Jinping Liu , Yi Cheng , Enfu Huang , Zhixiang Liu , Yun Zhou
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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.
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.