| 305 | 0 | 119 |
| 下载次数 | 被引频次 | 阅读次数 |
双酚A(bisphenol A, BPA)是一种广泛存在的环境内分泌干扰物,其暴露与免疫介导性哮喘发生密切相关,但其具体分子机制仍不清楚。阐明BPA诱发哮喘的机制,对于认识环境污染物相关哮喘的发病基础并指导其预防和干预具有重要意义。本文通过整合网络毒理学、生物信息学及分子对接技术,从公共数据库获取BPA作用靶点及哮喘相关基因并取交集,随后对候选靶点进行基因本体(gene ontology, GO)功能注释与京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)通路富集分析,结合机器学习筛选核心基因,并通过免疫浸润分析评估其与免疫细胞的相关性,最终采用分子对接验证BPA与核心靶点的结合能力,确定BPA诱发哮喘的靶点。共鉴定出145个BPA诱发哮喘的潜在关键靶点, GO与KEGG分析显示这些靶点主要富集于酶活性与结合活性、补体与凝血级联等生物过程与通路,进一步筛选获得5个核心基因(RIPK2、 CDC25B、 CRBN、 RELA、 IL13RA1),分子对接结果显示BPA与5个核心基因均表现出稳定的结合构象。该研究通过多组学整合分析初步阐明了其参与哮喘发生的潜在分子机制,为深入认识BPA的呼吸道毒性及探索哮喘的防治策略提供了依据。
Abstract：Bisphenol A( BPA) is a ubiquitous environmental endocrine disruptor, and its exposure is closely associated with the development of immune-mediated asthma. However, the specific molecular mechanisms underlying BPA-induced asthma remain elusive. Elucidating these mechanisms is of great significance for understanding the pathogenic basis of environmental pollutant-related asthma and guiding its prevention and intervention. In this study, we integrated network toxicology, bioinformatics approaches, and molecular docking. We retrieved BPA-targeted genes and asthma-associated genes from public databases and identified their intersection. Subsequently, gene ontology( GO) functional annotation and kyoto encyclopedia of genes and genomes( KEGG) pathway enrichment analysis were performed on these candidate targets. Core genes were further screened using machine learning algorithms, and their correlation with immune cells was evaluated via immune infiltration analysis. Finally, molecular docking was employed to validate the binding capacity between BPA and these core genes, thereby confirming the key targets involved in BPA-induced asthma. A total of 145 potential key targets of BPA-induced asthma were identified. GO and KEGG analyses revealed that these targets were mainly enriched in biological processes and pathways related to enzyme activity, binding activity, as well as the complement and coagulation cascades. Further screening yielded 5 core genes(RIPK2, CDC25B, CRBN, RELA, IL13 RA1). The molecular docking analysis demonstrated that BPA stably bound to all five core genes, as evidenced by favorable binding conformations. This study preliminarily elucidated the potential molecular mechanisms by which BPA participates in the pathogenesis of asthma through integrated multi-omics analysis. This provides a basis for further understanding the respiratory toxicity of BPA and for exploring strategies for the prevention and treatment of asthma.
何洁,许洁,俞捷,2022.环境内分泌干扰物在哮喘发生发展中的作用机制研究进展[J].中国药理学与毒理学杂志,36(11):872-880.[He J,Xu J,Yu J,2022.Roles of environmental endocrine disruptors in the development of asthma:a review[J].Chinese Journal of Pharmacology and Toxicology,36(11):872-880.]
Abma W,Dahlén S E,Wheelock C E,et al.,2026.Protectin D1 and maresin 1 attenuate airway hyperreactivity induced by IL-13 in human isolated small bronchi[J].Br.J.Pharmacol.,183(9):2049-2060.
Abraham A,Chakraborty P,2020.A review on sources and health impacts of bisphenol A[J].Rev.Environ.Heal.,35(2):201-210.
Ait Yahia S,Audousset C,Alvarez-Simon D,et al.,2021.NOD1 sensing of house dust mite-derived microbiota promotes allergic experimental asthma[J].J.Allergy Clin.Immunol.,148(2):394-406.
