{"title":"Integrative computational dissection of monobenzyl phthalate spermatotoxicity: High-affinity binding disrupts ACE2-CYP17A1 coregulation in non-obstructive azoospermia","authors":"Guangqiang Zhu , Chunlin Tan , Yugen Li","doi":"10.1016/j.reprotox.2025.109063","DOIUrl":null,"url":null,"abstract":"<div><div>Phthalates, as typical environmental endocrine disruptors, can lead to reproductive toxicity by disrupting human endocrine homeostasis with their metabolites. However, the complexity of human co-exposure to multiple metabolites, confounding biases in traditional studies, and reverse causality issues obscure the causative contributions and pathogenic mechanisms of key toxic metabolites. This study employs a multi-omics integrative strategy, leveraging Mendelian Randomization (MR) to identify Monobenzyl phthalate (MBzP) as a causative risk factor for testicular damage (β = 1.26, P = 0.002). Focusing on Non-obstructive azoospermia (NOA), we integrated network toxicology to identify 15 shared molecular targets. By combining interpretable machine learning, we discovered that core targets ACE2/CYP17A1 are significantly overexpressed in Sertoli cells. Gene Set Enrichment Analysis (GSEA) of single genes revealed critical pathway differentiation: low expression states activate spermatogenesis pathways, while high expression drives inflammatory-apoptotic networks (TGF-β, p53 pathways, interferon response). Molecular docking and dynamics simulation (MDS) confirmed that MBzP forms stable complexes with ACE2 (binding energy = −7.2 kcal/mol) and CYP17A1 (binding energy = −7.5 kcal/mol), interfering with their physiological functions through allosteric effects. This study for the first time elucidates the MBzP-ACE2/CYP17A1 interaction-inflammatory/apoptotic cascade activation-spermatogenesis inhibition molecular axis, providing new targets for precise intervention in male infertility.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"138 ","pages":"Article 109063"},"PeriodicalIF":2.8000,"publicationDate":"2025-09-15","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/S0890623825002345","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
Phthalates, as typical environmental endocrine disruptors, can lead to reproductive toxicity by disrupting human endocrine homeostasis with their metabolites. However, the complexity of human co-exposure to multiple metabolites, confounding biases in traditional studies, and reverse causality issues obscure the causative contributions and pathogenic mechanisms of key toxic metabolites. This study employs a multi-omics integrative strategy, leveraging Mendelian Randomization (MR) to identify Monobenzyl phthalate (MBzP) as a causative risk factor for testicular damage (β = 1.26, P = 0.002). Focusing on Non-obstructive azoospermia (NOA), we integrated network toxicology to identify 15 shared molecular targets. By combining interpretable machine learning, we discovered that core targets ACE2/CYP17A1 are significantly overexpressed in Sertoli cells. Gene Set Enrichment Analysis (GSEA) of single genes revealed critical pathway differentiation: low expression states activate spermatogenesis pathways, while high expression drives inflammatory-apoptotic networks (TGF-β, p53 pathways, interferon response). Molecular docking and dynamics simulation (MDS) confirmed that MBzP forms stable complexes with ACE2 (binding energy = −7.2 kcal/mol) and CYP17A1 (binding energy = −7.5 kcal/mol), interfering with their physiological functions through allosteric effects. This study for the first time elucidates the MBzP-ACE2/CYP17A1 interaction-inflammatory/apoptotic cascade activation-spermatogenesis inhibition molecular axis, providing new targets for precise intervention in male infertility.
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.