Deoxynivalenol exposure promotes apoptosis and disrupts GnRH-dependent LH production in pituitary gonadotrope-like cells.

Deoxynivalenol (DON) is a highly prevalent mycotoxin contaminating cereals and cereal-based products and is increasingly recognized for its adverse effects on reproductive function. DON is known to activate mitogen-activated protein kinases (MAPKs), which are also critical mediators of gonadotropin-releasing hormone (GnRH)-dependent synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by pituitary gonadotrope cells. Despite this mechanistic overlap, the direct endocrine-disrupting effects of DON on pituitary gonadotropin production remain poorly understood. Here, we demonstrate that exposure of murine gonadotrope-like LβT2 cells to DON compromises cell viability at nanomolar concentrations and reduces GnRH-induced LH production at higher concentrations in a concentration-dependent manner. Notably, distinct biological endpoints displayed different sensitivity thresholds, with viability being affected at lower concentrations than those required to alter GnRH-dependent signaling and hormone production. Mechanistically, DON promotes an apoptotic phenotype and selectively attenuates GnRH-induced extracellular signal-regulated kinase (ERK) phosphorylation. This attenuation of GnRH-induced ERK activation was associated with reduced expression of Cga and Lhb, two key genes involved in LH synthesis and secretion. Collectively, these findings identify the pituitary gland as a direct target of DON toxicity and provide evidence that DON directly targets pituitary gonadotrope-like cells and can disrupt GnRH-dependent endocrine function under exposure conditions that impair intracellular signaling and hormone production, thereby expanding current understanding of the neuroendocrine mechanisms underlying DON-induced reproductive dysfunction.