We are all living with hundreds of anthropogenic chemicals in our bodies every day, a situation that threatens the reproductive health of present and future generations. This review focuses on endocrine-disrupting compounds (EDCs), both naturally occurring and man-made, and summarizes how they interfere with the neuroendocrine system to adversely impact pregnancy outcomes, semen quality, age at puberty, and other aspects of human reproductive health. While obvious malformations of the genitals and other reproductive organs are a clear sign of adverse reproductive health outcomes and injury to brain sexual differentiation, the hypothalamic-pituitary-gonadal (HPG) axis can be much more difficult to discern, particularly in humans. It is well-established that, over the course of development, gonadal hormones shape the vertebrate brain such that sex-specific reproductive physiology and behaviors emerge. Decades of work in neuroendocrinology have elucidated many of the discrete and often very short developmental windows across pre- and postnatal development in which this occurs. This has allowed toxicologists to probe how EDC exposures in these critical windows can permanently alter the structure and function of the HPG axis. This review includes a discussion of key EDC principles including how latency between exposure and the emergence of consequential health effects can be long, along with a summary of the most common and less well-understood EDC modes of action. Extensive examples of how EDCs are impacting human reproductive health, and evidence that they have the potential for multi-generational physiological and behavioral effects are also provided.
Wendy N Jefferson, Heather B Patisaul, and Carmen J Williams
Phytoestrogens, estrogenic compounds derived from plants, are ubiquitous in human and animal diets. These chemicals are generally much less potent than estradiol but act via similar mechanisms. The most common source of phytoestrogen exposure to humans is soybean-derived foods that are rich in the isoflavones genistein and daidzein. These isoflavones are also found at relatively high levels in soy-based infant formulas. Phytoestrogens have been promoted as healthy alternatives to synthetic estrogens and are found in many dietary supplements. The aim of this review is to examine the evidence that phytoestrogen exposure, particularly in the developmentally sensitive periods of life, has consequences for future reproductive health.
Jinyan Cao, Linwood Joyner, Jillian A Mickens, Stephanie M Leyrer, and Heather B Patisaul
Perinatal life is a critical window for sexually dimorphic brain organization, and profoundly influenced by steroid hormones. Exposure to endocrine-disrupting compounds may disrupt this process, resulting in compromised reproductive physiology and behavior. To test the hypothesis that neonatal bisphenol A (BPA) exposure can alter sex-specific postnatal Esr2 (Erβ) expression in brain regions fundamental to sociosexual behavior, we mapped Esr2 mRNA levels in the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), paraventricular nucleus (PVN), anterior portion of the medial amygdaloid nucleus (MeA), super optic nucleus, suprachiasmatic nucleus, and lateral habenula across postnatal days (PNDs) 0–19. Next, rat pups of both sexes were subcutaneously injected with 10 μg estradiol benzoate (EB), 50 μg/kg BPA (LBPA), or 50 mg/kg BPA (HBPA) over the first 3 days of life and Esr2 levels were quantified in each region of interest (ROI) on PNDs 4 and 10. EB exposure decreased Esr2 signal in most female ROIs and in the male PVN. In the BNSTp, Esr2 expression decreased in LBPA males and HBPA females on PND 10, thereby reversing the sex difference in expression. In the PVN, Esr2 mRNA levels were elevated in LBPA females, also resulting in a reversal of sexually dimorphic expression. In the MeA, BPA decreased Esr2 expression on PND 4. Collectively, these data demonstrate that region- and sex-specific Esr2 expression is vulnerable to neonatal BPA exposure in regions of the developing brain critical to sociosexual behavior in rat.