Chlorpyrifos induces spermatogenic dysfunction via ferroptosis in Sertoli cells

IF 6.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yan Fu , Xu Huang , Siyuan Wang , Qitong Guo , Yuhao Wu , Xiangqin Zheng , Junke Wang , Shengde Wu , Lianju Shen , Guanghui Wei
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Abstract

Chlorpyrifos (CPF), a widely used organophosphate pesticide, accumulates in the environment and affects human health. Its neurotoxicity has been extensively studied, and recent research has revealed that it can also lead to abnormal spermatogenesis. However, the factors and molecular mechanisms involved remain unclear. In this study, male Sprague–Dawley rats were gavaged with different concentrations of CPF for 30 days, resulting in a disrupted blood-testis barrier (BTB) and abnormal spermatogenesis. RNA sequencing analysis of Sertoli cells, the primary components of the BTB and key targets of environmental toxins, revealed that ferroptosis-related genes were predominantly among the differentially expressed genes. The expression of ferroptosis-related markers was up-regulated, malondialdehyde and Fe2+ levels were elevated, and glutathione levels were reduced in CPF-exposed testicular tissue and its metabolite TCP-exposed Sertoli cells, confirming that CPF exposure triggered ferroptosis in testes and Sertoli cells. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, restored Sertoli cell junctional function. Given the important roles of clockophagy and the HIF-1α pathway in ferroptosis, we investigated the activity of clockophagy in testes and Sertoli cells. Unexpectedly, clockophagy activity was found to be enhanced by the significantly reduced expression levels of ARNTL and HIF-1α following CPF and TCP exposure. Notably, Arntl knockdown impaired Sertoli cell junctional function. Collectively, these findings strongly indicate that CPF induces ferroptosis in Sertoli cells through activating clockophagy, resulting in the decreased expression of HIF-1α and BTB-associated proteins; this ultimately leads to the disruption of BTB integrity and spermatogenesis dysfunction.
毒死蜱通过支持细胞的铁下垂诱导生精功能障碍
毒死蜱(Chlorpyrifos, CPF)是一种广泛使用的有机磷农药,在环境中积累,影响人体健康。它的神经毒性已被广泛研究,最近的研究表明,它还可以导致异常的精子生成。然而,相关因素和分子机制尚不清楚。本研究用不同浓度CPF灌胃雄性sd大鼠30 d,造成血睾丸屏障(BTB)破坏和精子发生异常。对BTB的主要组成部分和环境毒素的关键靶点Sertoli细胞的RNA测序分析显示,在差异表达基因中,铁中毒相关基因占主导地位。CPF暴露的睾丸组织及其代谢物tcp暴露的Sertoli细胞中,铁中毒相关标志物表达上调,丙二醛和Fe2+水平升高,谷胱甘肽水平降低,证实CPF暴露引发睾丸和Sertoli细胞铁中毒。此外,用铁他汀-1(一种铁下垂抑制剂)治疗,恢复了Sertoli细胞的连接功能。鉴于时钟自噬和HIF-1α通路在铁下垂中的重要作用,我们研究了时钟自噬在睾丸和支持细胞中的活性。出乎意料的是,CPF和TCP暴露后,ARNTL和HIF-1α的表达水平显著降低,时钟吞噬活性增强。值得注意的是,Arntl敲低会损害支持细胞的连接功能。综上所述,这些发现强烈表明,CPF通过激活时钟吞噬诱导支持细胞铁下垂,导致HIF-1α和btb相关蛋白的表达降低;这最终导致BTB完整性的破坏和精子发生功能障碍。
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来源期刊
Genes & Diseases
Genes & Diseases Multiple-
CiteScore
7.30
自引率
0.00%
发文量
347
审稿时长
49 days
期刊介绍: Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. Aims and Scopes Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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