Yale scientists show how bisphenol A induces epigenetic changes in pregnant mice that cause hormonal imbalance in the later life of female progeny

Here’s more evidence that “safe” plastics are not as safe as once presumed: New research published online in The FASEB Journal suggests that exposure to Bisphenol A (BPA) during pregnancy leads to epigenetic changes that may cause permanent reproduction problems for female offspring. BPA, a common component of plastics used to contain food, is a type of estrogen that is ubiquitous in the environment.

“Exposure to BPA may be harmful during pregnancy; this exposure may permanently affect the fetus,” said Hugh S. Taylor, Ph.D., co-author of the study from Yale University School of Medicine in New Haven, Connecticut. “We need to better identify the effects of environmental contaminants on not just crude measures such as birth defects, but also their effect in causing more subtle developmental errors.”

Taylor and colleagues made this discovery by exposing fetal mice to BPA during pregnancy and examining gene expression and DNA in the uteruses of female fetuses. Results showed that BPA exposure permanently affected the uterus by decreasing regulation of gene expression. These epigenetic changes caused the mice to over-respond to estrogen throughout adulthood, long after the BPA exposure. This suggests that early exposure to BPA genetically “programmed” the uterus to be hyper-responsive to estrogen. Extreme estrogen sensitivity can lead to fertility problems, advanced puberty, altered mammary development and reproductive function, as well as a variety of hormone-related cancers. BPA has been widely used in plastics and other materials. Examples include use in water bottles, baby bottles, epoxy resins used to coat food cans, and dental sealants.

“The BPA baby bottle scare may be only the tip of the iceberg.” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “Remember how diethylstilbestrol (DES) caused birth defects and cancers in young women whose mothers were given such hormones during pregnancy. We’d better watch out for BPA, which seems to carry similar epigenetic risks across the generations. ”

Author: FASEB* – Federation of American Societies for Experimental Biology, Why BPA leached from ’safe’ plastics may damage health of female offspring, 25-Feb-2010.

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* FASEB comprises 23 societies with more than 90,000 members, making it the largest coalition of biomedical research associations in the United States

The Massachusetts Department of Public Health (DPH) is issuing a public health advisory for consumers concerning bisphenol A (BPA). BPA is present in baby products, including baby bottles and some infant formula. A number of studies in laboratory animals have raised concerns about potential health effects during fetal development and among nursing or formula-fed children who may be exposed to BPA. These effects include but are not limited to: changes in the infant’s developing nervous system, such as thyroid function and brain growth; changes in behavioral development, such as hyperactivity; and changes in the normal development of the prostate gland.  

Avoid products that may contain BPA

DPH is specifically advising parents and caretakers of children up to two years old to avoid the use of products that contain BPA for making or storing infant formula and breast milk. DPH is further advising pregnant and breastfeeding women to avoid products that may contain BPA. Current research suggests that BPA levels in newborns may be much higher than in adults. While researchers caution that more research needs to be conducted, it seems prudent to reduce exposures for pregnant and breastfeeding women to the extent possible in order to reduce levels in their newborn children. 

BPA is used as a liner in some food and beverage cans to prevent spoilage. It is used in a variety of other consumer products to enhance the structural integrity of plastic containers. Alternatives to plastic containers that have BPA as a component are available, and some are made by the same companies that produce products containing BPA. 

Recycling number 7 should be avoided to the extent possible

Transparent (clear or colored) plastic containers or baby bottles with the recycling number 7 and the letters PC, which stand for “polycarbonate” plastic, should be avoided to the extent possible. Heat can increase the release of BPA from polycarbonate plastic. Therefore, consumers should consider the following:

• Avoid heating plastic containers with the recycling number 7 and the letters PC in microwave ovens, in water on the stovetop, or by adding boiling water into them, particularly when preparing infant formula.
• Wash the containers by hand with warm water and soap, instead of in dishwashers.
• Stainless steel and glass do not contain BPA.
• Replace worn or scratched polycarbonate plastic containers, preferably with glass or stainless steel containers.
• Pregnant or breastfeeding women can eat or cook with fresh or frozen products instead of canned foods — which may contain BPA — to reduce fetal or infant exposure to BPA.

