steroid hormone binding to selective plasma transport proteins, namely transcortin and sex hormone-binding globulin. Little information is available so far on the effects of EDs on the major hypothalamo-pituitary-adrenal/gonadal axes, of which the kisspeptin/GPR54 system is of particular importance. Kisspeptins act as stimulators for hormone-induced gonadotropin secretion and their expression is regulated by sex steroids via a feed-back mechanism. Kisspeptin is now believed to be one of the key factors triggering puberty in mammals, and various EDs affect its expression and function. Finally, advances in analytics of EDs, especially those persisting in the environment, in various body fluids (plasma, urine, seminal fluid, and follicular fluid) are mentioned. Surprisingly, relatively scarce information is available on the simultaneous determination of EDs and steroids in the same biological material. This article is part of a Special Issue entitled 'Endocrine disruptors & steroids'.
Copyright © 2014 Elsevier Ltd. All rights reserved.
KEYWORDS:
Endocrine disruptors; Overreview; Sites of action; Steroids.
[Soybean isoflavones- contain fluctuating dosage levels of several estrogenic hormone disruptors.  One never knows the soybean plant hormone disruptor dosage he/she is receiving].
PMID:
24816231
DOI:
10.1016/j.jsbmb.2014.04.013


-        Oncol Rep. 2016 Aug;36(2):603-12. doi: 10.3892/or.2016.4886. Epub 2016 Jun 21.
Carcinogenetic mechanisms of endocrine disruptors in female cancers (Review).
Del Pup L1, Mantovani A2, Cavaliere C3, Facchini G3, Luce A4, Sperlongano P5, Caraglia M4, Berretta M6.
Author information
Abstract
Endocrine disruptors (EDs) are pollutants that alter the endocrine system and are involved in carcinogenesis. EDs have multiple and complex levels of action. They can affect the synthesis, release and transport of natural hormones. In target tissues, EDs can reduce or increase the effects of natural hormones on their receptors and change signaling cascades. When ED exposure happens at critical periods of life, from embryo to puberty, they can act at doses considered safe for an adult. Furthermore, their epigenetic effects can also influence the cancer risk of future generations. The cancer mechanisms of known EDs are hereby reviewed, There are thousands of newly introduced substances whose potential endocrine-disrupting and cancer effects are completely unknown. Although there are still gaps in our knowledge, these data support the urgent need for health and environmental policies aimed at protecting the public and in particular, the developing fetus and women of reproductive age.
PMID:
27349723
PMCID:
PMC4933552
DOI:
10.3892/or.2016.4886
[PubMed - in process]
Free PMC Article



-        Biol Reprod. 2014 Feb 27;90(2):40. doi: 10.1095/biolreprod.113.113787. Print 2014 Feb.
Testicular development in male rats is sensitive to a soy-based diet in the neonatal period.
Napier ID1, Simon L, Perry D, Cooke PS, Stocco DM, Sepehr E, Doerge DR, Kemppainen BW, Morrison EE, Akingbemi BT.
Author information
Abstract
Approximately 30% of infants in the United States are exposed to high doses of isoflavones resulting from soy infant formula consumption. Soybeans contain the isoflavones genistin and daidzin, which are hydrolyzed in the gastrointestinal tract to their genistein and daidzein aglycones. Both aglycones possess hormonal activity and may interfere with male reproductive development. Testosterone, which supports male fertility, is mainly produced by testicular Leydig cells. Our previous studies indicated that perinatal exposure of male rats to isoflavones induced proliferative activity in Leydig cells and increased testosterone concentrations into adulthood. However, the relevance of the neonatal period as part of the perinatal window of isoflavone exposure remains to be established. The present study examined the effects of exposure to isoflavones on male offspring of dams maintained on a casein-based control or whole soybean diet in the neonatal period, that is, Days 2 to 21 postpartum. The results showed that the soybean diet stimulated proliferative activity in developing Leydig cells while suppressing their steroidogenic capacity in adulthood. In addition, isoflavone exposure decreased production of anti-Müllerian hormone by Sertoli cells. Similar to our previous in vitro studies of genistein action in Leydig cells, daidzein induced proliferation and interfered with signaling pathways to suppress steroidogenic activity. Overall, the data showed that the neonatal period is a sensitive window of exposure to isoflavones and support the view that both genistein and daidzein are responsible for biological effects associated with soy-based diets.
KEYWORDS:
Leydig cells; androgen; androgens/androgen receptor; daidzein; endocrine disruptors; genistein; phytoestrogen; sex steroids; testis; toxicology
PMID:
24451983
PMCID:
PMC4076408
DOI:
10.1095/biolreprod.113.113787
[PubMed - indexed for MEDLINE]
Free PMC Article



-        Blood. 1995 Jun 1;85(11):3250-6.
ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children.
Felix CA1, Hosler MR, Winick NJ, Masterson M, Wilson AE, Lange BJ.
Author information
Abstract
We examined clinical, morphologic, and cytogenetic features and ALL-1 (MLL, Htrxl, HRX) gene rearrangements in 17 cases of secondary leukemia that occurred 11 months to 9 years from diagnoses of primary cancers in children who received topoisomerase II inhibitors or developed secondary leukemias typical of those associated with this therapy. Primary diagnoses included nine solid tumors and eight leukemias. Ten secondary leukemias were acute myeloid leukemia (AML), one was of mixed lineage, two were acute lymphoblastic leukemia (ALL), and four presented as myelodysplasia. Of 15 cases with 11q23 involvement, 11 (73%) were cytogenetically identifiable; four cases had molecular rearrangement only. By Southern blot, rearrangements within the ALL-1 gene were similar to sporadic cases. The results of this analysis suggest the following: (1) In most pediatric cases of topoisomerase II inhibitor-associated leukemia, there is disruption of the breakpoint cluster region of the ALL-1 gene at chromosomal band 11q23. (2) Exposure histories vary in secondary 11q23 leukemia, as the only topoisomerase II inhibitor was dactinomycin in one case, and, in another case, no topoisomerase II inhibitor was administered. (3) There is clinical, morphologic, cytogenetic, and molecular heterogeneity in pediatric secondary 11q23 leukemia. (4) There are some survivors of pediatric secondary 11q23 leukemia, but the outcome is most often fatal.
PMID:
7756657
[PubMed - indexed for MEDLINE]

[Several NIH Pubmed published studies conclude-SOY INHIBITS TOPOISOMERASE II, or is a TOPO II POISON}



-        Ann N Y Acad Sci. 2014 Mar;1310:98-110. doi: 10.1111/nyas.12358. Epub 2014 Feb 3.
Topoisomerase II and leukemia.
Pendleton M1, Lindsey RH Jr, Felix CA, Grimwade D, Osheroff N.
Author information
Abstract
Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
© 2014 New York Academy of Sciences.
KEYWORDS:
acute myeloid leukemia; acute promyelocytic leukemia; anticancer drug; chromosomal translocation; topoisomerase II poison
PMID:
24495080
PMCID:
PMC3961513
DOI:
10.1111/nyas.12358
[PubMed - indexed for MEDLINE]
Free PMC Article


