Identification of key genes involved in phthalate-induced male erectile dysfunction: Insights from network toxicology and bioinformatics analyses.

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Reproductive toxicology Pub Date : 2025-10-01 Epub Date: 2025-08-06 DOI:10.1016/j.reprotox.2025.109026
Yuqi Li, Juan Wang, Zhiyu Liu, Xinyao Zhu, Qilong Wu, Chunyang Meng, Qingfu Deng
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引用次数: 0

Abstract

Background: In recent years, phthalate plasticizers have been increasingly linked to various male reproductive health issues. However, their relationship with erectile dysfunction (ED) remains insufficiently studied. This study aims to elucidate the molecular mechanisms by which phthalate plasticizers contribute to ED.

Methods: Using a network toxicology approach, we predicted potential molecular targets of three common phthalates-DEHP, DIBP, and DMP-associated with ED through multiple online databases. Next, we integrated transcriptomic datasets from three established ED rat models (diabetic, neurogenic, and hypertensive) to identify more robust and representative candidate genes. Subsequently, LASSO and SVM-RFE machine learning algorithms were employed to screen for key phthalate related ED genes. Molecular docking was then conducted to validate the binding affinity between phthalates and these candidate targets.

Results: Network toxicology analysis identified 101 genes potentially linking phthalates to ED. Enrichment analyses revealed that these genes are primarily involved in endothelial dysfunction, oxidative stress, and cell growth regulation. From the integrated ED transcriptomic dataset, 1002 differentially expressed genes were identified, among which 12 overlapped with the phthalate-ED associated genes. These overlapping genes were closely related to neurodegenerative diseases and metabolic disorders. LASSO and SVM-RFE models further narrowed the list to four key genes: CDKN1B, IDH1, CASR, and PRNP.

Conclusion: The four key genes-CDKN1B, IDH1, CASR, and PRNP-appear to play critical roles in phthalate-induced ED. These genes are potentially involved in mechanisms such as oxidative stress dysregulation, neural injury, and endocrine disorders. Our findings provide important theoretical insights into the pathogenesis and prevention of environmentally induced ED.

邻苯二甲酸盐诱导男性勃起功能障碍的关键基因鉴定:来自网络毒理学和生物信息学分析的见解。
背景:近年来,邻苯二甲酸酯增塑剂越来越多地与各种男性生殖健康问题联系在一起。然而,它们与勃起功能障碍(ED)的关系仍未得到充分研究。本研究旨在阐明邻苯二甲酸酯增塑剂促进ED的分子机制。方法:利用网络毒理学方法,我们通过多个在线数据库预测了与ED相关的三种常见邻苯二甲酸酯- dehp, DIBP和dmp的潜在分子靶点。接下来,我们整合了三种已建立的ED大鼠模型(糖尿病、神经源性和高血压)的转录组学数据集,以确定更具稳健性和代表性的候选基因。随后,采用LASSO和SVM-RFE机器学习算法筛选邻苯二甲酸盐相关ED关键基因。然后进行分子对接以验证邻苯二甲酸酯与这些候选靶点之间的结合亲和力。结果:网络毒理学分析鉴定出101个可能与邻苯二甲酸盐与ED相关的基因。富集分析显示,这些基因主要参与内皮功能障碍、氧化应激和细胞生长调节。从整合的ED转录组数据集中,鉴定出1002个差异表达基因,其中12个与邻苯二甲酸盐ED相关基因重叠。这些重叠基因与神经退行性疾病和代谢紊乱密切相关。LASSO和SVM-RFE模型进一步将列表缩小到四个关键基因:CDKN1B、IDH1、CASR和PRNP。结论:cdkn1b、IDH1、CASR和prnp这四个关键基因似乎在邻苯二甲酸盐诱导的ED中发挥了关键作用。这些基因可能参与氧化应激失调、神经损伤和内分泌紊乱等机制。我们的研究结果为环境性男性ED的发病机制和预防提供了重要的理论见解。
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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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