Some studies have found BPA in containers of canned liquid infant formula. Powdered formula does not appear to contain detectable levels of BPA. If special formula is required because of a medical condition, parents should not make any changes to their baby’s diet without consulting with their health care provider first. It is likely that known medical risks from discontinuing the use of special formula may be far greater than those that may result from BPA exposure from this source. The most effective means of reducing BPA exposure to infants is to breast feed. For both baby and mother, breastfeeding has many well-documented health benefits: 

• Breastfed babies have lower rates of some of the most serious chronic diseases: asthma, diabetes, and some childhood cancers.
• Breastfeeding reduces the risk and severity of infectious diseases: pneumonia, diarrhea, and ear infections.
•  Women who breastfeed have lower levels of ovarian and breast cancer, and breastfed daughters also have lower rates of breast cancer when they grow up.

FDA is currently considering scientific evidence

The federal Food and Drug Administration (FDA) is currently considering the scientific evidence related to health risks associated with BPA in foods and consumer products and is expected to determine the need for regulatory action in 2009. Current research on health effects associated with BPA exposure includes effects during fetal developmental and among infants, and children. Recent preliminary studies also suggest that BPA may interfere with the effectiveness of breast cancer chemotherapeutic drugs in cell culture, and may also be associated with diabetes and cardiovascular conditions in adults.

An educational brochure on this topic can be found at the DPH web site at: How to Protect Your Baby from BPA (Bisphenol A) (PDF) 

Reference:  Massachusetts Department of Public Health (DPH), DEVAL L. PATRICK – GOVERNOR, TIMOTHY P. MURRAY – LIEUTENANT GOVERNOR, JUDYANN BIGBY, M.D. – SECRETARY, JOHN AUERBACH – COMMISSIONER, For Immediate Release: Public Health Advisory Regarding Bisphenol A (BPA), August 03, 2009

Racial disparities in pregnancy outcome in the United States are significant, persistent and costly, but the causes are poorly understood. We propose that disproportionate exposure of African-American women to environmental endocrine disrupting compounds (EDCs) may contribute to birth outcome disparities. Marked racial segregation, as well as health behaviors associated with poverty could result in differences in exposure to particular EDCs. One EDC that has aroused concern in recent years is bisphenol-A (BPA), a widely used industrial plasticizer with known estrogenic properties.  

Published studies indicate that excessive BPA exposure is associated with reduced fetal survival, as well as reductions in maternal weight and fetal body weight. Related findings include adverse effects of BPA exposure on ovarian function, mammary gland development, earlier age of puberty onset and some metabolic parameters. However, these findings are largely limited to experimental animal studies, and need to be validated in human populations.  

Our review supports the need to move beyond the currently dominant toxicological approach to examining the effects of BPA exposure, and rely more on observational human studies and epidemiological methods. Many of the risk factors for racial disparities in pregnancy outcome are global or difficult to modify, but exposure to BPA is a potentially malleable risk factor. If BPA contributes to racial disparities in pregnancy outcome, there are important implications for prevention. It is our hope that this review will stimulate further research in this important and neglected area. 

Reference: Ranjit N, Siefert K, Padmanabhan V., Bisphenol-A and disparities in birth outcomes: a review and directions for future research, Journal of Perinatology advance online publication, 9 July 2009; doi:10.1038/jp.2009.90.

Bisphenol A, a chemical widely used in plastics and known to cause reproductive problems in the offspring of pregnant mice exposed to it, also has been found to retard the growth of follicles of adult mice and hinder their production of steroid hormones, researchers report. 

Their study is the first to show that chronic exposure to low doses of BPA can impair the growth and function of adult reproductive cells. The researchers will describe their findings this month at the annual meeting of the Society for the Study of Reproduction. 

A healthy, mature follicle, called an antral follicle, includes a single egg cell surrounded by layers of cells and fluid which support the egg and produce steroid hormones, said University of Illinois veterinary biosciences professor Jodi Flaws, who led the study with graduate student Jackye Peretz. 

“These are the only follicles that are capable of ovulating and so if they don’t grow properly they’re not going to ovulate and there could be fertility issues,” Flaws said. “These follicles also make sex steroid hormones, and so if they don’t grow properly you’re not going to get proper amounts of these hormones.” Such hormones are essential for reproduction, she said, “but they’re also required for healthy bones, a healthy heart and a healthy mood.” 

BPA is widely used in plastics and is a common component of food containers and baby bottles.  

The chemical structure of BPA is similar to that of estradiol, a key steroid hormone, and it can bind to estrogen receptors on the surface of some cells. It is not known whether BPA blocks, or mimics or enhances estrogen’s activity on these cells, Flaws said. 