-    Endocr Metab Immune Disord Drug Targets. 2014 Mar;14(1):38-46.
Soy- and rice-based formula and infant allergic to cow's milk.
Tzifi F, Grammeniatis V, Papadopoulos M1.
Author information
Abstract
Soy milk formula has limited medical indications for infants feeding, although in several parts of the world it has been used as a source of nutrition in a large number of children. It used to be the main alternative feeding for infants allergic to cow's milk who did not breastfeed before the introduction of extensively hydrolyzed formulas. Although there is a debate, the fact that some children are allergic to soy or some children with cow's milk allergy can present with concomitant soy allergy, restricted the use of soy formulas for treatment of infants allergic to cow's milk. Other grain-based formulas like the rice-based ones are promising in infants with cow's milk allergy. Grain-based formulas could be an alternative and cheaper way of nutrition for infants allergic to cow's milk than extensively hydrolyzed formulas. Further large scale longitudinal clinical studies are required to clarify the safety of soy and other grain-based formulas for treatment of cow's milk allergy.
PMID:
24450453
[PubMed - indexed for MEDLINE]


-        Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003741.
Soy formula for prevention of allergy and food intolerance in infants.
Osborn DA1, Sinn J.
Author information
Abstract
BACKGROUND:
Allergies and food reactions in infants and children are common and may be associated with a variety of foods including adapted cow's milk formula. Soy based formulas have been used to treat infants with allergy or food intolerance. However, it is unclear whether they can help prevent allergy and food intolerance in infants without clinical evidence of allergy or food intolerance.
OBJECTIVES:
To determine the effect of feeding adapted soy formula compared to human milk, cow's milk formula or a hydrolysed protein formula on preventing allergy or food intolerance in infants without clinical evidence of allergy or food intolerance.
SEARCH STRATEGY:
The standard search strategy of the Cochrane Neonatal Review Group was used. Updated searches were performed of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966-March 2006), EMBASE (1980-March 2006), CINAHL (1982-March 2006) and previous reviews including cross references.
SELECTION CRITERIA:
Randomised and quasi-randomised trials that compare the use of an adapted soy formula to human milk, an adapted cow's milk or a hydrolysed protein formula for feeding infants without clinical allergy or food intolerance in the first six months of life. Only trials with > 80% follow up of participants and reported in group of assignment were eligible for inclusion.
DATA COLLECTION AND ANALYSIS:
Eligibility of studies for inclusion, methodological quality and data extraction were assessed independently by each review author. Primary outcomes included clinical allergy, specific allergies and food intolerance. Where no heterogeneity of treatment effect was found, the fixed effect model was used for meta-analysis. Where significant or apparent heterogeneity was found, results were reported using the random effects model and potential causes of the heterogeneity were sought.
MAIN RESULTS:
Three eligible studies enrolling high risk infants with a history of allergy in a first degree relative were included. No eligible study enrolled infants fed human milk. No study examined the effect of early, short term soy formula feeding. All compared prolonged soy formula to cow's milk formula feeding. One study was of adequate methodology and without unbalanced allergy preventing co-interventions in treatment groups. One study with unclear allocation concealment and 19.5% losses reported a significant reduction in infant allergy, asthma and allergic rhinitis. However, no other study reported any significant benefits from the use of a soy formula. Meta-analysis found no significant difference in childhood allergy incidence (2 studies; typical RR 0.73, 95% CI 0.37, 1.44). No significant difference was reported in one study in infant asthma (RR 1.10, 95% CI 0.86, 1.40), infant eczema (RR 1.20, 95% CI 0.95, 1.52), childhood eczema prevalence (RR 1.10, 95% CI 0.73, 1.68), infant rhinitis (RR 0.94, 95% CI 0.76, 1.16) or childhood rhinitis prevalence (RR 1.20, 95% CI 0.73, 2.00). Meta-analysis found no significant difference in childhood asthma incidence (3 studies, 728 infants; typical RR 0.71, 95% CI 0.26, 1.92), childhood eczema incidence (2 studies, 283 infants; typical RR 1.57, 95% CI 0.90, 2.75) or childhood rhinitis incidence (2 studies, 283 infants; typical RR 0.69, 95% CI 0.06, 8.00). One study reported no significant difference in infant CMPI (RR 1.09, 95% CI 0.45, 2.62), infant CMA (RR 1.09, 95% CI 0.24, 4.86), childhood soy protein allergy incidence (RR 3.26, 95% CI 0.36, 29.17) and urticaria. No study compared soy formula to hydrolysed protein formula.
AUTHORS' CONCLUSIONS:
Feeding with a soy formula cannot be recommended for prevention of allergy or food intolerance in infants at high risk of allergy or food intolerance. Further research may be warranted to determine the role of soy formulas for prevention of allergy or food intolerance in infants unable to be breast fed with a strong family history of allergy or cow's milk protein intolerance.
Update of
Soy formula for prevention of allergy and food intolerance in infants. [Cochrane Database Syst Rev. 2004]
PMID:
17054183
DOI:
10.1002/14651858.CD003741.pub4
[PubMed - indexed for MEDLINE]

[There is NO proven benefit of soy formulas for milk allergies, soy too is a high risk allergen.  Plus the added risks of severe and irreversible adverse body and brain effects does not warrant the use of soy phyto-poisons in infant formulas].




-        Int J Mol Sci. 2015 May 22;16(5):11728-49. doi: 10.3390/ijms160511728.
Soy and breast cancer: focus on angiogenesis.
Varinska L1, Gal P2,3,4,5, Mojzisova G6, Mirossay L7, Mojzis J8.
Author information
Abstract
Epidemiological studies have revealed that high consumption of soy products is associated with low incidences of hormone-dependent cancers, including breast and prostate cancer. Soybeans contain large amounts of isoflavones, such as the genistein and daidzain. Previously, it has been demonstrated that genistein, one of the predominant soy isoflavones, can inhibit several steps involved in carcinogenesis. It is suggested that genistein possesses pleiotropic molecular mechanisms of action including inhibition of tyrosine kinases, DNA topoisomerase II, 5α-reductase, galectin-induced G2/M arrest, protein histidine kinase, and cyclin-dependent kinases, modulation of different signaling pathways associated with the growth of cancer cells (e.g., NF-κB, Akt, MAPK), etc. Moreover, genistein is also a potent inhibitor of angiogenesis. Uncontrolled angiogenesis is considered as a key step in cancer growth, invasion, and metastasis. Genistein was found to inhibit angiogenesis through regulation of multiple pathways, such as regulation of VEGF, MMPs, EGFR expressions and NF-κB, PI3-K/Akt, ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This review focuses on the antiangiogenic properties of soy isoflavonoids and examines their possible underlying mechanisms.
KEYWORDS:
angiogenesis; breast cancer; galectins; genistein; soy
PMID:
26006245
PMCID:
PMC4463727
DOI:
10.3390/ijms160511728
[PubMed - indexed for MEDLINE]
Free PMC Article


-        Mol Nutr Food Res. 2015 Mar;59(3):413-23. doi: 10.1002/mnfr.201300780. Epub 2014 Feb 24.
Long-term exposure to dietary sources of genistein induces estrogen-independence in the human breast cancer (MCF-7) xenograft model.
Andrade JE1, Ju YH, Baker C, Doerge DR, Helferich WG.
Author information
Abstract
SCOPE:
The long-term effect of exposure to relevant dietary levels of genistein (GEN) on estrogen receptor-positive (ER+) human breast cancer (MCF-7) progression after GEN withdrawal in athymic mice xenograft model was studied.
MATERIALS AND METHODS:
Feeding studies were conducted to determine the estrogenic effect of diets on MCF-7 tumor growth: (1) implantation (19 weeks) and withdrawal (6 weeks) of 17β-estradiol (E2 ); (2) dietary GEN 500 and 750 ppm during treatment/withdrawal for 23/10 and 15/9 weeks, respectively; and, (3) dietary soy protein isolate (SPI) containing GEN 180 ppm for 31/9 weeks of treatment/withdrawal. MCF-7 tumors grew fast in the presence of E2 implantation and abruptly regressed completely after E2 withdrawal. At different rates, dietary GEN alone (500 and 750 ppm) and GEN (180 ppm)-containing SPI stimulated MCF-7 tumor growth. After removal of the stimulus diet, tumors induced by 750 ppm GEN, but not 500 ppm GEN or SPI, regressed completely. The protein expression of epidermal growth factor receptor 2 (HER2) was higher in the GEN- and SPI-induced nonregressing (GINR) tumors compared to MCF-7 and E2 controls.
CONCLUSION:
Long-term consumption of low GEN doses (≤500 ppm) promotes MCF-7 tumor growth and results in GINR tumors with more aggressive and advanced growth phenotypes.
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
KEYWORDS:
Athymic mice; Breast cancer progression; Genistein; MCF-7; Soy protein isolate
PMID:
24668689
PMCID:
PMC4143497
DOI:
10.1002/mnfr.201300780
[PubMed - indexed for MEDLINE]
Free PMC Article



