Melatonin protects Leydig cells from HT-2 toxin-induced ferroptosis and apoptosis via glucose-6-phosphate dehydrogenase/glutathione -dependent pathway

Elsevier

Available online 4 April 2023, 106410

The International Journal of Biochemistry & Cell BiologyAuthor links open overlay panel, , , , , 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.

Section snippetsIntroducion

HT-2 toxin, a type A trichothecene mycotoxins produced by Fusarium, is a widespread contaminant of animal feed and food products (Ok et al., 2013). It has become a serious problem in Europe and China due to its contamination of grains and drinking water (Langseth and Rundberget, 1999, Pleadin et al., 2017). HT-2 toxin has been shown to cause male reproductive toxicity in rabbits by suppressing spermatogenesis and testosterone secretion (Kolesarova et al., 2017). Due to its high activity of

Animals

The experimental procedures conducted on the male mice aged six weeks were performed in strict adherence to the guidelines established by the Animal Research Institute Committee of Nanjing Agricultural University, China. The 6 week-aged male mice were provided with ad libitum access to food and water and were housed in a controlled environment maintained at a temperature of 22 ± 2°C, with a lighting cycle of 12 hours per day throughout the duration of the experiment.

HT-2 toxin and melatonin treatment

For in vivo treatment, HT-2

HT-2 toxin inhibited cell proliferation and testosterone secretion of LCs in vitro

In vitro analysis was conducted to investigate the effects of HT-2 toxin on cell viability, testosterone secretion, and cell proliferation. As depicted in Fig. 1 A, a gradual decline in cell viability was observed with an increase in HT-2 toxin concentration from 0 nM to 400 nM. Moreover, the treatment with HT-2 toxin resulted in a significant decrease in the concentration of testosterone in the culture medium as illustrated in Fig. 1B. Furthermore, the expression of the testosterone synthesis

Discussion

HT-2 toxin, commonly found in food and water, has been shown to have adversely effects on male reproduction, including spermatogenesis and the synthesis of male sex hormones. Our previous study demonstrated that HT-2 toxin inhibits cell viability of goat spermatogonial stem cells through AMPK-ULK1 autophagy pathways (Pang et al., 2021). Testosterone, which plays a crucial role in spermatogenesis and male function, is also likely affected by HT-2 toxin exposure, but has not been extensively

Conclusions

In summary, our study demonstrates the beneficial effects of melatonin on LCs and testes of male mice subjected to HT-2 toxin treatment, both in vitro and in vivo. We found that HT-2 toxin treatment led to the accumulation of ROS in LCs, resulting in ferroptosis and apoptosis. However, treatment with melatonin in vitro effectively reduced excessive ROS levels and inhibited ferroptosis and apoptosis in HT-2 treated LCs by activating G6PD.

CRediT authorship contribution statement

J.M. carried out the experiments and wrote the manuscript; H.Y., L.L., Y.H. and Y.W. revised the manuscript; Y.W. and Z.W. conducted the study and funded this research. All authors have reviewed the manuscript before submission.

Acknowledgments

This research was funded by Jiangsu Agricultural Industry Technology System(JATS[2021]141 and China Agriculture Research System (CARS-38)

Conflicts of Interest

The authors declare no conflict of interest.

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