Human studies have found BPA in many tissues and fluids, including urine, blood, breast milk, the amniotic fluid of pregnant women and the antral fluid of mature follicles. A national survey conducted by the federal Centers for Disease Control and Prevention in 2003-2004 found BPA in 93 percent of the 2,517 people (age 6 and up) who were tested. 

BPA has a short half-life, Peretz said, and the chemical is quickly eliminated from the body. The fact that so many people tested positive “probably means that we’re being constantly exposed to BPA,” she said. The new study found that follicle growth was impaired after 48 hours of exposure to BPA, Peretz said. Reductions in three key steroid hormones – progesterone, testosterone and estradiol – were also seen after 120 hours of exposure to BPA.

The drop in steroid hormone production was quite dramatic. After 120 hours in a medium that included 10 micrograms per milliliter of BPA, mouse follicle cells produced about 85 percent less estradiol, 97 percent less progesterone and 95 percent less testosterone. Lower doses of BPA had a less dramatic – but still considerable – dampening effect on steroid hormone levels. And at 120 hours, follicle cells grown in the BPA medium were 25 percent smaller than normal, the researchers report. 

A review of the health risks of BPA by the National Toxicology Program of the U.S. Department of Health and Human Services concluded in 2008 that while BPA has been shown to harm the reproductive health of laboratory animals in some studies, such adverse effects “are observed at levels of exposure that far exceed those encountered by humans.” 

However, the NTP reported that laboratory studies that showed effects in animals exposed to low doses of BPA led it to have “some concern for effects on the brain, behavior and prostate gland in fetuses, infants and children at current human exposures to bisphenol A.” 

The new study points to possible concerns in adults as well, Flaws said. 

“I think there’s a need for more studies where people look in adult humans to see if BPA is affecting follicle growth and steroid hormone levels,” she said. If it is, that might help explain some infertility or menopausal symptoms, she said. 

Reference: University of Illinois at Urbana-Champaign, Plastics chemical retards growth, function of adult reproductive cells, CHAMPAIGN, Ill., July 8, 2009

Photo: by L. Brian Stauffer, U. of I. News Bureau

The chemical bisphenol A, commonly found in many plastic household items, has been linked to yet another health problem in animals—an increased frequency of arrhythmias, or , a new study found. The results, seen only in females, will be presented Saturday at The Endocrine Society’s 91st Annual Meeting in Washington, D.C.

Past animal studies show that bisphenol A, or BPA, can have harmful effects on the reproductive, nervous and immune systems. Also, a study in humans reported last year found an increased prevalence of cardiovascular disease in people with high levels of BPA in the urine.

However, the effects of BPA on the heart are unknown, said study co-author Scott Belcher, PhD, associate professor in the University of Cincinnati’s Department of Pharmacology and Cell Biophysics.

In the new study, funded by the National Institutes of Health, the University of Cincinnati researchers found that low-dose BPA and estrogen can act alone or in combination to increase harmful arrhythmias in female rats and mice. Because BPA has properties similar to the main female hormone estrogen, it is considered an “environmental estrogen.”

Mice and rats in the study had normal heart rhythms at baseline, before administration of BPA or estrogen (estradiol), Belcher said. The investigators studied heart rhythms in both the working heart and in cultured heart muscle cells. In both models, exposure to BPA increased the frequency of arrhythmias, compared to baseline, in females but not in male animals, the authors found. Administration of estrogen alone also increased the frequency of arrhythmias in females.

Arrhythmias were most frequent in the female rats and mice when they received both BPA and estrogen, at levels normally found in female humans.

“We have identified a new possible risk for female heart health, caused by increased levels of estrogens in the body and exposure to the environmental estrogen BPA,” Belcher said.

BPA is found in polycarbonate-plastic baby bottles, refillable water bottles and food containers as well as the linings of metal food cans. Last year the U.S. Food and Drug Administration said more research on the safety of BPA is needed.

Arrhythmias occur when the heart beats too slowly or too fast or when it skips heartbeats. These heart rhythm irregularities can cause fatigue, lightheadedness, fainting or sudden cardiac death. If a fast heart rate affects the heart’s ability to pump, it can cause a heart attack.

The study’s lead author, Hong-Sheng Wang, PhD, assistant professor at the University of Cincinnati, will present the results.

Reference: The Endocrine Society, Bisphenol A exposure increases risk of abnormal heart rhythms in female rodents, 10-Jun-2009