-    Biol Reprod. 2015 Jul;93(1):20. doi: 10.1095/biolreprod.115.130336. Epub 2015 Jun 10.
Effects of Endocrine-Disrupting Chemicals on the Ovary.
Patel S1, Zhou C1, Rattan S1, Flaws JA2.
Author information
Abstract
Endocrine-disrupting chemicals (EDCs) are found abundantly in the environment, resulting in daily human exposure. This is of concern because many EDCs are known to target the female reproductive system and, more specifically, the ovary. In the female, the ovary is the key organ responsible for reproductive and endocrine functions. Exposure to EDCs is known to cause many reproductive health problems such as infertility, premature ovarian failure, and abnormal sex steroid hormone levels. Some EDCs and their effects on adult ovarian function have been studied extensively over the years, whereas the effects of others remain unclear. This review covers what is currently known about the effects of selected EDCs (bisphenol A, methoxychlor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phthalates, and genistein) on the adult ovary and the mechanisms by which they act upon the ovary, focusing primarily on their effects on folliculogenesis and steroidogenesis. Furthermore, this review discusses future directions needed to better understand the effects of EDCs, including the need to examine the effects of multiple and more consistent doses and to study different mechanisms of action.
© 2015 by the Society for the Study of Reproduction, Inc.
KEYWORDS:
2,3,7,8-tetrachloro-p-dibenzodioxin; bisphenol A; folliculogenesis; genistein; methoxychlor; ovary; phthalates; steroidogenesis
PMID:
26063868
DOI:
10.1095/biolreprod.115.130336
[PubMed - indexed for MEDLINE]
Free full text


-        Kaohsiung J Med Sci. 2012 Jul;28(7 Suppl):S37-42. doi: 10.1016/j.kjms.2012.05.008. Epub 2012 Jul 4.
Immunomodulatory effects of environmental endocrine disrupting chemicals.
Kuo CH1, Yang SN, Kuo PL, Hung CH.
Author information
Abstract
During recent decades more than 100,000 new chemicals have been introduced as common consumer products into our environment. Among these chemicals, endocrine-disrupting chemicals (EDCs) are of particular concern owing to their toxicity in animal studies and their impacts on human health. EDCs are ubiquitous in the environment, including the air, water, and soil. The endocrine-disrupting effect of EDCs has been found to imitate the action of steroid hormones and promote several endocrine and reproductive disorders in both animal and human studies. In the present review, we focus on the effects of EDCs on the immune system. EDCs interfere with the synthesis of cytokines, immunoglobulins, and inflammatory mediators, and they also affect the activation and survival of immune cells. The dysfunction of the immune system caused by EDCs may lead to the attenuation of immunity (immunodeficiency) against infection or hyperreactivity of immune responses (allergy and autoimmune disease). In this review, we summarize epidemiologic, animal, and cell studies to demonstrate the potential effects of EDCs on immunity, allergy, and autoimmune diseases. We also address the impact of EDCs on epigenetic regulation.
Copyright © 2012. Published by Elsevier B.V.
[Soy contains multiple estrogenic endocrine disruptors]
PMID:
22871600
DOI:
10.1016/j.kjms.2012.05.008
[PubMed - indexed for MEDLINE]
Free full text

AMONG COUNTLESS PUBLISHED STUDIES, THE MOST RECENT NIEHS STUDY AGAIN ESTABLISHES SOY PHYTO-ESTROGENS AS ENDOCRINE DISRUPTING CHEMICALS- http://www.niehs.nih.gov/health/topics/agents/index.cfm

Format: Abstract



        J Neuroendocrinol. 2012 Jan;24(1):144-59. doi: 10.1111/j.1365-2826.2011.02229.x.
Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems.
Frye CA1, Bo E, Calamandrei G, Calzà L, Dessì-Fulgheri F, Fernández M, Fusani L, Kah O, Kajta M, Le Page Y, Patisaul HB, Venerosi A, Wojtowicz AK, Panzica GC.
Author information
Abstract
Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α-ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or nonreproductive, sexually-dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific 'critical periods' of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator-activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonising or altering steroidal actions.
© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.
PMID:
21951193
PMCID:
PMC3245362
DOI:
10.1111/j.1365-2826.2011.02229.x
[PubMed - indexed for MEDLINE]
Free PMC Article
Format: Abstract



-    Environ Health Perspect. 2009 Oct;117(10):1556-62. doi: 10.1289/ehp.0900699. Epub 2009 Jun 5.
Exposure to a complex cocktail of environmental endocrine-disrupting compounds disturbs the kisspeptin/GPR54 system in ovine hypothalamus and pituitary gland.
Bellingham M1, Fowler PA, Amezaga MR, Rhind SM, Cotinot C, Mandon-Pepin B, Sharpe RM, Evans NP.
Author information
Abstract
BACKGROUND:
Ubiquitous environmental chemicals, including endocrine-disrupting chemicals (EDCs), are associated with declining human reproductive health, as well as an increasing incidence of cancers of the reproductive system. Verifying such links requires animal models exposed to "real-life," environmentally relevant concentrations/mixtures of EDC, particularly in utero, when sensitivity to EDC exposure is maximal.
OBJECTIVES:
We evaluated the effects of maternal exposure to a pollutant cocktail (sewage sludge) on the ovine fetal reproductive neuroendocrine axes, particularly the kisspeptin (KiSS-1)/GPR54 (G-protein-coupled receptor 54) system.
METHODS:
KiSS-1, GPR54, and ERalpha (estrogen receptor alpha) mRNA expression was quantified in control (C) and treated (T) maternal and fetal (110-day) hypothalami and pituitary glands using semiquantitative reverse transcription polymerase chain reaction, and colocalization of kisspeptin with LHbeta (luteinizing hormone beta) and ERalpha in C and T fetal pituitary glands quantified using dual-labeling immunohistochemistry.
RESULTS:
Fetuses exposed in utero to the EDC mixture showed reduced KiSS-1 mRNA expression across three hypothalamic regions examined (rostral, mid, and caudal) and had fewer kisspetin immunopositive cells colocalized with both LHbeta and ERalpha in the pituitary gland. In contrast, treatment had no effect on parameters measured in the adult ewe hypothalamus or pituitary.
CONCLUSIONS:
This study demonstrates that the developing fetus is sensitive to real-world mixtures of environmental chemicals, which cause significant neuroendocrine alterations. The important role of kisspeptin/GPR54 in regulating puberty and adult reproduction means that in utero disruption of this system is likely to have long-term consequences in adulthood and represents a novel, additional pathway through which environmental chemicals perturb human reproduction.
KEYWORDS:
GPR54; environmental chemicals; hypothalamus; kisspeptin; pituitary; prenatal exposure; sheep
PMID:
20019906
PMCID:
PMC2790510
DOI:
10.1289/ehp.0900699
[PubMed - indexed for MEDLINE]
Free PMC Article

[SOY PHYTO-ENDOCRINE DISRUPTORS ARE ESTABLISHED CAUSE OF KISSPEPTIN DISREGULATION]


 -       Adv. Exp.Med Biol 2013;784:455-79.

