Impact of Low Dose Oral Exposure to Bisphenol A (BPA) on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: A CLARITY-BPA Consortium Study

Abstract

Bisphenol A (BPA) is an endocrine disrupting, high volume production chemical found in a variety of products. Evidence of prenatal exposure has raised concerns that developmental BPA may disrupt sex-specific brain organization and, consequently, induce lasting changes on neurophysiology and behavior. We and others have shown that exposure to BPA at doses below the noobserved-adverse-effect level can disrupt the sex-specific expression of estrogen-responsive genes in the neonatal rat brain including estrogen receptors (ERs). The present studies, conducted as part of the Consortium Linking Academic and Regulatory Insights of BPA Toxicity program, expanded this work by examining the hippocampal and hypothalamic transcriptome on postnatal day 1 with the hypothesis that genes sensitive to estrogen and/or sexually dimorphic in expression would be altered by prenatal BPA exposure. NCTR Sprague-Dawley dams were gavaged from gestational day 6 until parturition with BPA (0-, 2.5-, 25-, 250-, 2500-, or 25 000-g/kg body weight [bw]/d). Ethinyl estradiol was used as a reference estrogen (0.05-or 0.5-g/kg bw/d). Postnatal day 1 brains were microdissected and gene expression was assessed with RNA-sequencing (0-, 2.5-, and 2500-g/kg bw BPA groups only) and/or quantitative real-time PCR (all exposure groups). BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ER and ER (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain. (Endocrinology 157: 3856 -3872, 2016) B isphenol A (BPA) is a well-known endocrine-disrupt- ing compound (EDC) used in a wide range of products, including food and beverage containers, medical equipment, plastic water pipes, and thermal receipts, from which it can leach, thereby resulting in human exposure (1-3). BPA has been found in human fetal plasma and in placental tissue (1, 2), indicating that maternal BPA is able to cross the placenta. Evidence of prenatal exposure has raised concern that subtle effects of developmental BPA exposure on brain organization and sexual differentiation may have long-term impacts on neurophysiology and behavior (3-5). Over the past decade, the National Toxicology Program (NTP), World Health Organization, Food and Agricultural Organization, and others have expressed concern for effects on the brain and behavior (6 -10). The Food and Drug Administration (FDA), however, subsequently departed from this view and in 2014 stated that