Perfluorooctanoic acid (PFOA) induces apoptosis by disrupting mitochondrial function via the SIRT1/FOXO1-SOD2 pathway in human granulosa cells: Implications for PCOS

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-07-07 DOI:10.1016/j.reprotox.2025.108986

Yumeng Ren , Yun Liang , Shuyi Zhang , Fumei Gao

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引用次数: 0

Abstract

Perfluorooctanoic acid (PFOA), a widely used perfluoroalkyl substance (PFAS), has been associated with adverse reproductive health outcomes, including polycystic ovary syndrome (PCOS). However, the molecular mechanisms remain poorly understood. In this study, we explored the effects of PFOA exposure on granulosa cell apoptosis, a key contributor to PCOS pathogenesis. Human ovarian granulosa-like tumor cell line (KGN) was exposed to PFOA (0–100 μM), resulting in a significant increase in cell apoptosis and impaired mitochondrial function, as evidenced by elevated reactive oxygen species (ROS) levels, decreased mitochondrial membrane potential (MMP), and reduced adenosine triphosphate (ATP) production. Mechanistically, PFOA exposure led to the downregulation of the SIRT1/FOXO1–SOD2 signaling pathway. Notably, activation of this pathway via pharmacological agonizts attenuated PFOA-induced apoptosis and restore mitochondrial function. These findings demonstrate that PFOA exposure can induce granulosa cell apoptosis by downregulating the SIRT1/FOXO1-SOD2 pathway, leading to impaired mitochondrial antioxidant capacity. This study provides novel mechanistic insights into the reproductive toxicity of PFOA and its potential role in the etiology of PCOS.

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全氟辛酸（PFOA）通过SIRT1/FOXO1-SOD2途径破坏人颗粒细胞的线粒体功能诱导细胞凋亡：对PCOS的影响

全氟辛酸（PFOA）是一种广泛使用的全氟烷基物质（PFAS），与不利的生殖健康结果有关，包括多囊卵巢综合征（PCOS）。然而，分子机制仍然知之甚少。在这项研究中，我们探讨了PFOA暴露对颗粒细胞凋亡的影响，颗粒细胞凋亡是PCOS发病的关键因素。人卵巢颗粒样肿瘤细胞系（KGN）暴露于PFOA（0-100 μM）中，细胞凋亡显著增加，线粒体功能受损，表现为活性氧（ROS）水平升高，线粒体膜电位（MMP）降低，三磷酸腺苷（ATP）生成减少。机制上，PFOA暴露导致SIRT1/ FOXO1-SOD2信号通路下调。值得注意的是，通过药物激活该途径可以减轻pfoa诱导的细胞凋亡并恢复线粒体功能。这些结果表明，PFOA暴露可通过下调SIRT1/FOXO1-SOD2通路诱导颗粒细胞凋亡，导致线粒体抗氧化能力受损。本研究为PFOA的生殖毒性及其在PCOS病因学中的潜在作用提供了新的机制见解。

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

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.