Benzo(a)pyrene induces cardiac hypertrophy via the aryl hydrocarbon receptor-mediated DNA damage.

Benzo(a)pyrene (BaP), one of the most extensively studied polycyclic aromatic hydrocarbons, is prevalent in the environment. BaP exposure has been linked to cardiovascular diseases, but the underlying mechanisms remain elusive. In this study, we observed that BaP exposure induces cardiac hypertrophic effects (enlarged cell surface area and increased expression of Nppa, Nppb, and Myh7) in rat H9c2 cardiomyoblasts. Notably, these effects are dependent on the aromatic hydrocarbon receptor (AHR)-Cyp1a1/Cyp1b1 axis. AHR-Cyp1a1/Cyp1b1 signaling also mediates BaP-induced cellular senescence, evidenced by an increased percentage of β-galactosidase-positive cells, p21 overexpression, and Lamin B1 deficiency. We then demonstrated that AHR activation by BaP promotes BPDE-DNA adducts and γ-H2AX foci formation, not only by upregulating Cyp1a1/Cyp1b1 expression but also by repressing nucleotide excision repair (NER). Further experiments revealed that BaP-activated AhR suppresses Sirt1 expression, which may inhibit NER by downregulating Ddb2 expression. Additionally, inhibition of cellular senescence through P21 inhibition counteracted BaP-induced cardiac hypertrophy. Furthermore, we demonstrated that either AHR inhibition or Sirt1 activation attenuated BaP-induced cardiac hypertrophy in zebrafish larvae. In conclusion, our findings indicate that AhR activation by BaP induces DNA damage both by promoting its conversion to BPDE and by repressing NER, leading to cellular senescence and ultimately resulting in cardiac hypertrophy.