Multi- and transgenerational disruption of maternal behavior and female puberty by Endocrine Disrupting Chemical (EDC) mixture exposure

Female reproductive development and maternal behavior are two intertwined phenotypes centrally controlled by the hypothalamus. Endocrine disrupting chemicals (EDC) can alter these processes especially when animals are exposed during development. We propose the concept that developmental exposure to a low environmentally relevant dose of EDC mixture induces a transgenerational alteration of female rat pubertal timing and ovarian physiology throughout epigenetic reprograming of hypothalamic Kiss1, Esr1 and Oxt1 loci. Such exposure also caused a multigenerational reduction of maternal behavior induced by the loss in hypothalamic dopaminergic signaling. Our results identify the hypothalamic Polycomb Group of epigenetic repressors as actors of this mechanism of transgenerational reproductive disruption. Using a cross-fostering approach, we identified that while the reduction in maternal phenotype was normalized in EDC exposed pups raised by unexposed dams, no reversal of the pubertal phenotype was achieved, suggesting a germline transmission of the reproductive phenotype.