Elucidating Mechanisms of Benzo[a]pyrene Mediated Apoptotic and Autophagic Cell Death and its Prevention with Phytotherapeutics

Abstract

Polycyclic aromatic hydrocarbons form an active source of air pollution that affects our health and environment. In this study, we deciphered the role of benzo[a]pyrene (B[a]P) on cellular mechanism associated cell death. The particulate matter collected from an industrial area of Rourkela city found to have B[a]P and other unidentified environmental pollutants that had mutagenic and proapoptotic activity. The apoptotic potential of B[a]P was supported by ligand-protein and protein-protein interaction in silico which was validated on human keratinocyte (HaCaT) cell line. Our prediction showed that B[a]P was activated by cytochrome P450 (CYP1B1) to induce multiple cellular effects related to activation of the aryl hydrocarbon receptor (AhR) due to formation of toxic metabolites and this in turn activated caspases. Further, we showed that B[a]P induced mitochondrial mediated autophagy dependent cell death through the canonical pathway in HaCaT cells. The autophagic cell death induced by B[a]P was found to be mediated through AMPK/mTOR pathway. We showed that B[a]P abrogated ATP generation and activated reactive oxygen production to induce toxic mitophagy in HaCaT cells. In addition, we identified Bacopa monneiri (BM) plant extract as an inducer of protective autophagy, which may directly contribute to the antioxidant promoting potential of BM on B[a]P induced cell death through Beclin-1 dependent autophagy activation. The present study provided deep insight into the mechanism of B[a]P-mediated cellular toxicity and elucidated the further scope for the development of phytotherapeutics against environmental air pollutants.