Amberger J S,Bocchini C A,Schiettecatte F,et al.,2015.OMIM.org:Online Mendelian Inheritance in Man (OMIMⓇ),an online catalog of human genes and genetic disorders[J].Nucleic Acids Res.,43(D1):D789-D798.
Bai D H,Sun T X,Lu F,et al.,2022.Eupatilin suppresses OVA-induced asthma by inhibiting NF-κB and MAPK and activating Nrf2 signaling pathways in mice[J].Int.J.Mol.Sci.,23(3):1582.
Bento A P,Gaulton A,Hersey A,et al.,2014.The ChEMBLbioactivity database:an update[J].Nucleic Acids Res.,42(D1):D1083-D1090.
Chiba Y,Ueda C,Kohno N,et al.,2020.Attenuation of relaxing response induced by pituitary adenylate cyclase-activating polypeptide in bronchial smooth muscle of experimental asthma[J].Am.J.Physiol.Lung Cell.Mol.Physiol.,319(5):L786-L793.
Cimmino I,Fiory F,Perruolo G,et al.,2020.Potential mechanisms of bisphenol A (BPA) contributing to human disease[J].Int.J.Mol.Sci.,21(16):5761.
Cox J K,Lockey R,Cardet J C,2025.Cough-variant asthma:a review of clinical characteristics,diagnosis,and pathophysiology[J].J.Allergy Clin.Immunol.Pract.,13 (3):490-498.
Dai J P,Gu L M,Su Y,et al.,2018.Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress,TLR2/4,p38/JNK MAPK and NF-κB pathways[J].Int.Immunopharmacol.,54:177-187.
Daina A,Michielin O,Zoete V,2019.Swiss Target Prediction:updated data and new features for efficient prediction of protein targets of small molecules[J].Nucleic Acids Res.,47(W1):W357-W364.
Ding F X,Liu B,Zou W J,et al.,2018.LPS exposure in early life protects against mucus hypersecretion in ovalbumininduced asthma by down-regulation of the IL-13 and JAK-STAT6 pathways[J].Cell.Physiol.Biochem.,46 (3):1263-1274.
Figat M,Wisniewska A,Plichta J,et al.,2025.Asthma and COPD beyond the airways:exploring neurocognitive links through NF-κB subunits c-rel and p65[J].Int.J.Mol.Sci.,26(11):5217.
Furue M,2020.Regulation of skin barrier function via competition between AHR axis versus IL-13/IL-4-JAK-STAT6/STAT3 axis:pathogenic and therapeutic implications in atopic dermatitis[J].J.Clin.Med.,9(11):3741.
Goh F Y,Cook K L T P,Upton N,et al.,2013.Receptorinteracting protein 2 gene silencing attenuates allergic airway inflammation[J].J.Immunol.,191(5):2691-2699.
Guo Y J,Liu Y Y,Chen Y B,et al.,2025.The mechanisms of environmental pollutant acetyl tributyl citrate induced oral squamous cell carcinoma using network toxicology,molecular docking and molecular dynamics simulation[J].Int.J.Surg.,111(11):7873-7885.
Hammad H,Ahmed E,Lambrecht B N,2025.Immunotherapy for asthma[J].Cell.Mol.Immunol.,22(12):1521-1532.
Han Y L,Zhang Z C,Wang Z J,et al.,2025.Integrated network toxicology,machine learning,molecular docking and experimental validation to elucidate mechanism of polyethylene terephthalate microplastics inducing periodontitis[J].Environ.Int.,203:109784.
Hatem G,Faria A M,Pinto M B,et al.,2025.Association between exposure to airborne endocrine disrupting chemicals and asthma in children or adolescents:a systematic review and meta-analysis[J].Environ.Pollut.,369:125830.
Huang J,Wang L,Zhou J F,et al.,2025.Unveiling the ageingrelated genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning[J].Artif.Cells Nanomed.Biotechnol.,53(1):57-68.
