Investigating the potential causal link between BPA and ovarian carcinogenesis: a network toxicology and mendelian randomization study on the CTRC/PRDX1/SKP1 pathway

This study elucidates the association between Bisphenol A (BPA) exposure and ovarian cancer development, along with its underlying mechanisms. We employed a ‘Toxicological Prediction-Causal Inference-Structural Validation’ framework, integrating network toxicology and Mendelian Randomization (MR) analysis, enabling insights into BPA’s carcinogenic effects. This approach used network toxicology to predict molecular targets of BPA in the ovary, MR to establish genetic evidence for the causal link, and molecular docking to validate structural basis of interaction with key pathways. Our findings indicate BPA may influence cellular processes, including homeostasis, stress, and cycle regulation, while activating PI3K/Akt signaling. Enrichment analysis revealed pathways associated with amoebic infection, suggesting interactions between infection status and chemical exposure. With evidence that emetine enhances cancer cell sensitivity, we hypothesize BPA may activate inflammation pathways shared with amoebic infection, particularly in predisposed individuals. Consequently, BPA might induce inflammatory microenvironment, thereby influencing progression and treatment response. This study identifies CTRC/PRDX1/SKP1 as crucial and proposes hypothesis of synergistic effects between exposure and infection history. These findings underscore incorporating environmental exposure into risk assessment, offering perspectives on carcinogenesis and avenues for prevention. Unraveling the BPA-Ovarian Cancer Connection with a Novel 3D Analytical Framework: We developed and applied an integrated ‘ToxPredict-CauseInfer-StructValidate’ approach, combining network toxicology and Mendelian randomization, to elucidate a potential causal pathway linking BPA exposure to ovarian carcinogenesis. Uncovering Potential Mechanisms of BPA in Ovarian Cancer: Our analysis suggests that BPA’s potential cancer-promoting effects may involve dysregulation of proteostasis, oxidative stress, cell cycle, and PI3K/Akt signaling. We identified the CTRC/PRDX1/SKP1 axis as a central hub in these BPA-associated oncogenic processes. Amoebic Infection as a Novel Potential Co-factor in BPA-Associated Ovarian Cancer: We propose a novel hypothesis that BPA exposure may synergize with a history of amoebic infection. This interaction, potentially via TLR4-NF-κB activation, could contribute to the development of a pro-tumorigenic inflammatory microenvironment, thereby promoting ovarian cancer progression. Informing Future Ovarian Cancer Risk Models: This study provides a strong rationale for integrating environmental chemical exposures (e.g., BPA) and infectious disease history into the framework of ovarian cancer risk assessment and personalized oncology.