Effects of environmental endocrine disruptors and phytoestrogens on the kisspeptin system.
Patisaul HB1.
Author information
Abstract
Sex steroid hormones, most notably estradiol, play a pivotal role in the sex-specific organization and function of the kisspeptin system. Endocrine--disrupting compounds are anthropogenic or naturally occurring compounds that interact with steroid hormone signaling. Thus, these compounds have the potential to disrupt the sexually dimorphic ontogeny and function of kisspeptin signaling pathways, resulting in adverse effects on neuroendocrine physiology. This chapter reviews the small but growing body of evidence for endocrine disruption of the kisspeptin system by the exogenous estrogenic compounds bisphenol A, polychlorinated biphenyl mixtures, and the phytoestrogen genistein. Disruption is region, sex, and compound specific, and associated with shifts in the timing of pubertal onset, irregular estrous cycles, and altered sociosexual behavior. These effects highlight that disruption of kisspeptin signaling pathways could have wide ranging effects across multiple organ systems, and potentially underlies a suite of adverse human health trends including precocious female puberty, idiopathic infertility, and metabolic syndrome.
PMID:
23550019
DOI:
10.1007/978-1-4614-6199-9_21
[PubMed - indexed for MEDLINE]


-          Reprod Toxicol. 2011 Apr;31(3):280-9. doi: 10.1016/j.reprotox.2010.10.002. Epub 2010 Oct 15.
Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat.
Losa SM1, Todd KL, Sullivan AW, Cao J, Mickens JA, Patisaul HB.
Author information
Abstract
Neonatal exposure to estrogenic endocrine disrupting compounds (EDCs) can advance pubertal onset and induce premature anestrous in female rats. It was recently discovered that hypothalamic kisspeptin (KISS) signaling pathways are sexually dimorphic and regulate both the timing of pubertal onset and estrous cyclicity. Thus we hypothesized that disrupted sex specific ontogeny of KISS signaling pathways might be a mechanism underlying these EDC effects. We first established the sex specific development of KISS gene expression, cell number and neural fiber density across peripuberty in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), hypothesizing that the sexually dimorphic aspects of KISS signaling would be most vulnerable to EDCs. We next exposed female rats to the phytoestrogen genistein (GEN, 1 or 10 mg/kg bw), estradiol benzoate (EB, 10 μg), or vehicle from post natal day (P) 0-3 via subcutaneous (sc) injection. Animals were sacrificed on either P21, 24, 28, or 33 (n=5-14 per group at each age). Vaginal opening was significantly advanced by EB and the higher dose of GEN compared to control animals and was accompanied by lower numbers of KISS immunoreactive fibers in the AVPV and ARC. Ovarian morphology was also assessed in all age groups for the presence of multiple oocyte follicles (MOFs). The number of MOFs decreased over time in each group, and none were observed in control animals by P24. MOFs were still present, however, in the EB and 10 mg/kg GEN groups beyond P24 indicating a disruption in the timing of ovarian development.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID:
20951797
PMCID:
PMC3034101
DOI:
10.1016/j.reprotox.2010.10.002




-        J Pediatr Endocrinol Metab. 2010 Sep;23(9):855-61.
Soy as an endocrine disruptor: cause for caution?
Bar-El DS1, Reifen R.
Author information
Abstract
Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.
Comment in
The soy that surrounds us: an endless debate. [J Pediatrics].
PMID:
21175082



-        Mol Cell Endocrinol. 2012 May 22;355(2):192-200. doi: 10.1016/j.mce.2011.05.049. Epub 2011 Dec 22.
Soy, phytoestrogens and their impact on reproductive health.
Cederroth CR1, Zimmermann C, Nef S.
Author information
Abstract
There is growing interest in the potential health threats posed by endocrine-disrupting chemicals (EDCs) to the reproductive system. Soybean is the most important dietary source of isoflavones, an important class of phytoestrogen. While consumption of soy food or phytoestrogen supplements has been frequently associated with beneficial health effects, the potentially adverse effects on development, fertility, and the reproductive and endocrine systems are likely underappreciated. Here we review the available epidemiological, clinical and animal data on the effects of soy and phytoestrogens on the development and function of the male and female reproductive system, and weigh the evidence as to their detrimental impact.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
PMID:
22210487
DOI:
10.1016/j.mce.2011.05.049
[PubMed - indexed for MEDLINE]


-·        Mol Cell Endocrinol. 2010 Jun 10;321(2):152-60. doi: 10.1016/j.mce.2010.02.011. Epub 2010 Feb 18.
Potential detrimental effects of a phytoestrogen-rich diet on male fertility in mice.
Cederroth CR1, Zimmermann C, Beny JL, Schaad O, Combepine C, Descombes P, Doerge DR, Pralong FP, Vassalli JD, Nef S.
Author information
Abstract
Soy and soy-based products are widely consumed by infants and adult individuals. There has been speculation that the presence of isoflavone phytoestrogens in soybean cause adverse effects on the development and function of the male reproductive system. The purpose of this study was to examine the influence of dietary soy and phytoestrogens on testicular and reproductive functions. Male mice were fed from conception to adulthood with either a high soy-containing diet or a soy-free diet. Although adult mice fed a soy-rich diet exhibited normal male behaviour and were fertile, we observed a reduced proportion of haploid germ cells in testes correlating with a 25% decrease in epididymal sperm counts and a 21% reduction in litter size. LH and androgens levels were not affected but transcripts coding for androgen-response genes in Sertoli cells and Gapd-s, a germ cell-specific gene involved in sperm glycolysis and mobility were significantly reduced. In addition, we found that dietary soy decreased the size of the seminal vesicle but without affecting its proteolytic activity. Taken together, these studies show that long-term exposure to dietary soy and phytoestrogens may affect male reproductive function resulting in a small decrease in sperm count and fertility.
Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
PMID:
20171261
DOI:
10.1016/j.mce.2010.02.011

[It is well established that SOY PHYTOESTROGENS ARE ENDOCRINE-DISRUPTING CHEMICALS]



-        J Toxicol Environ Health B Crit Rev. 2014;17(3):127-74
Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases.
Yoon K1, Kwack SJ, Kim HS, Lee BM.
Author information
Abstract
Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17β-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ERα and ERβ) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.
PMID:
24749480
DOI:
10.1080/10937404.2014.882194
[PubMed - indexed for MEDLINE]



-     Endocr Relat Cancer. 2014 Mar 12;21(2):T13-31. doi: 10.1530/ERC-13-0342. Print 2014 Apr.

