Perinatal exposure to an environmentally-relevant mixture of BFRs and ovarian gene expression in the adult rat. Perinatal exposure to an environmentally-relevant mixture of BFRs and ovarian gene expression in the adult rat

Brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD), leach out from consumer products into the environment. Exposure to BFRs has been associated with effects on endocrine homeostasis. To test the hypothesis that in utero and lactational exposure to BFRs may affect the reproductive system of female offspring, adult female Sprague-Dawley rats were fed nominal doses (0, 0.06, 20, or 60 mg/kg/day) of a BFR dietary mixture formulated to mimic the levels of congeners in house dust from prior to mating until weaning. Vaginal opening and the day of first estrus occurred at a significantly earlier age among offspring from the 20 mg/kg/day BFR group, indicating that the onset of puberty was advanced. Histological analysis of ovaries from post-natal day 46 offspring revealed an increase in the incidence of multi-oocyte follicles. Toxicogenomics analysis of ovarian gene expression identified upstream regulators, including HIF1A, CREB1, EGF, the β-estradiol and PPARA pathways, predicted to be downregulated in the 20 mg/kg/day or the 60 mg/kg/day group and to contribute to the gene expression patterns observed. Thus, perinatal exposure to BFRs dysregulated ovarian folliculogenesis and signaling pathways that are fundamental for ovarian function. Overall design: For each of the 4 treatment groups (0, 0.06, 20 and 60 mg/kg/day), RNA was extracted from the ovaries of 5-6 animals from independent litters. One animal in the low group was found to be an outlier and was removed (Ovary_PND46_0.06_rep4)