Meta-analysis And Network Pharmacologic Study Of Correlation Between Three Endocrine Disrupting Chemicals And Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome(PCOS)is a common reproductive endocrine metabolic disorder characterized by hyperandrogenemia,persistent anovulation and polycystic ovarian changes,and is a common cause of infertility in women of reproductive age.Environmental endocrine disruptors are environmental pollutants that people are widely exposed to in daily life,and long-term exposure can enter the human body through various pathways and disrupt the regulation of the normal hormone homeostasis system in the body,posing a serious threat to human health.The association between exposure to bisphenol a(BPA),phthalates(PAEs)and per-and polyfluoroalkyl substances(PFAS),which are the most common environmental endocrine disruptors,and the risk of PCOS is still controversial.Therefore,in this study,we first conducted a systematic review of the correlation between BPA,PAEs and PFAS exposure and PCOS through Meta-analysis;and then further explored the potential mechanisms of the role of compound BPA exposure in the pathogenesis of PCOS based on network pharmacology and molecular docking approaches.Chapter 1: Meta analysis of the correlation between BPA,PAEs,PFAS exposure and PCOSObjective: To systematically evaluate the correlation between BPA,PAEs,PFAS exposure and PCOS.Method: Online searches of Chinese and English databases: CNKI,VIP,Wanfang,PubMed,Embase,Web of Science,MEDLINE and The Cochrance Library,the published literature on the correlation between BPA,PAEs and PFAS exposure and PCOS was collected.The retrieval time is from the establishment of each database to December 1,2022.The literatures were screened according to the established inclusion and exclusion criteria,and the literature quality of the included studies was evaluated and relevant data were extracted.Stata 15.0 and Rev Man 5.3 software were selected for Metaanalysis.Results:1.A total of 18 literatures were included in this study,all of which were casecontrol studies.Eleven literatures focused on the correlation between BPA and PCOS;3 literatures studied on the correlation between PAEs and PCOS;2 literatures focused on the correlation between PFAS and PCOS,and there were 2 literatures studied on the correlation between BPA,PAEs and PCOS.2.The exposure level of the compound BPA was statistically significant between the PCOS group and the control group [SMD = 1.35,95% CI(0.91,1.79),P < 0.001].Subgroup analysis further suggested that BPA exposure was associated with PCOS in both Asian and European populations(P < 0.001).In addition,BPA exposure was significantly associated with the occurrence of PCOS in older [SMD = 0.99,95% CI(0.58,1.39),P < 0.001] and lower BMI [SMD = 1.6,95% CI(0.99,2.22),P < 0.001]populations.It is suggested that the degree of association between BPA exposure and PCOS may be related to the age group and the change of body weight.3.There was no significant difference in the exposure level of PAEs between PCOS group and control group [SMD = 0.08,95% Cl(-0.17,0.34),P = 0.53].However,when subgroup analysis of country and detection methods was performed,the difference in PAEs exposure levels between PCOS group and control group in the Chinese study was statistically significant [SMD = 0.31,95% CI(0.30,0.60),P = 0.03].When LC-MS/MS or GC-MS were used as detection methods,PAEs was a risk factor for PCOS [SMD = 0.49,95% CI(0.30,0.68),P < 0.001].4.PFAS metabolites include Perfluorooctane sulfonic acid [SMD = 0.32,95% Cl(-0.16,0.80),P = 0.187],Perfluorooctanoic Acid [SMD =-0.12,95% Cl(-0.30,0.05),P = 0.17],Perfluorohexane sulfonic acid [SMD = 0.18,95% Cl(-0.001,0.36),P =0.052] and Perfluorononanoic acid [SMD = 0.08,95% Cl(-0.10,0.26),P = 0.361]were not significantly associated with the incidence of PCOS,but subgroup analysis suggested that in the UK population [SMD = 0.57,95% Cl(0.21,0.94),P = 0.002] and follicle fluid as biological samples [SMD = 0.54,95% Cl(0.02,1.06),P = 0.04],Perfluorooctane sulfonic acid exposure was correlated with the incidence of PCOS.Conclusions: Exposure to the compound BPA is an important environmental factor in the development of PCOS;the association between PAEs and PCOS is unclear due to the limitations of the population and the type of compounds;only Perfluorooctane sulfonic acid exposure among PFAS metabolites is associated with the development of PCOS,and the above findings need to be further confirmed by higher quality studies.Chapter 2: A network pharmacology study of the association between BPA exposure and PCOSObjective: To explore the potential mechanism of action of compound BPA exposure in the pathogenesis of PCOS based on network pharmacology and molecular docking.Methods: 1.The CAS number of BPA was obtained from the chemical source network,according to which the 2D structural formula of BPA was searched and downloaded from PubChem database,and the gene target of BPA was screened out through Swiss Target Prediction database and Pharm Mapper database;2.Disease genes of PCOS were searched in DisGeNet database,GeneCards database,DrugBank database and OMIM database;3.The intersection targets of BPA and PCOS were obtained by Venn diagram,and PPI network diagram of intersection targets was plotted on STRING data platform.The key targets were obtained by using Cytoscape 3.9.1software to visualize the PPI network diagram;4.GO and KEGG enrichment analysis of the intersection targets by DAVID data platform and the core pathways were selected.The "compound-target-pathway-disease" network diagram of BPA induced PCOS was constructed by Cytoscape 3.9.1 software;5.Molecular docking of key genes using Auto Dock Tools-1.5.6 software to verify the affinity between compound BPA and key targets.Results:1.A total of 242 BPA targets were collected in Swiss Target Prediction database and Pharm Mapper database.A total of 2038 disease genes related to PCOS were retrieved from DisGeNet database,GeneCards database,DrugBank database and OMIM database,and 81 common genes were obtained after intersection.2.Ten key targets were screened by constructing PPI network maps,in order of ALB,AKT1,ESR1,EGFR,SRC,IGF1,HSP90AA1,PPARG,MAPK1,and AR.3.GO enrichment analysis obtained a total of 425 biological processes,50 cellular components and 121 molecular functions,and found that the expression of key genes is closely related to biological processes such as signal transduction,positive regulation of cell proliferation,protein phosphorylation and positive regulation of cell migration.KEGG enrichment analysis obtained a total of 140 signaling pathways,suggesting that the mechanism pathway of BPA-induced PCOS pathogenesis involves PI3K/AKT signaling pathway,estrogen receptor pathway,VEGF signaling pathway and MAPK signaling pathway,among which PI3K/AKT signaling pathway is the core pathway.4.Molecular docking of each of the above 10 key targets showed that AKT1,AR,ESR1,ALB,and HSP90AA1 had the strongest binding ability to the compound BPA,indicating that the binding between BPA and the key targets was stable and induced PCOS by regulating the expression of the core targets.Conclusion: Environmental estrogen BPA can bind stably to AKT1,AR,ESR1,ALB,HSP90AA1 and participate in regulating cell proliferation,apoptosis and autophagy,steroid synthesis and protein phosphorylation and other biological processes through PI3K/AKT signaling pathway,estrogen receptor pathway,VEGF signaling pathway,MAPK signaling pathway and other pathways to cause the development of PCOS.