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Melatonin protects Leydig cells from HT-2 toxin-induced ferroptosis and apoptosis via glucose-6-phosphate
Jianyu Ma1, Yuquan Han1, Hua Yang1
1Institute of Sheep and Goat Science, Nanjing Agricultural University, Nanjing, China.
Abstract:
HT-2 toxin is a mycotoxin commonly found in food and water that can have adverse effects on male reproductive systems, including testosterone secretion. Ferroptosis and apoptosis are two types of programmed cell death that have been implicated in the regulation of cellular functions. Melatonin, a powerful antioxidant with various physiological functions, has been shown to regulate testosterone secretion. However, the mechanisms underlying the protective effects of melatonin against HT-2 toxin-induced damage in testosterone secretion are not fully understood. In this study, we investigated the effects of HT-2 toxin on sheep Leydig cells and the potential protective role of melatonin. We found that HT-2 toxin inhibited cell proliferation and testosterone secretion of Leydig cells in a dose-dependent manner and induced ferroptosis and apoptosis through intracellular reactive oxygen species accumulation, leading to lipid peroxidation. Exposure of Leydig cells to melatonin in vitro reversed the defective phenotypes caused by HT-2 toxin via a glucose-6-phosphate dehydrogenase/glutathione-dependent mechanism. Interference of glucose-6-phosphate dehydrogenase disrupted the beneficial effect of melatonin on ferroptosis and apoptosis in HT-2 toxin-treated Leydig cells. Furthermore, similar results were observed in vivo in the testes of male mice injected with HT-2 toxin with or without melatonin treatment for 30 days. Our findings suggest that melatonin inhibits ferroptosis and apoptosis by elevating the expression of glucose-6-phosphate dehydrogenase to eliminate reactive oxygen species accumulation in HT-2 toxin-treated Leydig cells. These results provide fundamental evidence for eliminating the adverse effects of HT-2 toxin on male reproduction.
Insights
Melatonin protects male reproductive health by preventing HT-2 toxin-induced cell death (ferroptosis and apoptosis) in Leydig cells. It achieves this by boosting glucose-6-phosphate dehydrogenase, reducing oxidative stress, and preserving testosterone secretion.
Area of Science:
- Reproductive Toxicology
- Cellular Biology
- Endocrinology
Background:
- HT-2 toxin, a foodborne mycotoxin, impairs male reproductive function, specifically testosterone secretion.
- Ferroptosis and apoptosis are programmed cell death pathways implicated in cellular dysfunction.
- Melatonin, an antioxidant, influences testosterone secretion, but its protective mechanisms against mycotoxins are unclear.
Purpose of the Study:
- To investigate the effects of HT-2 toxin on sheep Leydig cells and testosterone secretion.
- To determine the protective role of melatonin against HT-2 toxin-induced damage.
- To elucidate the underlying molecular mechanisms of melatonin's protective effects.
Main Methods:
- In vitro studies using sheep Leydig cells exposed to HT-2 toxin and melatonin.
- Assessment of cell proliferation, testosterone secretion, reactive oxygen species (ROS), and lipid peroxidation.
- In vivo studies in male mice treated with HT-2 toxin and melatonin.
- Investigation of the role of glucose-6-phosphate dehydrogenase (G6PD) and glutathione.
Main Results:
- HT-2 toxin inhibited Leydig cell proliferation and testosterone secretion, inducing ferroptosis and apoptosis via ROS accumulation and lipid peroxidation.
- Melatonin treatment reversed HT-2 toxin-induced defects in vitro through a G6PD/glutathione-dependent pathway.
- Melatonin's protective effects were diminished when G6PD was interfered with.
- In vivo studies corroborated the protective effects of melatonin against HT-2 toxin in mouse testes.
Conclusions:
- Melatonin protects male reproductive Leydig cells from HT-2 toxin-induced ferroptosis and apoptosis.
- Melatonin enhances G6PD expression, which aids in eliminating ROS and preventing lipid peroxidation.
- These findings highlight melatonin as a potential therapeutic agent against mycotoxin-induced male reproductive toxicity.
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