Estrogen receptor 1 (ESR1) promotes Di-butyl phthalate (DBP)-induced hypospadias by regulating mitophagy through PINK1-Parkin axis to inhibit ferroptosis

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Jinping Liu , Yi Cheng , Enfu Huang , Zhixiang Liu , Yun Zhou
{"title":"Estrogen receptor 1 (ESR1) promotes Di-butyl phthalate (DBP)-induced hypospadias by regulating mitophagy through PINK1-Parkin axis to inhibit ferroptosis","authors":"Jinping Liu ,&nbsp;Yi Cheng ,&nbsp;Enfu Huang ,&nbsp;Zhixiang Liu ,&nbsp;Yun Zhou","doi":"10.1016/j.reprotox.2025.109036","DOIUrl":null,"url":null,"abstract":"<div><div>This study reveals how Di-butyl phthalate (DBP), an estrogen-mimicking environmental pollutant, induces hypospadias by inhibiting ferroptosis through ESR1 activation and PINK1-Parkin-dependent mitophagy. Utilizing a prenatal DBP-exposed fetal rat hypospadias model, we observed significant downregulation of pro-ferroptotic ACSL4 and upregulation of anti-ferroptotic GPX4/SLC7A11 in urethral tissues, alongside elevated oxidative stress markers (MDA, Fe²⁺) and reduced glutathione (GSH). In vitro experiments using rat urethral plate fibroblasts (RUPFs) demonstrated that DBP enhanced ferroptosis resistance and promoted proliferation at concentrations below 200 μM. Mechanistically, DBP activated ESR1, which triggered mitophagy via the PINK1-Parkin pathway, reducing mitochondrial damage and reactive oxygen species (ROS) accumulation, thereby suppressing ferroptosis. Inhibition or silencing of ESR1 reversed these effects, restoring ferroptosis sensitivity and oxidative stress. These findings unveil a novel ESR1-mitophagy-ferroptosis regulatory axis, linking DBP exposure to hypospadias pathogenesis. The study not only elucidates a previously unrecognized molecular pathway underlying phthalate-induced congenital malformations but also identifies ESR1 and mitophagy as potential therapeutic targets. By integrating in vivo and in vitro approaches, this work advances the understanding of environmental endocrine disruptors’ role in developmental toxicity and provides actionable insights for mitigating their health impacts, aligning with current priorities in reproductive and environmental health research.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"137 ","pages":"Article 109036"},"PeriodicalIF":2.8000,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reproductive toxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0890623825002072","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

This study reveals how Di-butyl phthalate (DBP), an estrogen-mimicking environmental pollutant, induces hypospadias by inhibiting ferroptosis through ESR1 activation and PINK1-Parkin-dependent mitophagy. Utilizing a prenatal DBP-exposed fetal rat hypospadias model, we observed significant downregulation of pro-ferroptotic ACSL4 and upregulation of anti-ferroptotic GPX4/SLC7A11 in urethral tissues, alongside elevated oxidative stress markers (MDA, Fe²⁺) and reduced glutathione (GSH). In vitro experiments using rat urethral plate fibroblasts (RUPFs) demonstrated that DBP enhanced ferroptosis resistance and promoted proliferation at concentrations below 200 μM. Mechanistically, DBP activated ESR1, which triggered mitophagy via the PINK1-Parkin pathway, reducing mitochondrial damage and reactive oxygen species (ROS) accumulation, thereby suppressing ferroptosis. Inhibition or silencing of ESR1 reversed these effects, restoring ferroptosis sensitivity and oxidative stress. These findings unveil a novel ESR1-mitophagy-ferroptosis regulatory axis, linking DBP exposure to hypospadias pathogenesis. The study not only elucidates a previously unrecognized molecular pathway underlying phthalate-induced congenital malformations but also identifies ESR1 and mitophagy as potential therapeutic targets. By integrating in vivo and in vitro approaches, this work advances the understanding of environmental endocrine disruptors’ role in developmental toxicity and provides actionable insights for mitigating their health impacts, aligning with current priorities in reproductive and environmental health research.
雌激素受体1 (ESR1)通过PINK1-Parkin轴调控丝裂,促进邻苯二甲酸二丁酯(DBP)诱导的尿道下裂,抑制铁下垂
本研究揭示了邻苯二甲酸二丁酯(DBP)是一种模拟雌激素的环境污染物,它是如何通过ESR1激活和pink1 - parkin依赖的有丝分裂抑制铁下沉,从而诱导尿道下裂的。利用产前dbp暴露的胎鼠尿道下裂模型,我们观察到尿道组织中促铁性ACSL4显著下调,抗铁性GPX4/SLC7A11上调,同时氧化应激标志物(MDA、Fe 2 +)和还原性谷胱甘肽(GSH)升高。大鼠尿道板成纤维细胞(RUPFs)体外实验表明,浓度低于200 μM的DBP可增强铁下垂抵抗并促进增殖。在机制上,DBP激活ESR1,通过PINK1-Parkin途径触发线粒体自噬,减少线粒体损伤和活性氧(ROS)积累,从而抑制铁下垂。抑制或沉默ESR1可逆转这些作用,恢复铁下垂敏感性和氧化应激。这些发现揭示了一个新的esr1 -有丝分裂-铁下垂调节轴,将DBP暴露与尿道下裂发病机制联系起来。该研究不仅阐明了邻苯二甲酸盐诱导先天性畸形的先前未被认识的分子途径,而且还确定了ESR1和线粒体自噬作为潜在的治疗靶点。通过整合体内和体外方法,这项工作促进了对环境内分泌干扰物在发育毒性中的作用的理解,并为减轻其对健康的影响提供了可行的见解,与当前生殖和环境健康研究的优先事项保持一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Reproductive toxicology
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信