Endocrine disruption of oestrogen action and female reproductive tract cancers.
Gibson DA1, Saunders PT.
Author information
Abstract
Endocrine disrupting chemicals (EDC) are ubiquitous and persistent compounds that have the capacity to interfere with normal endocrine homoeostasis. The female reproductive tract is exquisitely sensitive to the action of sex steroids, and oestrogens play a key role in normal reproductive function. Malignancies of the female reproductive tract are the fourth most common cancer in women, with endometrial cancer accounting for most cases. Established risk factors for development of endometrial cancer include high BMI and exposure to oestrogens or synthetic compounds such as tamoxifen. Studies on cell and animal models have provided evidence that many EDC can bind oestrogen receptors and highlighted early life exposure as a window of risk for adverse lifelong effects on the reproductive system. The most robust evidence for a link between early life exposure to EDC and adverse reproductive health has come from studies on women who were exposed in utero to diethylstilbestrol. Demonstration that EDC can alter expression of members of the HOX gene cluster highlights one pathway that might be vulnerable to their actions. In summary, evidence for a direct link between EDC exposure and cancers of the reproductive system is currently incomplete.
KEYWORDS:
HOX genes; bisphenol A; diethylstilbestrol; dioxin; endocrine disrupting chemical; endocrine disruptor; endometrial cancer; genistein; obesity; oestrogen receptor; phytoestrogen; reproductive cancer
PMID:
24163391
DOI:
10.1530/ERC-13-0342
[PubMed - indexed for MEDLINE]
Free full text




-        J Cell Mol Med. 2013 Jan;17(1):1-11. doi: 10.1111/j.1582-4934.2012.01649.x. Epub 2012 Dec 20.
Molecular mechanism(s) of endocrine-disrupting chemicals and their potent oestrogenicity in diverse cells and tissues that express oestrogen receptors.
Lee HR1, Jeung EB, Cho MH, Kim TH, Leung PC, Choi KC.
Author information
Abstract
Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds present in the environment which can interfere with hormone synthesis and normal physiological functions of male and female reproductive organs. Most EDCs tend to bind to steroid hormone receptors including the oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR). As EDCs disrupt the actions of endogenous hormones, they may induce abnormal reproduction, stimulation of cancer growth, dysfunction of neuronal and immune system. Although EDCs represent a significant public health concern, there are no standard methods to determine effect of EDCs on human beings. The mechanisms underlying adverse actions of EDC exposure are not clearly understood. In this review, we highlighted the toxicology of EDCs and its effect on human health, including reproductive development in males and females as shown in in vitro and in vivo models. In addition, this review brings attention to the toxicity of EDCs via interaction of genomic and non-genomic signalling pathways through hormone receptors.
© 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 
PMID:
23279634
PMCID:
PMC3823132
DOI:
10.1111/j.1582-4934.2012.01649.x


-    Reprod Toxicol. 2011 Jul’ 32(1):15-25
Abnormal peripubertal development of the rat mammary gland following exposure in utero and during lactation to a mixture of genistein and the food contaminant vinclozolin.
El Sheikh Saad H1, Meduri G, Phrakonkham P, Bergès R, Vacher S, Djallali M, Auger J, Canivenc-Lavier MC, Perrot-Applanat M.
Author information
Abstract
The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and GV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of GV- and to a lesser extent, V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland.
Copyright © 2011 Elsevier Inc. All rights reserved.
PMID:
21539910
DOI:
10.1016/j.reprotox.2011.03.001
[PubMed - indexed for MEDLINE]


-        Crit Rev Food Sci Nutr. 2014;54(7):850-62. doi: 10.1080/10408398.2011.613534.
Advances of research on glycinin and β-conglycinin: a review of two major soybean allergenic proteins.
Wang T1, Qin GX, Sun ZW, Zhao Y.
Author information
Abstract
Being an important crop, soybean is widely used in the world and plays a vital role in human and animal nutrition. However, it contains several antinutritional factors (ANFs) including soybean agglutinin, soybean protease inhibitors, soybean allergenic proteins, etc., that may result in poor food utilization, decreased growth performance, and even disease. Among these ANFs, soybean allergenic proteins can lead to allergic reactions in human and animals, which has become a public problem all over the world, but our knowledge on it is still inadequate. This paper aims to provide an update on the characteristics, detection or exploration methods, and in vivo research models of soybean allergenic proteins; especially glycinin and β-conglycinin are deeply discussed. Through this review, we may have a better understanding on the advances of research on these two soybean allergenic proteins.
PMID:
24499064
DOI:
10.1080/10408398.2011.613534
[PubMed - indexed for MEDLINE]



-        J Proteome Res. 2016 Apr 1;15(4):1135-42. doi: 10.1021/acs.jproteome.5b00922. Epub 2016 Feb 25.
Comparative Proteomics Provides Insights into Metabolic Responses in Rat Liver to Isolated Soy and Meat Proteins.
Song S1, Hooiveld GJ2, Zhang W3, Li M1, Zhao F1, Zhu J1, Xu X1, Muller M4, Li C1, Zhou G1.
Author information
Abstract
It has been reported that isolated dietary soy and meat proteins have distinct effects on physiology and liver gene expression, but the impact on protein expression responses are unknown. Because these may differ from gene expression responses, we investigated dietary protein-induced changes in liver proteome. Rats were fed for 1 week semisynthetic diets that differed only regarding protein source; casein (reference) was fully replaced by isolated soy, chicken, fish, or pork protein. Changes in liver proteome were measured by iTRAQ labeling and LC-ESI-MS/MS. A robust set totaling 1437 unique proteins was identified and subjected to differential protein analysis and biological interpretation. Compared with casein, all other protein sources reduced the abundance of proteins involved in fatty acid metabolism and Pparα signaling pathway. All dietary proteins, except chicken, increased oxidoreductive transformation reactions but reduced energy and essential amino acid metabolic pathways. Only soy protein increased the metabolism of sulfur-containing and nonessential amino acids. This study further shows the distinct effects of soy and meat proteins on liver metabolism in rats.
KEYWORDS:
animal protein; chicken protein; fish protein; isolated protein; metabolic syndrome; molecular nutrition; nutrigenomics; pork protein; proteomics
PMID:
26886706
DOI:
10.1021/acs.jproteome.5b00922Format: Abstract



-        Amino Acids. 2016 Aug;48(8):1785-91. doi: 10.1007/s00726-016-2188-1. Epub 2016 Feb 13.
The role of dietary creatine.
Brosnan ME1, Brosnan JT2.
Author information
Abstract
The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body Creatine is a carninutrient, which means that it is only available to adults via animal foodstuffs, principally skeletal muscle, or via supplements. Infants receive creatine in mother's milk or in milk-based formulas. Vegans and infants fed on soy-based formulas receive no dietary creatine. Plasma and muscle creatine levels are usually somewhat lower in vegetarians than in omnivores. Human intake of creatine was probably much higher in Paleolithic times than today; some groups with extreme diets, such as Greenland and Alaskan Inuit, ingest much more than is currently typical. Creatine is synthesized from three amino acids: arginine, glycine and methionine (as S-adenosylmethionine). Humans can synthesize sufficient creatine for normal function unless they have an inborn error in a creatine-synthetic enzyme or a problem with the supply of substrate amino acids. Carnivorous animals, such as lions and wolves, ingest much larger amounts of creatine than humans would. The gastrointestinal tract and the liver are exposed to dietary creatine in higher concentrations before it is assimilated by other tissues. In this regard, our observations that creatine supplementation can prevent hepatic steatosis (Deminice et al. J Nutr 141:1799-1804, 2011) in a rodent model may be a function of the route of dietary assimilation. Creatine supplementation has also been reported to improve the intestinal barrier function of the rodent suffering from inflammatory bowel disease.

