Nrf2 activation contributes to hepatic tumor-augmenting effects of developmental arsenic exposure.

Abstract

Developmental arsenic exposure increases cancer risk in later life with the mechanism elusive. Oxidative stress is a dominant determinant in arsenic toxicity. However, the role of Nrf2, a key regulator in antioxidative response, in tumor-augmenting effects by developmental arsenic exposure is unclear. In the present study, wild-type C57BL/6J and Nrf2-konckout (Nrf2-KO) were developmentally exposed to inorganic arsenic via drinking water. For hepatic tumorigenesis analysis, mice were intraperitoneally injected with diethylnitrosamine (DEN) at two weeks of age. Developmental arsenic exposure aggravated tumor multiplicity and burden, and expression of PCNA and AFP in hepatic tumors induced by DEN. Nrf2 activation as indicated by over-expression of Nrf2 and its downstream genes, including Gss, Gsr, p62, Gclc and Gclm, was found in liver tumors, as well as in the livers in developmentally arsenic-exposed pups at weaning. Notably, Nrf2 deficiency attenuated tumor-augmenting effects and over-expression of Nrf2 downstream genes due to developmental arsenic exposure. Furthermore, the levels of urinary DEN metabolite (acetaldehyde) and hepatic DNA damage markers (O6-ethyl-2-deoxyguanosine adducts and γ-histone H2AX) after DEN treatment were elevated by Nrf2 agonist, 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide. Collectively, our data suggest that augmentation of DEN-induced hepatic tumorigenesis by developmental arsenic exposure is dependent on Nrf2 activation, which may be related to the role of Nrf2 in DEN metabolic activation. Our findings reveal, at least in part, the mechanism underlying increased susceptibility to developing cancer due to developmental arsenic exposure.