Prenatal Bisphenol A Exposure and Early Childhood Behavior
Joe M. Braun1, Kimberly Yolton2, Kim N. Dietrich3, Richard Hornung2, Xiaoyun Ye4,
Antonia M. Calafat4, Bruce P. Lanphear2,5

1-Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC,
27514
2-Department of Pediatrics, Division of General and Community Pediatrics, Cincinnati
Children's Hospital Medical Center, Cincinnati, OH 45229
3-Department of Environmental Health, Division of Epidemiology and Biostatistics, University
of Cincinnati College of Medicine, Cincinnati, OH 45267
4- Division of Laboratory Sciences, National Center for Environmental Health, Centers for
Disease Control and Prevention, Atlanta, GA 30341
5-Child & Family Research Institute, BC Children’s Hospital and the Faculty of Health Sciences,
Simon Fraser University, Vancouver, British Columbia

Abstract
Background: Prenatal exposure Bisphenol A (BPA) increases offspring aggression and
diminishes differences in sexually dimorphic behaviors in rodents.
Objective: We examined the association between prenatal BPA exposure and behavior in 2-year
old children.
Methods: We used data from 249 mothers and their children in Cincinnati OH. Maternal urine
was collected around 16 and 26 weeks gestation and at birth. BPA concentrations were
quantified using high performance liquid chromatography-isotope dilution-tandem mass
spectrometry. Child behavior was assessed at 2-years of age using the Behavioral Assessment
System for Children-2 (BASC-2). The association between prenatal BPA concentrations and
BASC-2 scores was analyzed using linear regression.
Results: Median BPA concentrations were 1.8 (16 week), 1.7 (26 week), and 1.3 (birth) ng/ml.
Mean externalizing and internalizing scores were 47.6 (standard deviation [SD]:7.8) and 44.8
(SD:7.0), respectively. After adjustment for confounders, log10-transformed mean prenatal BPA
concentrations were associated with externalizing scores, but only among females (:6.0; 95%
confidence interval [CI]:0.1, 12.0). Compared to 26 week and birth concentrations, BPA
concentrations collected around 16 weeks were more strongly associated with externalizing
scores among all children (:2.9; 95% CI: 0.2, 5.7); and this association was stronger in females
than males. Among all children, measurements collected < 16 weeks showed a stronger
association (:5.1; 95% CI:1.5, 8.6) with externalizing scores than measurements taken from 17-
21 weeks (:0.6, 95% CI:-2.9, 4.1).
Conclusions: These results suggest that prenatal BPA exposure may be associated with
externalizing behaviors in two-year old children, especially among female children.

Environ Health Perspect doi:10.1289/ehp.0900979 available via http://dx.doi.org/ [Online 06 October 2009]

Context Bisphenol A (BPA) is widely used in epoxy resins lining food and beverage containers. Evidence of effects in animals has generated concern over low-level chronic exposures in humans.

Objective To examine associations between urinary BPA concentrations and adult health status.

Design, Setting, and Participants Cross-sectional analysis of BPA concentrations and health status in the general adult population of the United States, using data from the National Health and Nutrition Examination Survey 2003-2004. Participants were 1455 adults aged 18 through 74 years with measured urinary BPA and urine creatinine concentrations. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, body mass index, waist circumference, and urinary creatinine concentration. The sample provided 80% power to detect unadjusted odds ratios (ORs) of 1.4 for diagnoses of 5% prevalence per 1-SD change in BPA concentration, or standardized regression coefficients of 0.075 for liver enzyme concentrations, at a significance level of P < .05.

Main Outcome Measures Chronic disease diagnoses plus blood markers of liver function, glucose homeostasis, inflammation, and lipid changes.

Results Higher urinary BPA concentrations were associated with cardiovascular diagnoses in age-, sex-, and fully adjusted models (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.18-1.63; P = .001 with full adjustment). Higher BPA concentrations were also associated with diabetes (OR per 1-SD increase in BPA concentration, 1.39; 95% confidence interval [CI], 1.21-1.60; P < .001) but not with other studied common diseases. In addition, higher BPA concentrations were associated with clinically abnormal concentrations of the liver enzymes {gamma}-glutamyltransferase (OR per 1-SD increase in BPA concentration, 1.29; 95% CI, 1.14-1.46; P < .001) and alkaline phosphatase (OR per 1-SD increase in BPA concentration, 1.48; 95% CI, 1.18-1.85; P = .002).