[Soy fed infants are routinely reported with severe gastrointestinal distress syndrome].
KEYWORDS:
Creatine kinase; Creatine synthesis; Intestinal barrier function; Paleolithic diet; Steatohepatitis
PMID:
26874700
DOI:
10.1007/s00726-016-2188-1
[PubMed - in process]



-        Life Sci. 2015 May 1;128:1-7. doi: 10.1016/j.lfs.2015.02.002. Epub 2015 Mar 2

[As defined as adulterated and misbranded, an unknown number of people metabolize soy phyto-estrogen daidzein to equal, an additional potent estrogenic hormone disruptor, of which is especially dangerous to developing fetus.  The unknown number of child producers of equol increase their health risks].
The influence of equol on the hypothalamic-pituitary-thyroid axis and hepatic lipid metabolic parameters in adult male rats.
Loutchanwoot P1, Srivilai P2, Jarry H3.
Author information
1Department of Biology Faculty of Science, Mahasarakham University, Khamriang Sub-district, Kantharawichai District, Mahasarakham Province 44150 Thailand. Electronic address: panida.l@msu.ac.th.
2Department of Biology Faculty of Science, Mahasarakham University, Khamriang Sub-district, Kantharawichai District, Mahasarakham Province 44150 Thailand.
3Department of Endocrinology, University Medical Center Göttingen, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.
Abstract
AIMS:
Equol, the principal active metabolite of soy-derived phytoestrogen daidzein, has well-known estrogenic actions. Results of several studies indicate that equol may also have anti-androgenic activities. However, mechanisms of action of equol on hypothalamic-pituitary-thyroid axis (HPTA) and hepatic lipid metabolism in adult male rats have not been determined yet.
MAIN METHODS:
Equol at two doses of 100 and 250mg/kgbodyweight(BW)/day was orally gavaged for 5days to groups of 4-month-old male rats. As a positive anti-androgenic control group, animals received 100mg of pure anti-androgenic drug flutamide/kgBW/day. Circulating concentrations of thyroid hormones and lipids, and expression levels of genes underlying HPTA function were determined by radioimmunoassay and TaqMan® real-time reverse transcription polymerase chain reaction, respectively.
KEY FINDINGS:
Flutamide significantly decreased relative prostate weight, whereas equol did not. Both equol and flutamide caused a significant increase in relative liver weights, and decreases in plasma levels of total tetraiodothyronine (T4) and triiodothyronine (T3), whereas free T4 and T3 concentrations were not reduced. Equol caused the marked down-regulation of hypothalamic thyrotropin-releasing hormone mRNA expression, whereas flutamide did not. Equol as well as flutamide significantly down-regulated the expression levels of pituitary thyrotropin beta-subunit mRNA, without altering thyrotropin secretion. Equol caused reductions in plasma levels of total cholesterol, high- and low-density lipoproteins and triglycerides, whereas flutamide exerted opposite effects.
SIGNIFICANCE:
This is the first study to reveal that in male rats the intrinsic estrogenic actions of equol were observed.
Copyright © 2015 Elsevier Inc. All rights reserved.
KEYWORDS:
Equol; Prostate; Serum lipids; Thyroid hormones; Thyrotropin secretion; Thyrotropin-releasing hormone
PMID:
25744395
DOI:
10.1016/j.lfs.2015.02.002
[PubMed - indexed for MEDLINE]


-        Toxicology. 2013 Feb 8;304:69-75. doi: 10.1016/j.tox.2012.11.017. Epub 2012 Dec 7.
Effects of the natural endocrine disruptor equol on the pituitary function in adult male rats.
Loutchanwoot P1, Srivilai P, Jarry H.
Author information
Abstract
Equol (EQ), a potent biologically active metabolite of the soy isoflavone daidzein, interacts with estrogen receptors (ERs), however, as suggested recently, EQ may also exert anti-androgenic actions in androgen regulated tissues like prostate and seminal vesicles in adult male rats. However, data regarding a putative anti-androgenic activity of EQ on pituitary function in male individuals are still lacking. Therefore, we investigated the effects of EQ on androgen- and estrogen-regulated gene expressions in the pituitary and circulating luteinizing hormone (LH) and prolactin (PRL) levels in adult male rats. 3-Month-old male Sprague-Dawley rats (n=12 per group) were treated by gavage for 5 days with either EQ (100 and 250 mg/kg BW/day) or vehicle olive oil (1 ml/rat/day). As reference compound, the pure anti-androgenic drug flutamide (FLUT) was employed at a dose of 100 mg/kg BW/day. At day 5, animals were sacrificed. Levels of pituitary hormones and gene expression were measured by radioimmunoassays and quantitative TaqMan(®) real-time reverse transcription polymerase chain reaction, respectively. The present findings revealed that the pituitary mechanisms involved in the effects of EQ and FLUT were different due to the opposite changes in the mRNA expression levels of estrogen receptor subtype alpha (ERα)-, truncated estrogen receptor product-1 (TERP-1)- and -2 (TERP-2)-, gonadotropin releasing hormone receptor (GnRH receptor)-, beta-subunit of LH (LHβ)-, and gonadotropin alpha subunit (α-subunit) genes. EQ displayed typical ER-agonistic actions as shown by the significant increases in ERα-, TERP-1/-2 mRNA expressions and serum PRL levels along with the significant reduction in serum LH levels, whereas FLUT exerted opposite effects on gonadotropin secretion and expression. Taken together, our findings are the first in vivo data that upon sub-acute oral exposure of EQ show an estrogenic effect on reproductive endocrine activity of the pituitary in adult male rats.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
PMID:
23220561
DOI:
10.1016/j.tox.2012.11.017
[PubMed - indexed for MEDLINE]




-    Brain Res Rev. 2008 Mar;57(2):376-85. Epub 2007 Sep 19.
Neuroendocrine and behavioral effects of embryonic exposure to endocrine disrupting chemicals in birds.
Ottinger MA1, Lavoie E, Thompson N, Barton A, Whitehouse K, Barton M, Abdelnabi M, Quinn M Jr, Panzica G, Viglietti-Panzica C.
Author information
Abstract
Endocrine disrupting chemicals (EDCs) exert hormone-like activity in vertebrates and exposure to these compounds may induce both short- and long-term deleterious effects including functional alterations that contribute to decreased reproduction and fitness. An overview of the effects of a number of EDCs, including androgenic and estrogenic compounds, will be considered. Many studies have been conducted in the precocial Japanese quail, which provides an excellent avian model for testing these compounds. Long-term impacts have also been studied by raising a subset of animals through maturation. The EDCs examined included estradiol, androgen active compounds, soy phytoestrogens, and atrazine. Effects on behavior and hypothalamic neuroendocrine systems were examined. All EDCs impaired reproduction, regardless of potential mechanism of action. Male sexual behavior proved to be a sensitive index of EDC exposure and embryonic exposure to a variety of EDCs consistently resulted in impaired male sexual behavior. Several hypothalamic neural systems proved to be EDC responsive, including arginine vasotocin (VT), catecholamines, and gonadotropin releasing hormone system (GnRH-I). Finally, EDCs are known to impact both the immune and thyroid systems; these effects are significant for assessing the overall impact of EDCs on the fitness of avian populations. Therefore, exposure to EDCs during embryonic development has consequences beyond impaired function of the reproductive axis. In conclusion, behavioral alterations have the advantage of revealing both direct and indirect effects of exposure to an EDC and in some cases can provide a valuable clue into functional deficits at different physiological levels.
PMID:
18006066
DOI:
10.1016/j.brainresrev.2007.08.011
[PubMed - indexed for MEDLINE]




