Deoxynivalenol exposure promotes apoptosis and disrupts GnRH-dependent LH production in pituitary gonadotrope-like cells.
Deoxynivalenol exposure can compromise cell viability and disrupt hormone production in pituitary cells, but the implications for human health are not fully understood.
Where it sits
this study against the rest of the gonadorelin (gnrh) corpusSummary and findings
This study examined the effects of deoxynivalenol (DON) on murine gonadotrope-like LβT2 cells, focusing on cell viability and GnRH-induced LH production. Exposure to DON compromised cell viability at nanomolar concentrations and reduced LH production at higher concentrations. The findings suggest that DON disrupts GnRH-dependent endocrine function.
Abstract
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.
Background
This paper addresses the endocrine-disrupting effects of deoxynivalenol (DON), a prevalent mycotoxin, on reproductive function. Prior knowledge indicates that DON activates mitogen-activated protein kinases (MAPKs), which are critical for gonadotropin-releasing hormone (GnRH)-dependent hormone synthesis. Understanding the direct effects of DON on pituitary gonadotropin production is essential for assessing its impact on reproductive health.
Methods
The study utilized murine gonadotrope-like LβT2 cells to assess the effects of DON exposure. Specific concentrations of DON were applied to evaluate cell viability and GnRH-induced LH production. The primary outcome measures included cell viability and levels of LH production in response to GnRH stimulation.
Results
Exposure to DON compromised cell viability at nanomolar concentrations. LH production was reduced in a concentration-dependent manner at higher concentrations. The study noted that distinct biological endpoints had different sensitivity thresholds, with viability being affected at lower concentrations than those required for altering GnRH-dependent signaling.
Interpretation
The findings indicate that DON directly targets pituitary gonadotrope-like cells, disrupting GnRH-dependent endocrine function. While the study provides insights into the mechanisms of DON-induced reproductive dysfunction, the effect sizes may not be clinically meaningful due to the use of murine models and in vitro conditions. The limitations include potential confounds from the experimental design and the need for further studies to confirm these findings in vivo.
Key findings
- DON compromised cell viability at nanomolar concentrations.
- LH production was reduced in a concentration-dependent manner at higher concentrations of DON.
- Distinct biological endpoints displayed different sensitivity thresholds.
- Viability was affected at lower concentrations than those required to alter GnRH-dependent signaling.
- DON promoted an apoptotic phenotype and attenuated GnRH-induced ERK phosphorylation.
Limitations
- Conducted in murine cells, not human subjects.
- Concentrations may not reflect in vivo exposure levels.
- Short-term exposure does not assess long-term effects.
- Single-cell line used may limit generalizability.