基于网络毒理学、机器学习和分子对接技术的邻苯二甲酸单-(2-乙基己基)酯和邻苯二甲酸单苯酯对子宫内膜异位症的影响。

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Reproductive toxicology Pub Date : 2025-10-01 Epub Date: 2025-08-08 DOI:10.1016/j.reprotox.2025.109024
Qi Wu, Yu Meng Sun, Qiong Hua Liu, Xing Yue Zhao, Ze Li, Li Xu, Wei Shi
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引用次数: 0

摘要

邻苯二甲酸酯代谢物邻苯二甲酸单己基酯(MEHP)和邻苯二甲酸单苯酯(MBZP)广泛存在于环境中,可干扰内分泌系统并在人体组织中积累,与子宫内膜异位症的发生发展密切相关。本研究通过整合ChEMBL、STITCH等多个数据库,筛选出这两种代谢物的503个人类靶基因。在与1735个与子宫内膜异位症相关的基因交叉后,获得了50个核心基因集。GO和KEGG富集分析显示,这些基因主要参与花生四烯酸代谢、IL-17信号通路、细胞埋藏、补体-凝血级联反应等通路,参与氧化应激驱动异位子宫内膜细胞的存活、迁移和纤维化重塑过程。通过构建PPI网络和机器学习模型验证,ACE、MMP2、PPARG和SERPINE1被确定为关键枢纽蛋白。各单基因的诊断能力AUC达到0.80。分子对接实验证实,MEHP和MBZP对上述蛋白具有高亲和力(ΔG-8.5 ~ -6.3kcal/mol),为其分子调控机制提供了原子水平的证据。本研究系统阐明了邻苯二甲酸盐暴露导致子宫内膜异位症的多层次机制,提出了基于核心基因的精准诊断策略,为环境污染物相关疾病的预防和靶向治疗提供了新思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Effects of Mono- (2-ethylhexyl) phthalate and Phthalic Acid Monobenzyl Ester on endometriosis using network toxicology, machine learning and molecular docking techniques.

Phthalate metabolites Mono- (2-ethylhexyl) phthalate(MEHP) and Phthalic Acid Monobenzyl Ester (MBZP) are widely present in the environment, can interfere with the endocrine system and accumulate in human tissues, and are closely related to the occurrence and development of endometriosis. In this study, by integrating multiple databases such as ChEMBL and STITCH, 503 human target genes of the two metabolites were screened out. After intersection with 1735 genes related to endometriosis, a core gene set of 50 was obtained. GO and KEGG enrichment analyses revealed that these genes were mainly involved in pathways such as arachidonic acid metabolism, IL-17 signaling pathway, cell burial, and complement-coagulation cascade reaction, and were involved in the processes of survival, migration, and fibrotic remodeling of ectopic endometrial cells driven by oxidative stress. Through the construction of PPI networks and the validation of machine learning models, ACE, MMP2, PPARG and SERPINE1 were identified as key hub proteins.The diagnostic ability AUC of each single gene reaches 0.80.Molecular docking experiments confirmed that MEHP and MBZP have high affinity (ΔG - 8.5 to - 6.3 kcal/mol) for the above-mentioned proteins, providing atomic-level evidence for their molecular regulatory mechanisms. This study systematically elucidated the multi-level mechanisms of endometriosis caused by phthalate exposure and proposed a precise diagnostic strategy based on core genes, providing new ideas for the prevention and targeted treatment of diseases related to environmental pollutants.

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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.
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