Conclusion Higher BPA exposure, reflected in higher urinary concentrations of BPA, may be associated with avoidable morbidity in the community-dwelling adult population.

JAMA. 2008;300(11):1303-1310. Published online September 16, 2008 (doi:10.1001/jama.300.11.1303)

In this issue of JAMA, Lang and colleagues1 report the results of the first major epidemiologic study to examine the health effects associated with the ubiquitous estrogenic chemical bisphenol A (BPA). This compound is the base chemical (monomer) used to make polycarbonate plastic food and beverage containers, the resin lining of cans, and dental sealants; it also is found in "carbonless" paper used for receipts as well as a wide range of other common household products. Based on their analysis of data from the National Health and Nutrition Examination Survey 2003-2004, Lang et al report a significant relationship between urine concentrations of BPA and cardiovascular disease, type 2 diabetes, and liver-enzyme abnormalities in a representative sample of the adult US population. This report, suggesting links between BPA and some of the most significant and economically burdensome human diseases, is based . . .

JAMA. 2008;300(11):1353-1355. Published online September 16, 2008 (doi:10.1001/jama.300.11.1353)

The function of pancreatic β-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ERα and ERβ, are important molecules involved in glucose metabolism, yet their role in pancreatic β-cell physiology is still greatly unknown. In this report we show that both ERα and ERβ are present in pancreatic β-cells. Long term exposure to physiological concentrations of 17β-estradiol (E2) increased β-cell insulin content, insulin gene expression and insulin release, yet pancreatic β-cell mass was unaltered. The up-regulation of pancreatic β-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ERα and ERβ agonists as well as ERαKO and ERβKO mice suggests that the estrogen receptor involved is ERα. The up-regulation of pancreatic insulin content by ERα activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

PLoS ONE 3(4): e2069. doi:10.1371/journal.pone.0002069

Background: The incidence of obesity has risen dramatically over the last few decades. This
epidemic may be affected by exposure to xenobiotic chemicals. Bisphenol A (BPA), an
endocrine disruptor, is detectable at nM levels in human serum worldwide. Adiponectin is an
adipocyte-specific hormone which increases insulin sensitivity and reduces tissue inflammation.
Thus, any factor which suppresses adiponectin release could lead to insulin resistance and
increased susceptibility to obesity-associated diseases.

Objectives: To compare: a) the effects of low doses of BPA and estradiol (E2) on adiponectin
secretion from human breast, subcutaneous (sc) and visceral (vis) adipose explants and mature
adipocytes, and b) expression of putative estrogen and estrogen-related receptors in these tissues.

Methods: Adiponectin levels in conditioned media (CM) from adipose explants or adipocytes
were determined by enzyme-linked immunosorbant assay (ELISA). Expression of estrogen
receptors (ER) α and β, G-protein-coupled receptor 30 (GPR30), and estrogen-related receptors
(ERR) α, β and γ was determined by quantitative real-time PCR.

Results: BPA at 0.1 and 1 nM doses suppressed adiponectin release from all adipose depots
examined. In spite of a substantial variability among patients, BPA was as effective, and often
more effective, than equimolar concentrations of E2. Adipose tissue expresses similar mRNA
levels of ERα, ERβ and ERRγ, and 20-30 fold lower levels of GPR30, ERRα and ERRβ.

Conclusions: BPA at environmentally-relevant doses inhibits the release of a key adipokine that
protects humans from the metabolic syndrome. The mechanism by which BPA suppresses
adiponectin and the receptors involved remain to be determined.

Environ Health Perspect doi:10.1289/ehp.11537 available via http://dx.doi.org/ [Online 14 August 2008]

Concern about potential health impacts of low-level exposures to organophosphorus (OP) pesticides, bisphenol A (BPA), and phthalates among the general population is increasing. We measured levels of six dialkyl phosphate (DAP) metabolites of OP pesticides, a chlorpyrifos-specific metabolite (3,5,6-trichloro-2-pyridinol, TCPy), BPA, and 14 phthalate metabolites in urine samples of 100 pregnant women from the Generation R study, the Netherlands. The unadjusted and creatinine-adjusted concentrations were reported, and compared to National Health and Nutrition Examination Survey and other studies. In general, these metabolites were detectable in the urine of the women from the Generation R study and compared with other groups, they had relatively high-level exposures to OP pesticides and several phthalates but similar exposure to BPA. The median concentrations of total dimethyl (DM) metabolites was 264.0nmol/g creatinine (Cr) and of total DAP was 316.0nmol/g Cr. The median concentration of mono-ethyl phthalate (MEP) was 222.0mug/g Cr; the median concentrations of mono-isobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were above 50mug/g Cr. The median concentrations of the three secondary metabolites of di-2-ethylhexyl phthalate (DEHP) were greater than 20mug/g Cr. The data indicate that the Generation R study population provides a wide distribution of selected environmental exposures. Reasons for the relatively high levels and possible health effects need investigation.

