The Role of the p62-Keap1-Nrf2 Pathway in Protecting Sertoli Cells Against Mono-(2-ethylhexyl)phthalate-induced Ferroptosis.

IF 2.8 4区医学 Q3 TOXICOLOGY

Journal of Applied Toxicology Pub Date : 2025-10-12 DOI:10.1002/jat.4963

Siyuan Wang, Dinggang Li, Wei Deng, Shengde Wu, Yi Wei, Guanghui Wei

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引用次数: 0

Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer linked to testicular toxicity. Mono-(2-ethylhexyl) phthalate (MEHP) is the main bioactive metabolite of DEHP. The aim of this study was to investigate the protective role of the p62-Keap1-Nrf2 pathway against ferroptosis in Sertoli cells, which are crucial for normal testicular function, utilizing a cell model of MEHP-induced damage. Sertoli cells were treated with MEHP in vitro to assess the effects of MEHP on cell viability, the occurrence of ferroptosis, and the activation status of the p62-Keap1-Nrf2 pathway. Exposure to MEHP resulted in elevated levels of lipid peroxidation and indicators of iron accumulation in Sertoli cells, indicating oxidative stress and cell death associated with iron overload. Following p62 and Nrf2 gene knockdown in Sertoli cells, MEHP-induced ferroptosis was exacerbated. The p62-Keap1-Nrf2 signaling pathway played a critical role in protecting Sertoli cells from MEHP-induced ferroptosis, potentially mitigating testicular injury in mice. These findings elucidate the molecular mechanisms underlying MEHP toxicity and reveal potential therapeutic strategies for preventing testicular dysfunction associated with MEHP exposure.

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p62-Keap1-Nrf2通路在保护支持细胞免受邻苯二甲酸单-（2-乙基己基）盐诱导的铁凋亡中的作用

邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛使用的增塑剂，与睾丸毒性有关。邻苯二甲酸单-（2-乙基己基）酯（MEHP）是DEHP的主要生物活性代谢物。本研究的目的是利用mehp诱导的细胞损伤模型，研究p62-Keap1-Nrf2通路对睾丸正常功能至关重要的支持细胞铁凋亡的保护作用。在体外用MEHP处理支持细胞，评估MEHP对细胞活力、铁凋亡的发生以及p62-Keap1-Nrf2通路激活状态的影响。暴露于MEHP导致Sertoli细胞中脂质过氧化水平升高和铁积累指标升高，表明氧化应激和细胞死亡与铁过载有关。在Sertoli细胞中敲低p62和Nrf2基因后，mehp诱导的铁下垂加重。p62-Keap1-Nrf2信号通路在保护Sertoli细胞免受mehp诱导的铁凋亡中发挥了关键作用，可能减轻小鼠睾丸损伤。这些发现阐明了MEHP毒性的分子机制，并揭示了预防MEHP暴露相关睾丸功能障碍的潜在治疗策略。

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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来源期刊

Journal of Applied Toxicology 医学-毒理学

CiteScore

7.00

自引率

6.10%

发文量

145

审稿时长

1 months

期刊介绍： Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.