Environmental pollutants affect the hypothalamic GnRH system development

Several environmental pollutants may act as endocrine disruptor chemicals causing adverse effects on many physiological functions, including reproduction. Indeed, there is growing evidence that hazardous environmental contaminants, such as polycyclic aromatic hydrocarbons (PAHs) and heavy metals may affect neuroendocrine circuits controlling the reproductive axis. In particular, the hypothalamic gonad- otropin-releasing hormone (GnRH) system appeared as a critical target. Using human fetal GnRH neuroblasts (FNCB4), we already demonstrated that benzo(a) pyrene (BaP), a prototypic PAH, affects their migratory properties, thus interfering with a crucial step of GnRH neuron maturation [1-2]. Moreover, BaP altered the ability of these neurons to respond to kisspeptin, the main physiological regulator of GnRH neuron activity. Here, we extended our studies analyzing the effect of cadmium (Cd), the main heavy metal environmental toxicant of anthropogenic origin, on FNCB4 maturation. Cd (10μM, 24h) induced oxidative stress and COX2 mRNA increase in FNCB4, as well as altered cell membrane properties and excitability. As a functional effect, Cd significantly reduced FNCB4 migration, and the expression of genes crucially involved in this process during fetal development. Cd- treated FNCB4 also exhibited cytoskeletal F-actin disassembly and a significantly increased NCAM1 mRNA expression, while Cd exposure significantly reduced GnRH and kisspeptin receptor (KISS1R) expression. Cd also affected the formation of primary cilium, a sensory no-motile organelle required for neurogenesis and KISS1R signaling in GnRH neurons. In conclusion, our data suggest that exposure to environmental toxicants, especially during fetal development, may influence human reproductive function.