Environ Res. 2008 Sep 4. [Epub ahead of print]

Exposure measurements from several countries indicate that humans are routinely exposed to low levels of bisphenol A (BPA), a synthetic xenoestrogen widely used in the production of polycarbonate plastics. There is considerable debate about whether this exposure represents an environmental risk, based on reports that BPA interferes with the development of many organs and that it may alter cognitive functions and mood. Consistent with these reports, we have previously demonstrated that BPA antagonizes spine synapse formation induced by estrogens and testosterone in limbic brain areas of gonadectomized female and male rats. An important limitation of these studies, however, is that they were based on rodent animal models, which may not be representative of the effects of human BPA exposure. To address this issue, we examined the influence of continuous BPA administration, at a daily dose equal to the current U.S. Environmental Protection Agency's reference safe daily limit, on estradiol-induced spine synapse formation in the hippocampus and prefrontal cortex of a nonhuman primate model. Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol. Because remodeling of spine synapses may play a critical role in cognition and mood, the ability of BPA to interfere with spine synapse formation has profound implications. This study is the first to demonstrate an adverse effect of BPA on the brain in a nonhuman primate model and further amplifies concerns about the widespread use of BPA in medical equipment, and in food preparation and storage.

Proc Natl Acad Sci U S A. 2008 Sep 3. [Epub ahead of print]

The function of pancreatic β-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ERα and ERβ, are important molecules involved in glucose metabolism, yet their role in pancreatic β-cell physiology is still greatly unknown. In this report we show that both ERα and ERβ are present in pancreatic β-cells. Long term exposure to physiological concentrations of 17β-estradiol (E2) increased β-cell insulin content, insulin gene expression and insulin release, yet pancreatic β-cell mass was unaltered. The up-regulation of pancreatic β-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ERα and ERβ agonists as well as ERαKO and ERβKO mice suggests that the estrogen receptor involved is ERα. The up-regulation of pancreatic insulin content by ERα activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

PLoS ONE 3(4): e2069. doi:10.1371/journal.pone.0002069 Lesen Sie mehr...

The link between endocrine disruptors and altered blood glucose homeostasis has been recently suggested. Epidemiological studies have correlated levels of phthalates, dioxins and persistent organic pollutants with alterations of blood glucose homeostasis in humans. Environmentally relevant doses of the ubiquitous endocrine disruptor bisphenol-A (BPA) have profound effects on mice endocrine pancreas--an essential tissue involved in glucose metabolism. BPA exerts rapid non-genomic effects on insulin releasing beta-cells and glucagon releasing alpha-cells within freshly isolated islets of Langerhans. In vivo, a single BPA injection of 10 microg/kg rapidly increases plasma insulin and concomitantly decreases glycaemia. When mice were treated with BPA 100 microg/kg/day for 4 days, the environmental oestrogen produced an increase in beta-cell insulin content along with a post-prandial hyperinsulinaemia and insulin resistance. The results reviewed here demonstrate that doses well below the current lowest observed adverse effect level considered by the US-EPA, disrupt pancreatic beta-cell function producing insulin resistance in male mice. Therefore, this altered blood glucose homeostasis by BPA exposure may enhance the risk of developing type II diabetes.

International Journal of Andrology, Volume 31 Issue 2, Pages 194 - 200, 2007

The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine-active compound shifted the coat color distribution of viable yellow agouti (A vy) mouse offspring toward yellow by decreasing CpG (cytosine-guanine dinucleotide) methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene. CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (Cabp IAP). DNA methylation at the A vy locus was similar in tissues from the three germ layers, providing evidence that epigenetic patterning during early stem cell development is sensitive to BPA exposure. Moreover, maternal dietary supplementation, with either methyl donors like folic acid or the phytoestrogen genistein, negated the DNA hypomethylating effect of BPA. Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements.

PNAS August 7, 2007 vol. 104 no. 32 13056-13061