The role of nGPx4 in resisting DEHP-induced DNA damage and reducing caspase-independent cell death in male germ cells.

IF 1.6 Q3 OBSTETRICS & GYNECOLOGY
Wei Gu, Jiaxin Wang, Xinqi Liu, Huizhe Tan, Hongming Yang, Zeshan Zhu, Peng Ran, Qing Ling, Weilin Mao
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Abstract

Objective: Di(2-ethyl-hexyl) phthalate (DEHP) is a widely used plasticizer that adversely affects sperm quality and function by inducing DNA damage and caspase-independent cell death (CICD). Nuclear glutathione peroxidase 4 (nGPx4) has been implicated in maintaining the structural integrity of sperm chromatin. However, it remains unclear whether nGPx4 can counteract the DNA damage caused by DEHP exposure.

Methods: We employed a germ cell line (GC-1) spg mouse cell model engineered to overexpress nGPx4 (OE-nGPx4). The cells were subsequently exposed to DEHP and its metabolite mono-2-ethylhexyl phthalate (MEHP) to simulate the DNA-damaging effects of environmental factors on reproductive cells. Following treatment, we assessed the proportion of apoptotic cells and the extent of DNA damage using molecular biological analyses, in addition to evaluating the expression of proteins associated with the apoptotic pathway in germ cells.

Results: nGPx4 overexpression protected against DEHP-induced DNA damage in germ cells, reducing the incidence of CICD and potentially preserving sperm quality. This protective effect was mediated by enhanced chromatin condensation in mouse sperm cells and downregulation of phosphorylated H2A histone variant (γ-H2A.X). The reduction in DNA degradation is attributed to a diminished formation of the complex between γ-H2A.X and apoptosis-inducing factor (AIF), resulting in decreased DNA fragmentation. Additionally, compared to MEHP-treated cells, OE-nGPx4 cells exhibited reduced expression of Bcl 2-associated X (Bax), thereby diminishing activation of the γ-H2A.X/AIF axis.

Conclusion: Our findings suggest that nGPx4 is involved in chromatin condensation and may contribute to downregulating the AIF/γ-H2A.X axis in male germ cells, ultimately reducing DNA damage-induced CICD.

nGPx4在抵抗dehp诱导的雄性生殖细胞DNA损伤和减少caspase非依赖性细胞死亡中的作用。
目的:邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种广泛使用的增塑剂,通过诱导DNA损伤和caspase非依赖性细胞死亡(CICD)对精子质量和功能产生不利影响。核谷胱甘肽过氧化物酶4 (nGPx4)参与维持精子染色质的结构完整性。然而,目前尚不清楚nGPx4是否能抵消DEHP暴露造成的DNA损伤。方法:采用过表达nGPx4的小鼠生殖细胞系(GC-1) spg细胞模型(OE-nGPx4)。随后将细胞暴露于DEHP及其代谢物邻苯二甲酸单-2-乙基己酯(MEHP)中,以模拟环境因素对生殖细胞的dna损伤作用。治疗后,除了评估生殖细胞中凋亡通路相关蛋白的表达外,我们还使用分子生物学分析评估了凋亡细胞的比例和DNA损伤的程度。结果:nGPx4过表达可保护生殖细胞免受dehp诱导的DNA损伤,降低CICD的发生率,并可能保持精子质量。这种保护作用是通过增强小鼠精子细胞的染色质凝聚和下调磷酸化H2A组蛋白变体(γ-H2A.X)介导的。DNA降解的减少是由于γ-H2A之间复合物形成的减少。X和凋亡诱导因子(AIF),导致DNA断裂减少。此外,与mehp处理的细胞相比,OE-nGPx4细胞表现出Bcl - 2相关X (Bax)的表达降低,从而降低了γ-H2A的激活。X /如果轴。结论:nGPx4参与染色质缩聚,并可能参与AIF/γ-H2A的下调。X轴在男性生殖细胞中,最终减少DNA损伤诱导的CICD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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