Benzo[a]pyrene alters electrophysiological properties and GnRH release in hfHypo cells.

Benzo[a]pyrene (BaP) is a widespread pollutant that can act as endocrine disrupting chemical (EDC) and interfere with reproductive function and embryo development. To date, the study of BaP effects on human reproductive axis at central level is lacking. The central regulatory network of the reproductive system is mediated by gonadotropin-releasing hormone (GnRH) neurons, which release in a pulsatile manner the GnRH into the hypothalamic-hypophyseal portal circulation and maintain the reproductive function. Here, we investigated the effects of BaP on GnRH neuron function taking advantage of a primary culture isolated from the human fetal hypothalamus (hfHypo). hfHypo cells express the enzymes cytochrome P450 (CYP1A1 and CYP1B1), required for metabolic activation of BaP and that expression was strongly induced by Bap exposure (10 µM, 24h). From a functional point of view, BaP exposure significantly reduced the mRNA level of the kisspeptin receptor (KISS1R), the main physiological regulator of GnRH neuron function. Interestingly, BaP increased phospho-ERK1/2 signaling which is a known intracellular mechanism associated with KISS1R by Kisspeptin activation. Moreover, BaP induced changes in electrophysiological membrane properties causing a significant depolarizing effect and significantly increased GnRH secretion, with both effects being not changed by the addiction of kisspeptin. In conclusion, our findings demonstrate that BaP may affect GnRH neuron function by altering electrophysiological properties and interfering with KISS1R signaling and GnRH secretion, suggesting a possible EDCs-related mechanism at central level underlying reproductive function alterations.