In Utero and Lactational Exposure to Flame Retardants Disrupts Rat Ovarian Follicular Development and Advances Puberty

Abstract

Abstract Brominated flame retardants (BFRs), including polybrominated diphenyl ethers and hexabromocyclododecane, 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 diets formulated to deliver nominal doses (0, 0.06, 20, or 60 mg/kg/day) of a BFR dietary mixture mimicking the relative congener levels 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 postnatal day 46 offspring revealed an increase in the incidence of abnormal follicles. A toxicogenomic 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 or 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 in the adult.