Differential effects of benzo[a]pyrene exposure on glutathione and purine metabolism in keratinocytes: Dose‐dependent and UV co‐exposure effects

Abstract

AbstractPolycyclic aromatic hydrocarbons with the key substance benzo[a]pyrene (B[a]P) are widespread pollutants in the environment and at working places. Nonetheless, the exact underlying mechanisms of toxicological effects caused by B[a]P especially in absence and presence of UV irradiation remain uncertain. This study examines variations in exposure conditions: low B[a]P (4 nM), low B[a]P + UV and high B[a]P (4 μM), selected based on pertinent cytotoxicity assessments. Following cell viability evaluations post‐treatment with varied B[a]P concentrations and UV irradiation, the identified concentrations underwent detailed metabolomic analysis via gas chromatography–mass spectrometry. Subsequently, resulting changes in metabolic profiles across these distinct exposure groups are comprehensively compared. Chemometric analyses showed modest regulation of metabolites after low B[a]P exposure compared to control conditions. High B[a]P and low B[a]P + UV exposure significantly increased regulation of metabolic pathways, indicating that additional UV irradiation plus low B[a]P is as demanding for the cells as higher B[a]P treatment alone. Further analysis revealed exposure‐dependent regulation of glutathione—important for oxidative defence—and purine metabolism—important for DNA base synthesis. Only after low B[a]P, oxidative defence appeared to be able to compensate for B[a]P‐induced perturbations of the oxidative homeostasis. In contrast, purine metabolism already responded towards adversity at low B[a]P. The metabolomic results give an insight into the mechanisms leading to the toxic response and confirm the strong effects of co‐exposure on oxidative defence and DNA repair in the model studied.