Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A

ABSTRACT

The effects of environmental chemicals on health outcomes may be underestimated due to deficiency of knowledge regarding the actions of compounds on toxico-pathogenic mechanisms underlying biological systems outcomes. In this regard, the current study aimed to explore the potential target-pathway-disease relationship attributed to bisphenol A (BPA) responses in target tissues. Computational methods including reverse pharmacophore mapping approach, structural similarity based search and kinome wide interaction profiling were employed with molecular docking validation. Gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network based illustrations were utilized to prioritize target-pathway and disease relationships. Data illustrated that BPA possessed multi-target nature since this chemical potentially interacted with various protein targets where many of these were validated through docking. Potential BPA targets were significantly enriched to various cellular signaling pathways including steroid biosynthesis, peroxisome proliferator-activated receptor gamma (PPARℽ) and cancer. Further, hypertension was prioritized as disease target. In addition, BPA targeted 17 cell signaling kinases encompassed in the human kinome. In addition, inflammatory (5-LO) and apoptosis regulators (Bcl-X and Bcl-2) were also explored as novel targets. Evidence indicates that the multi-target nature and plausible mechanisms underlying BPA actions in a system wide manner aids toward understanding of adverse effects. This observation may lead us to more precise method to elucidate the toxico-pathogenic mechanisms of BPA with an environmental health perspective.

ABSTRACT

KEYWORDS:

• Systems toxicology
• bisphenol A
• gene ontology
• estrogen
• pollutant
• docking

Acknowledgments

Manigandan Nagarajan was grateful to Bharathiar University for BU-URF as a research scholar fellowship.

Author contribution

Jeganathan Manivannan conceived and designed the experiments. Manigandan Nagarajan and Gobichettipalayam Balasubramaniam Maadurshni performed the experiments. Jeganathan Manivannan analyzed the data. Jeganathan Manivannan, Manigandan Nagarajan and Gobichettipalayam Balasubramaniam Maadurshni wrote the paper. All authors read and approved the manuscript.

Disclosure statement

The authors declare no competing interests.

Data availability

The data that support the findings of this study are available from the corresponding author, (Jeganathan Manivannan), upon reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.