Integrating Mendelian randomization and network toxicology to elucidate the causal role and mechanisms of Atrazine in breast cancer

Background Breast cancer (BC) is the leading cause of cancer-related mortality in women. Atrazine, a widely used herbicide, is increasingly recognized as an environmental pollutant due to bioaccumulation. In this study, we explored the mechanisms by which Atrazine exposure contributed to the occurrence and development of BC. Methods We integrated common targets of Atrazine in BC through multiple databases (e.g. PubChem, CTD, GeneCards, OMIM). The causal relationship between Atrazine exposure and BC was established via Mendelian randomization analysis. The protein-protein interaction (PPI) network of these targets was constructed using STRING database, with core targets analyzed via Cytoscape. GO and KEGG enrichment analyses were performed using the R package. Molecular docking simulations assessed Atrazine’s binding affinity to core targets. Results We identified 1267 potential targets for Atrazine-induced BC. Following single nucleotide polymorphism (SNP) - based selection criteria, SNPs from 1047 potential targets were utilized as instrumental variables, narrowing to 164 causally associated targets. PPI network analysis refined these to 38 core targets. KEGG enrichment highlighted the top three signaling pathways: cellular senescence pathway, human T-cell leukemia virus 1 infection, and small cell lung cancer. Molecular docking revealed strong binding affinities between Atrazine and these core targets (AKT1, CASP3, HSPA4, CCND1, and MAPK3). Conclusions Atrazine exposure is linked to BC via cellular senescence, HTLV-1 infection, and small cell lung cancer pathways, with AKT1, CASP3, HSPA4, CCND1, and MAPK3 as key targets. This study delineated a molecular framework for Atrazine-induced BC and a method to assess pollutants' toxicological effects.