Identification of the metabolomic alterations associated with the formation of bisphenol-A sulfate metabolite in HepG2 cells

Abstract

The elucidation of the causal relationship between bisphenol-A (BPA) exposure and hepatoxic outcomes is challenging because of the complexity in both the BPA-derived metabolites formed in the liver and the associated endogenous molecular responses. We performed parallel metabolism experiments with BPA to characterize the BPA sulfate formation and the associated alterations in the metabolome level in HepG2 cells using mass spectrometry-based metabolome wide association study. Briefly, HepG2 cells were exposed for 8 or 24 h to 1 or 10 μM BPA in DMSO or DMSO alone. The levels of BPA sulfate in the cell culture media were quantified, and the sulfation efficiency was about 0.4 % observed for both 1 and 10 μM BPA in HepG2 cells. Targeted metabolomic analyses revealed alterations belonging to forty metabolic pathways following BPA exposure. Featured by the decreasing of estrone sulfate, estrogen metabolism was observed as the top 1 enriched pathway in response to BPA exposure. MWAS suggests that BPA sulfate formation in HepG2 cells resulted in vitamin B6 deficiency and dysregulated vitamin B6-dependent processes, for example, the kynurenine pathway in tryptophan metabolism. These findings collectively provide insights into the linkage between exogenous and endogenous metabolism and the potential initial events in BPA exposure-relevant hepatoxicity.