Onset of puberty strongly depends on organizational processes taking place during the fetal and early postnatal life. Therefore, exposure to environmental pollutants such as Endocrine disrupting chemicals during critical periods of development can result in delayed/advanced puberty and long-term reproductive consequences. Human evidence of altered pubertal timing after exposure to endocrine disrupting chemicals is equivocal. However, the age distribution of pubertal signs points to a skewed distribution towards earliness for initial pubertal stages and towards lateness for final pubertal stages. Such distortion of distribution is a recent phenomenon and suggests environmental influences including the possible role of nutrition, stress and endocrine disruptors. Some rodent and ovine studies indicate a possible role of fetal and neonatal exposure to EDCs, along the concept of early origin of health and disease. Such effects involve neuroendocrine mechanisms at the level of the hypothalamus where homeostasis of reproduction is programmed and regulated. We have shown that neonatal exposure to the ubiquitous endocrine disruptor Bisphenol A (BPA) leads to opposing dose-dependent effects on the neuroendocrine control of puberty in the female rat. In particular, a very low and environmentally relevant dose of BPA delayed neuroendocrine reproductive maturation through increased inhibitory GABAergic neurotransmission. More recently, we studied the effect of a mixture of endocrine disrupting chemicals on female sexual development during three generations. Female rats (F0 generation) were orally exposed to a mixture of 14 anti-androgenic and estrogenic EDCs or corn oil for 2 weeks before and throughout gestation and until weaning. While F2 and F3 females showed delayed vaginal opening, decreased percentage of regular estrous cycles and decreased GnRH interpulse interval, no such changes were detected in F1 animals. These reproductive phenotypes were associated with alterations in both transcriptional and histone posttranslational modifications of hypothalamic genes involved in reproductive competence. F1 females that were exposed in utero to the EDC mixture, showed a reduction in thyroxin hydroxylase mRNA expression and impaired maternal behavior. Overall, our data shows that gestational and lactational exposure to an environmentally relevant EDC mixture transgenerationally affects sexual development throughout epigenetic reprogramming of the hypothalamus. Such effects could be mediated by alterations of maternal behavior caused by exposure of the first generation to the EDC mixture.
18 - 21 May 2019
European Society of Endocrinology