Environmental pollutant Di-(2-ethylhexyl) phthalate induces asthenozoospermia: new insights from network toxicology

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-09-11 DOI:10.1007/s11030-024-10976-9

Lei Xu, Menghua Shi, Guozheng Qin, Xuyao Lin, Bin Huang

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Abstract

The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets.

Graphical abstract

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环境污染物邻苯二甲酸二（2-乙基己酯）诱发无精子症：网络毒理学的新见解

全球男性精子质量下降与环境中暴露于增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）密切相关，但其诱导无精子症（AZS）的分子机制仍不完全清楚。本研究通过整合DEHP的毒理靶点和AZS患者的差异基因，并结合机器学习、分子对接和动力学模拟，成功鉴定了DEHP诱导AZS的枢纽基因和信号通路，旨在为该病的预防和治疗提供新策略。研究共发现了26个毒理学靶点，其中FGFR1、MMP7和ST14在DEHP诱导的AZS中发挥着关键的调控作用。这项研究还发现，DEHP可能通过调节mTORC1通路、通过NF-κB通路的TNF-α信号转导以及MYC靶标v1通路，诱发生殖系统炎症，影响生殖细胞的增殖和存活，进而影响精子活力。此外，免疫微环境的变化揭示了免疫状态对睾丸功能的重要影响。总之，这项研究为了解AZS的分子机制以及根据毒理学靶点制定预防和治疗策略提供了重要的科学证据。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;