Quantitative analysis and toxicological mechanisms of various male infertility inducers: A network meta-analysis and pharmacological approach

IF 3.4 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2026-03-01 Epub Date: 2025-12-05 DOI:10.1016/j.reprotox.2025.109134

Muhammad Arif Asghar , Ao Zhang , Shixin Tang , Hang Han , Bing Wan , Jingwei Wu , Li Ping Wong , Xiao Zhang , Qinjian Zhao

{"title":"Quantitative analysis and toxicological mechanisms of various male infertility inducers: A network meta-analysis and pharmacological approach","authors":"Muhammad Arif Asghar , Ao Zhang , Shixin Tang , Hang Han , Bing Wan , Jingwei Wu , Li Ping Wong , Xiao Zhang , Qinjian Zhao","doi":"10.1016/j.reprotox.2025.109134","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Male infertility is a global health concern, accounting for nearly half of all infertility cases. This study evaluates the toxicological effects of key infertility inducers in rodent models and explores underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>A systematic review and network meta-analysis (NMA) compared nine widely studied inducers: environmental toxicants (Bisphenol-A, Lead acetate, microplastics), pharmacological agents (Cyclophosphamide, Streptozotocin, Valproic acid, Tripterygium glycosides), and metabolic/physical stressors (High-Fat Diet, heat stress). Key endpoints included sperm count, motility, morphology, testis weight, and hormone levels. Network pharmacology and enrichment analyses identified molecular pathways, focusing on oxidative stress. Clinical relevance was assessed based on mechanistic alignment with human infertility.</div></div><div><h3>Results</h3><div>A total of 201 studies involving 3412 rodents were analyzed. NMA revealed significant differences in reproductive toxicity among inducers. Cyclophosphamide, STZ, and microplastics caused the most severe impairments, reducing sperm counts to 30.08 ± 19.1, 38.13 ± 8.2, and 18.97 ± 11.1 × 10⁶/mL, and motility to 31.73 ± 6.1 %, 30.74 ± 4.1 %, and 31.32 ± 10.2 %, respectively. Overall, sperm count, motility, and testosterone decreased by 1.46-, 1.21-, and 1.16-fold. Network pharmacology identified oxidative stress-related genes (NFE2L2, SOD1, HMOX1) as common targets, with oxidative stress emerging as shared mechanistic pathways. Trend analysis (2009–2024) revealed rising research on microplastics, HFD, and Lead acetate.</div></div><div><h3>Conclusions</h3><div>This first integrated toxicological and mechanistic analysis elucidates how diverse inducers impair male reproductive health. Oxidative stress contributes to toxicity, highlighting potential molecular targets for therapy. Findings support the translational relevance of rodent infertility models and guide risk assessment and mitigation strategies for stressors.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109134"},"PeriodicalIF":3.4000,"publicationDate":"2026-03-01","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/S0890623825003053","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/12/5 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"REPRODUCTIVE BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Male infertility is a global health concern, accounting for nearly half of all infertility cases. This study evaluates the toxicological effects of key infertility inducers in rodent models and explores underlying molecular mechanisms.

Methods

A systematic review and network meta-analysis (NMA) compared nine widely studied inducers: environmental toxicants (Bisphenol-A, Lead acetate, microplastics), pharmacological agents (Cyclophosphamide, Streptozotocin, Valproic acid, Tripterygium glycosides), and metabolic/physical stressors (High-Fat Diet, heat stress). Key endpoints included sperm count, motility, morphology, testis weight, and hormone levels. Network pharmacology and enrichment analyses identified molecular pathways, focusing on oxidative stress. Clinical relevance was assessed based on mechanistic alignment with human infertility.

Results

A total of 201 studies involving 3412 rodents were analyzed. NMA revealed significant differences in reproductive toxicity among inducers. Cyclophosphamide, STZ, and microplastics caused the most severe impairments, reducing sperm counts to 30.08 ± 19.1, 38.13 ± 8.2, and 18.97 ± 11.1 × 10⁶/mL, and motility to 31.73 ± 6.1 %, 30.74 ± 4.1 %, and 31.32 ± 10.2 %, respectively. Overall, sperm count, motility, and testosterone decreased by 1.46-, 1.21-, and 1.16-fold. Network pharmacology identified oxidative stress-related genes (NFE2L2, SOD1, HMOX1) as common targets, with oxidative stress emerging as shared mechanistic pathways. Trend analysis (2009–2024) revealed rising research on microplastics, HFD, and Lead acetate.

Conclusions

This first integrated toxicological and mechanistic analysis elucidates how diverse inducers impair male reproductive health. Oxidative stress contributes to toxicity, highlighting potential molecular targets for therapy. Findings support the translational relevance of rodent infertility models and guide risk assessment and mitigation strategies for stressors.

查看原文本刊更多论文

各种男性不育诱导剂的定量分析和毒理学机制：网络荟萃分析和药理学方法

男性不育症是一个全球性的健康问题，占所有不育症病例的近一半。本研究在啮齿动物模型中评估了主要不育诱导剂的毒理学效应，并探讨了其潜在的分子机制。方法系统回顾和网络荟萃分析（NMA）比较了9种广泛研究的诱导因子：环境毒物（双酚a、醋酸铅、微塑料）、药物（环磷酰胺、链脲佐菌素、丙戊酸、雷公藤苷）和代谢/物理应激因子（高脂肪饮食、热应激）。关键终点包括精子数量、活力、形态、睾丸重量和激素水平。网络药理学和富集分析确定了分子途径，重点是氧化应激。根据与人类不孕症的机制一致性评估临床相关性。结果共分析201项研究3412只啮齿动物。NMA显示不同诱导剂的生殖毒性存在显著差异。环磷酰胺、STZ和塑料微粒引起的最严重的障碍,精子数量减少到30.08 ± 19.1,38.13 ± 8.2,和18.97 ±11.1  × 10⁶/ mL,和运动性 31.73±6.1  %,30.74 ±  % 4.1和31.32 ±10.2  %,分别。总的来说，精子数量、活力和睾丸激素分别下降了1.46倍、1.21倍和1.16倍。网络药理学发现氧化应激相关基因（NFE2L2, SOD1, HMOX1）是共同的靶点，氧化应激是共同的机制途径。趋势分析（2009-2024）显示，对微塑料、HFD和醋酸铅的研究正在增加。结论首次综合毒理学和机制分析阐明了不同诱导剂如何损害男性生殖健康。氧化应激有助于毒性，突出潜在的分子靶点治疗。研究结果支持啮齿动物不育模型的翻译相关性，并指导压力源的风险评估和缓解策略。

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 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.