揭示增塑剂通过网络毒理学和分子对接分析诱导乳腺癌的机制

Elucidating the mechanism of plasticizers inducing breast cancer through network toxicology and molecular docking analysis

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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY

影响因子:6.1

分区:环境科学与生态学2区 / 毒理学1区环境科学2区

发表日期:2024 Oct 01

作者: Na He, Jing Zhang, Mingyu Liu, Li Yin

DOI: 10.1016/j.ecoenv.2024.116866

摘要

本研究旨在阐明常用增塑剂（邻苯二甲酸二乙酯（DEP）、邻苯二甲酸二甲酯（DMP）和邻苯二甲酸二辛酯（DOP））在乳腺癌发病机制中的潜在作用及其分子机制。研究重点在于揭示这些环境化学品与肿瘤发生相关的关键分子通路之间的复杂相互作用。利用网络毒理学和分子对接技术，分析增塑剂与乳腺癌相关关键蛋白的相互作用。通过TCGA等数据库分析乳腺癌组织与正常对照中关键基因的表达差异，并进行富集分析，识别相关的生物通路。分析显示，这些增塑剂靶向的基因与腺癌发生密切相关，提示其对激素依赖性及其他类型癌症具有广泛影响。TCGA乳腺癌数据分析进一步证实这些基因在乳腺癌组织中的显著表达变化，确认其在肿瘤生物学中的关键作用。分子对接结果显示，DEP、DMP和DOP等增塑剂可以与MAPK1、AKT1、SRC、ESR1和ALB等关键蛋白特异性结合，调控乳腺癌发病机制。研究提供证据表明，增塑剂通过与关键蛋白和信号通路的相互作用可能影响乳腺癌的发病过程。结合网络药理学、蛋白相互作用和分子对接分析，强调了增塑剂潜在的风险。未来需要进一步的流行病学和临床研究，以全面理解增塑剂暴露与乳腺癌风险的关系，为预防和治疗提供依据。

Abstract

The objective of this study was to elucidate the molecular mechanisms underlying the potential contribution of commonly utilized plasticizers, including Diethyl phthalate (DEP), Dimethyl phthalate (DMP), and Dioctyl phthalate (DOP), to the pathogenesis of breast cancer. This study aimed to highlight the complex interactions between these environmental chemicals and key molecular pathways implicated in tumorigenesis.We employed network toxicology and molecular docking techniques to analyze the interactions between plasticizers and key proteins implicated in breast cancer. Utilizing databases such as the TCGA, we performed an expression analysis of selected key genes in breast cancer tissue compared to normal controls. Enrichment analysis was conducted to identify the biological pathways associated with these genes.Enrichment analysis highlighted the association of these plasticizer-targeted genes with pathways integral to adenocarcinoma development, suggesting a broad impact of plasticizers on hormone-dependent and other forms of cancers. Subsequent expression analysis using data from the TCGA breast cancer database indicated significant upregulation or downregulation of these genes in breast cancer tissues compared to normal controls, confirming their pivotal roles in tumor biology. Furthermore, the molecular docking analysis revealed that plasticizers, including DEP, DMP, and DOP, exhibit specific binding interactions with key proteins such as MAPK1, AKT1, SRC, ESR1, and ALB, which are crucial in the regulation of breast cancer pathogenesis.The study provides evidence that exposure to plasticizers may influence breast cancer pathogenesis through interactions with critical proteins and signaling pathways. By employing network pharmacology, protein interactions, and molecular docking, our findings highlight the potential risks posed by plasticizers. These results underscore the need for further epidemiological and clinical research to fully understand the implications of plasticizer exposure on breast cancer risk, thus informing future preventive and therapeutic strategies.