Kanehisa M,Furumichi M,Sato Y,et al.,2023.KEGG for taxonomy-based analysis of pathways and genomes[J].Nucleic Acids Res.,51(D1):D587-D592.
Keiser M J,Roth B L,Armbruster B N,et al.,2007.Relating protein pharmacology by ligand chemistry[J].Nat.Biotechnol.,25(2):197-206.
Lazado C C,Iversen M,Sundaram A Y M,2023.Comparative basal transcriptome profiles of the olfactory rosette and gills of Atlantic salmon (Salmo salar) unveil shared and distinct immunological features[J].Genomics,115(3):110632.
Lee J X,Phipatanakul W,Gaffin J M,2023.Environment and the development of severe asthma in inner city population[J].Curr.Opin.Allergy Clin.Immunol.,23(2):179-184.
Li B,Zhao X,Ding Y,et al.,2025a.Network toxicology and molecular docking to investigate the mechanism of bisphenol toxicity in human diabetic cardiomyopathy[J].Ecotoxicol.Environ.Saf.,299:118301.
Li G,Li D,Zhai W B,et al.,2025b.Respiratory toxicity mechanism of 6PPD and 6PPD-quinone:an integrated study based on network toxicology and molecular docking[J].Ecotoxicol.Environ.Saf.,301:118494.
Liu Z Y,Li Y Q,Bao J Y,et al.,2025.Astaxanthin ameliorates benzalkonium chloride-induced dry eye disease through suppressing inflammation and oxidative stress via Keap1-Nrf2/HO-1 signaling pathways[J].Anim.Models Exp.Med.,8(6):1056-1079.
Luo D,Xie L G,Zhang J D,et al.,2025.Exploring the association between osteoporosis and kidney stones:a clinical to mechanistic translational study based on big data and bioinformatics[J].Biol.Direct,20(1):42.
Marone G,Granata F,Pucino V,et al.,2019.The intriguing role of interleukin 13 in the pathophysiology of asthma[J].Front.Pharmacol.,10:1387.
Miller M H,Shehat M G,Alcedo K P,et al.,2018.Frontline Science:RIP2 promotes house dust mite-induced allergic airway inflammation[J].J.Leukoc.Biol.,104(3):447-459.
Miller R L,Grayson M H,Strothman K,2021.Advances in asthma:new understandings of asthma′s natural history,risk factors,underlying mechanisms,and clinical management[J].J.Allergy Clin.Immunol.,148(6):1430-1441.
Oikonomopoulou K,Ricklin D,Ward P A,et al.,2012.Interactions between coagulation and complement:their role in inflammation[J].Semin.Immunopathol.,34(1):151-165.
Reddel H K,Bacharier L B,Bateman E D,et al.,2022.Global initiative for asthma strategy 2021:executive summary and rationale for key changes[J].Am.J.Respir.Crit.Care Med.,205(1):17-35.
Ren K,Dubner R,2010.Interactions between the immune and nervous systems in pain[J].Nat.Med.,16 (11):1267-1276.
Ren X M,Shah T A,Ustiyan V,et al.,2013.FOXM1 promotes allergen-induced goblet cell metaplasia and pulmonary inflammation[J].Mol.Cell.Biol.,33(2):371-386.
Satyam A,Graef E R,Lapchak P H,et al.,2019.Complement and coagulation cascades in trauma[J].Acute Med.Surg.,6(4):329-335.
Shan Y,Desouza N,Littman N,et al.,2025.A blockade of leukotriene-mediated Alox5 function provides a new strategy for the treatment of JAK2V617F-induced polycythemia vera[J].Haematologica,110(11):2702-2713.
Shi Q L,Chen L J,2017.Cereblon:a protein crucial to the multiple functions of immunomodulatory drugs as well as cell metabolism and disease generation[J].J.Immunol.Res.,2017:9130608.
Song S Y,Huang L J,Zhou X Q,et al.,2025.Exploring the toxicological network in diabetic microvascular disease[J].Int.J.Surg.,111(6):3895-3907.
