Benzo[a]pyrene and bisphenol A interact to induce combined pulmonary toxicity through an integrated transcriptomic-metabolomic network

Abstract

Widespread atmospheric pollutants such as benzo[a]pyrene (BaP) and bisphenol A (BPA) persistently coexist, yet their combined risks to the respiratory system remain largely overlooked. In this study, C57BL/6J mouse and A549 cell models were employed to investigate the combined pulmonary toxicity induced by BaP and BPA, with an integrated transcriptomic-metabolomic framework established to characterize their response patterns. Combined exposure to BaP and BPA caused pathological damage in mouse lung tissue and specifically induced a broader spectrum of adverse effects. In vitro experiments demonstrated that combined exposure induced cytotoxicity, including FOXM1-mediated changes in cell survival and EGFR/AKT pathway-mediated alterations in the invasive phenotype. Transcriptomic and metabolomic analyses indicated that combined exposure suppressed immune cell populations, especially CD8 T cells, and disrupted glycerophospholipid metabolism. We further categorized these outcomes into four interaction response patterns, which may facilitate the more precise identification of target information within specific interaction contexts. In addition, glycerophosphocholine (GPC) was found to mediate the overall immunosuppressive effects caused by combined exposure, while had a limited effect on changes in lung cell populations. We suggest that greater attention be paid to the interaction characteristics between mixed pollutants and their molecular targets within the framework of joint health risk assessment, to improve the mechanistic understanding of complex combined toxic effects.