-     Rev Endocr Metab Disord. 2007 Jun;8(2):143-59.
Estrogenic environmental endocrine-disrupting chemical effects on reproductive neuroendocrine function and dysfunction across the life cycle.
Dickerson SM1, Gore AC.
Author information
Abstract
Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that interfere with the normal function of an organism's endocrine system. Many EDCs are resistant to biodegradation, due to their structural stability, and persist in the environment. The focus of this review is on natural and artificial EDCs that act through estrogenic mechanisms to affect reproductive neuroendocrine systems. This endocrine axis comprises the hypothalamic gonadotropin-releasing hormone (GnRH), pituitary gonadotropins, and gonadal steroid hormones, including estrogens. Although it is not surprising that EDCs that mimic or antagonize estrogen receptors may exert actions upon reproductive targets, the mechanisms for these effects are complex and involve all three levels of the hypothalamic-pituitary-gonadal (HPG) system. Nevertheless, considerable evidence links exposure to estrogenic environmental EDCs with neuroendocrine reproductive deficits in wildlife and in humans. The effects of an EDC are variable across the life cycle of an animal, and are particularly potent when exposure occurs during fetal and early postnatal development. As a consequence, abnormal sexual differentiation, disrupted reproductive function, or inappropriate sexual behavior may be detected later in life. This review will cover the effects of two representative classes of estrogenic EDCs, phytoestrogens and polychlorinated biphenyls (PCBs), on neuroendocrine reproductive function, from molecules to behavior, across the vertebrate life cycle. Finally, we identify the gaps of knowledge in this field and suggest future directions for study.
PMID:
17674209
DOI:
10.1007/s11154-007-9048-y



-        J Nutr. 1995 Mar;125(3 Suppl):744S-750S.Possible adverse effects of soybean anticarcinogens.
Liener IE1.
Author information
Abstract
For soybeans to serve as a good source of protein for feeding animals as well as humans, a certain amount of heat treatment or some other form of processing must be applied. This is because there are present in soybeans certain heat-labile factors that exert an adverse effect on the nutritional value of the protein. The so-called protease inhibitors have received the most attention in this regard and have been shown to exert their antinutritional effect in the short term by causing pancreatic hypertrophy and hyperplasia in the rat, the underlying cause for an inhibition of growth in these animals. The prolonged feeding of raw soy flour or an enriched trypsin inhibitor fraction from soybeans to rats results in the development of hyperplastic and neoplastic nodules of the pancreas, including carcinomas. It should be emphasized that all of these adverse effects are seen when protease inhibitors are present in relatively high concentrations in the diet and may be completely unrelated to the anticarcinogenic effects seen at low concentrations of the Bowman-Birk inhibitor. Brief mention is also made of any possible adverse effects that may result from the presence of phytic acid and saponins in soybeans.
PMID:
7884560
[PubMed - indexed for MEDLINE]
Format: Abstract



-      Biomed Res Int. 2014;2014:619617. doi: 10.1155/2014/619617. Epub 2014 May 22.
Genistein induces deleterious effects during its acute exposure in Swiss mice.
Singh P1, Sharma S2, Rath SK2.
Author information
Abstract
Genistein is a soy derived isoflavone. It has wide variety of therapeutic effects against certain diseases including cancer. Although toxic effects of genistein have been studied, its effect on the gene expression and the reason behind toxicity have not been identified yet. In the present study, genistein was administered to age and body weight matched Swiss mice at the doses of 125, 250, 500 and 1000 mg/kg. The biomarkers of hepatotoxicity in serum, liver histology, oxidative stress parameters in tissue homogenates, and global gene expression were examined. Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and degenerated liver tissue were observed in 500, and 1000 mg/kg genistein treated groups. Oxidative stress was significant at these doses as considerable increase in lipid peroxidation (LPO) and decrease in total glutathione (GSH) were observed. Gene expression analysis showed 40 differentially expressed genes at twofold change and P < 0.05. Differentially expressed genes were corresponding to different biologically relevant pathways including metabolic and oxidative stress pathways. In 500 mg/kg group, Cyp4a14, Sult1e1, Gadd45g, Cidec, Mycs, and so forth genes were upregulated. These results suggested that the higher dose of genistein can produce several undesirable effects by affecting multiple cellular pathways.
PMID:
24967385
PMCID:
PMC4055018
DOI:
10.1155/2014/619617
[PubMed - indexed for MEDLINE]
Free PMC Article




      JIMD Rep. 2015;23:77-83. doi: 10.1007/8904_2015_432. Epub 2015 Apr 9.
Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model.
Kingma SD1, Wagemans T, IJlst L, Seppen J, Gijbels MJ, Wijburg FA, van Vlies N.
Author information
Abstract
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by diminished degradation of the glycosaminoglycans heparan sulfate (HS) and dermatan sulfate (DS). Patients present with a variety of symptoms, including severe skeletal disease. Current therapeutic strategies have only limited effects on bone disease. The isoflavone genistein has been studied as a potential therapy for the mucopolysaccharidoses because of its putative ability to inhibit GAG synthesis and subsequent accumulation. Cell, animal, and clinical studies, however, showed variable outcomes. To determine the effects of genistein on MPS I-related bone disease, wild-type (WT) and MPS I mice were fed a genistein-supplemented diet (corresponding to a dose of approximately 160 mg/kg/day) for 8 weeks. HS and DS levels in bone and plasma remained unchanged after genistein supplementation, while liver HS levels were decreased in genistein-fed MPS I mice as compared to untreated MPS I mice. Unexpectedly, genistein-fed mice exhibited significantly decreased body length and femur length. In addition, 60% of genistein-fed MPS I mice developed a scrotal hernia and/or scrotal hydrocele, manifestations, which were absent in WT or untreated MPS I mice. In contrast to studies in MPS III mice, our study in MPS I mice demonstraes no beneficial but even potential adverse effects of genistein supplementation. Our results urge for a cautious approach on the use of genistein, at least in patients with MPS I.
PMID:
25854773
PMCID:
PMC4484902
DOI:
10.1007/8904_2015_432
[PubMed]
Free PMC Article




-        Exp Biol Med (Maywood). 2010 May;235(5):590-8. doi: 10.1258/ebm.2009.009279.
Suppressive effects of genistein and daidzein on pituitary-thyroid axis in orchidectomized middle-aged rats.
Sosić-Jurjević B1, Filipović B, Ajdzanović V, Savin S, Nestorović N, Milosević V, Sekulić M.
Author information
Abstract
High intake of soybean phytoestrogens, isoflavones genistein (G) and daidzein (D), has been associated with health benefits. However, isoflavones were reported to affect adversely thyroid function in the presence of other goitrogenic factors. As the thyroid gland becomes functionally impaired with age, we examined whether supplementary doses of G or D would affect morphology and function of pituitary-thyroid axis in middle-aged male rats. Sixteen-month-old orchidectomized Wistar rats were treated with 10 mg/kg of either G or D, while the control sham-operated and orchidectomized group received just the vehicle for three weeks. The animals were fed soy-free diet with increased iodine content, and killed 24 h after the last treatment. Their pituitaries and thyroids were excised and prepared for further immunohistochemical and morphometric investigation. The concentrations of thyroid-stimulating hormone (TSH), total T(4) and T(3), in the serum were determined. In both isoflavone-treated groups, pituitary TSH-immunopositive cells had increased cellular volume and relative volume density (P < 0.05), as well as increased serum TSH levels (P < 0.05) in comparison to the controls; their thyroid tissue was characterized by increased volume of thyroglobulin-immunopositive epithelium (P < 0.05), epithelial height and index of activation rate (P < 0.05), while the volume of luminal colloid, and total serum T(4) and T(3) levels decreased (P < 0.05) in comparison to the controls. In conclusion, this study provides the first direct evidence that both G and D can induce microfollicular changes in the thyroid tissue and reduce the level of thyroid hormones in Orx middle-aged male rats, a model of andropause. This reduction consequently led to a feedback stimulation of pituitary TSH cells. The detected stimulatory effect was higher in the daidzein-treated rats.
PMID:
20463299
DOI:
10.1258/ebm.2009.009279
[PubMed - indexed for MEDLINE]




