Aflatoxin G1 induced TNF-α-dependent lung inflammation to enhance DNA damage in alveolar epithelial cells

Aflatoxin G(1) (AFG(1)), a member of the AF family with cytotoxic and carcinogenic properties, could cause DNA damage in alveolar type II (AT-II) cells and induce lung adenocarcinoma. Recently, we found AFG(1) could induce chronic lung inflammation associated with oxidative stress in the protumor stage. Chronic inflammation plays a critical role in cigarette smoke or benzo[a]pyrene-induced lung tissues damage. However, it is unclear whether and how AFG(1)-induced lung inflammation affects DNA damage in AT-II cells. In this study, we found increased DNA damage and cytochrome P450 (CYP2A13) expression in AFG(1)-induced inflamed lung tissues. Furthermore, we treated the mice with a soluble tumor necrosis factor (TNF)-alpha receptor and AFG(1) and found that TNF-alpha neutralization inhibited the AFG(1)-induced chronic lung inflammation in vivo, and then reversed the CYP2A13 expression and DNA damage in AT-II cells. The results suggest that AFG(1) induces TNF-alpha-dependent lung inflammation to regulate 2A13 expression and enhance DNA damage in AT-II cells. Then, we treated the primary mice AT-II cells and human AT-II like cells (A549) with AFG(1) and TNF-alpha and found that TNF-alpha enhanced the AFG(1)-induced DNA damage in mice AT-II cells as well as A549 cells in vitro. In AFG(1)-exposed A549 cells, TNF-alpha-enhanced DNA damage and apoptosis were reversed by CYP2A13 small interfering RNA. Blocking NF-kappa B pathway inhibited the TNF-alpha-enhanced CYP2A13 upregulation and DNA damage confirming that the CYP2A13 upregulation by TNF-alpha plays an essential role in the activation of AFG(1) under inflammatory conditions. Taken together, our findings suggest that AFG(1) induces TNF-alpha-dependent lung inflammation, which upregulates CYP2A13 to promote the metabolic activation of AFG(1) and enhance oxidative DNA damage in AT-II cells.