Identification of potential Bisphenol A (BPA) exposure biomarkers in ovarian cancer and to predict the consequences of SNPs on biomarkers of ovarian cancer

Abstract

There is a growing concern to public health posed by endocrine disrupting chemicals (EDCs). EDCs have been reported to exert a diverse range of health problems, as they mimic, interfere and subsequently alter endocrine signalling pathways. EDCs are linked with deleterious effects on both male and female reproductive systems e.g. infertility, PCOS, endometriosis, precocious puberty; and spermatogenesis. EDCs are commonly found in our food and consumer products, with bisphenol A (BPA) being a common culprit. Numerous studies have confirmed that BPA has xenoestrogenic activity and can exert adverse effects in female reproductive system. Currently, a significant knowledge gap remains regarding the role of BPA at ovarian level in health and disease. Thus, a deeper understanding of the molecular and cellular mechanisms describing the effect of BPA in ovarian cancer is urgently needed. To tackle this challenge, we analysed public data from ovarian cancer patients and studied the changes in the transcriptional landscape for genes known to have differential expression pattern upon exposure to BPA. Our results point at a small group of genes (namely GBP5, IRS2, KRT4, LINCOO707, MRPL55, RRS1 and SLC4A11) with potential predictive power for overall survival based on their expression pattern. Then I embarked on analyses on the association of these biomarkers with any phenotypes and mutations indicative of involvement in female cancers and subsequently predicted the structural and functional consequences of those SNPs using in silico tools. In this study I have demonstrated that a R831C/R804C mutation in the SLC4A11 gene is deleterious with predicting ΔΔG values suggestive of reduction in protein stability due to this mutation. I have then studied the impact of BPA in normal human ovaries using Epithelial Ovarian Cells (HOSEpiC) as an experimental in vitro model. HOSEpiC cells were treated with environmentally relevant concentrations of BPA (10nM and 100nM) and differentially expressed genes (DEGs) were identifid following RNAsequencing. Among the DEGs identifid in both groups, 76 genes were found to be commonly dysregulated irrespective of the level of BPA exposure. Biological pathways associated with the exposure of the different environmental doses of BPA included oocyte meiosis, cellular senescence and transcriptional dysregulation in cancer. Finally, during the peak of COVID pandemic in 2020, I have also contributed in an article arguing for a potential link between BPA and the severity of COVID-19. This is due to the fact that BPA is known to promote a wide spectrum of comorbidities that can be associated with severe COVID-19. In this study, I have provided evidence of co-expression of SARS-CoV-2 cell entry mediators (e.g. ACE2, TMPRSS2) with estrogen receptors that can be targeted by BPA. Collectively all these studies provide a better insight into the detrimental role of BPA in human reproduction and its involvement in the severity of other diseases (e.g., COVID-19). My data provides the basis for further research using more clinically-relevant models to study ovarian function and also lead to potentially new guidelines for reducing EDC exposure in high COVID-19 risk groups.