title: Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure.
abstract: Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.
authors.affiliation: Department of Psychology, Columbia University, New York, NY 10027, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Kundakovic
authors.forename: Kathryn
authors.initials: K
authors.lastname: Gudsnuk
authors.forename: Becca
authors.initials: B
authors.lastname: Franks
authors.forename: Jesus
authors.initials: J
authors.lastname: Madrid
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.forename: Frederica P
authors.initials: FP
authors.lastname: Perera
authors.forename: Frances A
authors.initials: FA
authors.lastname: Champagne
mesh_terms: D000818:Animals; D001483:Base Sequence; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D004968:Estrogens, Non-Steroidal / Q000633:toxicity; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008425:Maternal Behavior / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000523:psychology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D012919:Social Behavior; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D010636:Phenols; C000715535:Dnmt3a protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: environmental; fetal origin of adult disease