Low doses of the food contaminant Deoxynivalenol trigger apoptosis and alter GnRH stimulation of gonadotroph cells

Abstract

The Fusarium mycotoxin Deoxynivalenol (DON) represents a significant threat to both human and animal health. It can cross the blood-brain barrier and disrupt cerebral functions. One of the main mechanisms underlying DON toxicity involves the activation of mitogen-activated protein kinases (MAPKs). Gonadotropin-Releasing Hormone (GnRH) stimulation of pituitary gonadotroph cells to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH) triggers the MAPKs pathway too. Yet, no research investigated the endocrine-disrupting effects of DON on pituitary gonadotropins. To address this gap, our study investigated the effects of DON on gonadotroph cell viability, and its impact on the GnRH-stimulated secretion of FSH and LH, using the murine gonadotroph LβT2 cells. Our results uncovered that low-dose exposure to DON (1nM) significantly impairs viability in gonadotroph cells at both 24 and 48 h. Moreover, exposure to DON shows to induce membrane phosphatidylserine translocation without loss of membrane integrity, supporting a DON-induced cytotoxicity through apoptosis initiation. Furthermore, DON specifically inhibits GnRH-induced Erk phosphorylation, while leaving p38 unaffected. Subsequent experiments with DON-treated LβT2 cells stimulated with GnRH showed a dose-dependent reduction in gene expression associated Gonadotropin-Releasing Hormone receptor (GnRHr), Luteinizing Hormone subunit beta (LHβ), and Glycoprotein Hormones, alpha subunit (Cgα), along with a reduction in LH production. Our findings underscore the induction of DON cytotoxicity through active apoptosis and its impact on LH secretion by inhibiting Erk phosphorylation within the MAPKs pathway. This research contributes to a better understanding of the neurotoxic effects of DON and establishes a foundation for further studies exploring the neuroendocrine impact of mycotoxins.