-     Front Neurol. 2014 Sep 3;5:169. doi: 10.3389/fneur.2014.00169. eCollection 2014.
A hypothesis regarding the molecular mechanism underlying dietary soy-induced effects on seizure propensity.
Westmark CJ1.
Author information
Abstract
Numerous neurological disorders including fragile X syndrome, Down syndrome, autism, and Alzheimer's disease are co-morbid with epilepsy. We have observed elevated seizure propensity in mouse models of these disorders dependent on diet. Specifically, soy-based diets exacerbate audiogenic-induced seizures in juvenile mice. We have also found potential associations between the consumption of soy-based infant formula and seizure incidence, epilepsy comorbidity, and autism diagnostic scores in autistic children by retrospective analyses of medical record data. In total, these data suggest that consumption of high levels of soy protein during postnatal development may affect neuronal excitability. Herein, we present our theory regarding the molecular mechanism underlying soy-induced effects on seizure propensity. We hypothesize that soy phytoestrogens interfere with metabotropic glutamate receptor signaling through an estrogen receptor-dependent mechanism, which results in elevated production of key synaptic proteins and decreased seizure threshold.
KEYWORDS:
autism; daidzein; estrogen; fragile X syndrome; mGluR5; phytoestrogens; seizures; soy
PMID:
25232349
PMCID:
PMC4153031
DOI:
10.3389/fneur.2014.00169
[PubMed]
Free PMC Article



-        PLoS One. 2014 Mar 12;9(3):e80488. doi: 10.1371/journal.pone.0080488. eCollection 2014.
Soy infant formula and seizures in children with autism: a retrospective study.
Westmark CJ1.
Author information
Abstract
Seizures are a common phenotype in many neurodevelopmental disorders including fragile X syndrome, Down syndrome and autism. We hypothesized that phytoestrogens in soy-based infant formula were contributing to lower seizure threshold in these disorders. Herein, we evaluated the dependence of seizure incidence on infant formula in a population of autistic children. Medical record data were obtained on 1,949 autistic children from the SFARI Simplex Collection. An autism diagnosis was determined by scores on the ADI-R and ADOS exams. The database included data on infant formula use, seizure incidence, the specific type of seizure exhibited and IQ. Soy-based formula was utilized in 17.5% of the study population. Females comprised 13.4% of the subjects. There was a 2.6-fold higher rate of febrile seizures [4.2% versus 1.6%, OR = 2.6, 95% CI = 1.3-5.3], a 2.1-fold higher rate of epilepsy comorbidity [3.6% versus 1.7%, OR = 2.2, 95% CI = 1.1-4.7] and a 4-fold higher rate of simple partial seizures [1.2% versus 0.3%, OR = 4.8, 95% CI = 1.0-23] in the autistic children fed soy-based formula. No statistically significant associations were found with other outcomes including: IQ, age of seizure onset, infantile spasms and atonic, generalized tonic clonic, absence and complex partial seizures. Limitations of the study included: infant formula and seizure data were based on parental recall, there were significantly less female subjects, and there was lack of data regarding critical confounders such as the reasons the subjects used soy formula, age at which soy formula was initiated and the length of time on soy formula. Despite these limitations, our results suggest that the use of soy-based infant formula may be associated with febrile seizures in both genders and with a diagnosis of epilepsy in males in autistic children. Given the lack of data on critical confounders and the retrospective nature of the study, a prospective study is required to confirm the association.
PMID:
24622158
PMCID:
PMC3951190
DOI:
10.1371/journal.pone.0080488
[PubMed - indexed for MEDLINE]
Free PMC Article




-       Autism Open Access. 2013 Nov 18;3. pii: 20727.
Soy Infant Formula may be Associated with Autistic Behaviors.
Westmark CJ1.
Author information
Abstract
The effects of soy-based infant formulas on childhood development are not well understood. This exploratory study evaluates the severity of autistic behaviors in association with the use of soy-based infant formula in a population of high-functioning autistic children. Medical record data were analyzed from the Simons Foundation Autism Research Initiative Simplex Collection, which included data on infant formula use and autism diagnostic scores for 1,949 autistic children. We found exploratory associations between the use of soy-based infant formula and several autistic behaviors as assessed by line-item analysis of the Aberrant Behavior Checklist, Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. This study provides preliminary data that the use of soy-based infant formula may be associated with specific autistic behaviors.
KEYWORDS:
Autism; Autistic behavior; Phytoestrogen; Soy
PMID:
25401047
PMCID:
PMC4229689
DOI:
10.4172/2165-7890.1000120
[PubMed)

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How many more than the nearly one thousand NIH Pubmed published studies concluding treacherous developmental soy phyto-poisonous body and brain effects does the FDA, CFSAN, NIH need to comply with FSMA and several other U.S. food, health, and child safe laws? 

How many more of your FDA, CFSAN, NIH overwhelming numbers of concurring soy adverse developmental health testimonials do you need before the FDA, CFSAN, and NIH will disclose your acknowledgement of soy phyto-poisonous adverse developmental body and brain effects as critical public health information?

You, the FDA, CFSAN, and NIH acknowledge nearly ONE THOUSAND NIH Pubmed published studies, (and countless more), as well as your own ongoing testimonials, of which ALL confirm a variety of extreme and outrageously tragic lifelong adverse physiological, reproductive, and neurological fetal, infant, and child effects are caused by exposure to fluctuating dosage levels of multiple developmental soy phyto-poisons, of which are Food Safety Modernization Act REQUIRED for disclosure of an entire trusting and innocent American public. 

While without lawful public WARNING labels, STOP the U.S. marketing of adulterated and misbranded developmentally-contaminating soy phyto-poisons.  In cooperation with your promised duty to protect fetal, infant, and child health, your choice to lawfully disclose this terribly toxic truth as equal public knowledge, is unquestionably an established preventative for indefinite numbers of severe and irreversible developmental adverse body and brain effects as mass NIH Pubmed studies and your testimonials repeatedly confirm. 

Morally, ethically, and lawfully release the truth to put a  STOP to unnecessary child pain and suffering!  At this time care to confirm that your first and foremost priority is in fact dedicated to the protection of most valuable fetal, infant, and child health, and least of all powerful corporate profits. 

Once more- As required by U.S. health laws, it is past due that you disclose your acknowledgement of your enormous collection of decades-worth of NIH published studies, as well as your testimonials that overwhelmingy concludes developmental exposure to unknown numbers of fluctuating dosage levels of health-destructive soy phyto-poisons become equally available fair and law-abiding public knowledge.  As you know, here is a valid FDA, CFSAN, and NIH opportunity for all American people to AVOID soy phyto-poisonous fetal, infant, and child exposures of which promises the best resulting physiological, reproductive, and neurological health, at least until you are ever able to prove that the highly dangerous stockpile of soy phyto-poisons are developmentally body and brain safe. 

I look forward to FDA, CFSAN, and NIH immediate cooperation with your U.S. food, health, and child safety laws, and your lawful compliance with your Food Safety Modernization Act.

I will appreciate your signed reply.


Sincerely,
G.A. Elbek
Research scientist (retired)
@SoySorry



(As acknowledged by the FDA, CFSAN, and NIH, for those of you who have not yet read the near one thousand developmental soy phyto-poisonous NIH Pubmed published studies included in Part 1, please view: http://illegalfda.blogspot.com).