Stallone G,Pontrelli P,Rascio F,et al.,2020.Coagulation and fibrinolysis in kidney graft rejection[J].Front.Immunol.,11:1807.
Stelzer G,Plaschkes I,Oz-Levi D,et al.,2016.Var Elect:the phenotype-based variation prioritizer of the Gene Cards suite[J].BMC Genom.,17(Suppl 2):444.
Sullivan C,Liu Y H,Shen J J,et al.,2012.Novel interactions between FOXM1 and CDC25A regulate the cell cycle[J].PLo S ONE,7(12):e51277.
Sun L F,Ren X M,Wang I C,et al.,2017.The FOXM1 inhibitor RCM-1 suppresses goblet cell metaplasia and prevents IL-13 and STAT6 signaling in allergen-exposed mice[J].Sci.Signal.,10(475):eaai8583.
Szklarczyk D,Santos A,von Mering C,et al.,2016.STITCH 5:augmenting protein-chemical interaction networks with tissue and affinity data[J].Nucleic Acids Res.,44(D1):D380-D384.
Tan J Y,Zhang J N,Yang W D,et al.,2025.Integrated transcriptomics and network pharmacology to reveal the mechanism of Physochlainae Radix in the treatment of asthma[J].Phytomedicine,139:156470.
Thapa R,Bhat A A,Gupta G,et al.,2024.CRBN-PROTACs in cancer therapy:from mechanistic insights to clinical applications[J].Chem.Biol.Drug Des.,104(5):e70009.
Wiegner R,Chakraborty S,Huber-Lang M,2016.Complementcoagulation crosstalk on cellular and artificial surfaces[J].Immunobiology,221(10):1073-1079.
Xu J L,Zhou H,Cheng Y Y,et al.,2022.Identifying potential signatures for atherosclerosis in the context of predictive,preventive,and personalized medicine using integrative bioinformatics approaches and machine-learning strategies[J].EPMA J.,13(3):433-449.
Yadav S K,Kumar A,Yadav B G,et al.,2024.Sub-acute bisphenol A exposure induces proteomic alterations and impairs male reproductive health in mice[J].J.Biochem.Mol.Toxicol.,38(10):e23862.
Yang C F,Karmaus W J J,Yang C C,et al.,2020a.Bisphenol exposure,DNA methylation,and asthma in children[J].Int.J.Environ.Res.Public Heal.,17(1):298.
Yang H B,Song Z,Hong D H,2020b.CRBN knockdown mitigates lipopolysaccharide-induced acute lung injury by suppression of oxidative stress and endoplasmic reticulum (ER)stress associated NF-κB signaling[J].Biomed.Pharmacother.,123:109761.
Yao Z J,Dong J,Che Y J,et al.,2016.Target Net:a web service for predicting potential drug-target interaction profiling via multi-target SAR models[J].J.Comput.Aided Mol.Des.,30(5):413-424.
Yoon K,Kwack S J,Kim H S,et al.,2014.Estrogenic endocrine-disrupting chemicals:molecular mechanisms of actions on putative human diseases[J].J.Toxicol.Environ.Heal.Part B Crit.Rev.,17(3):127-174.
Zhang X,Köhl J,2010.A complex role for complement in allergic asthma[J].Expert Rev.Clin.Immunol.,6(2):269-277.
基本信息:
DOI：10.13417/j.gab.045.000828
中图分类号:R562.25;Q811.4
引用信息:
[1]胥俊宇,张紫玉,张志毕,等.基于生物信息学和机器学习阐明双酚A诱发哮喘的机制[J].基因组学与应用生物学,2026,45(04):828-840.DOI:10.13417/j.gab.045.000828.
基金信息:
国家自然科学基金项目(82260487); 云南省科技厅-昆明医科大学联合专项(202201AY070001-281); 昆明医科大学大学生创新性实验项目(2025-32)共同资助
2026-05-19
2026-05-19
2026-05-19