Epigenetic downregulation of O6-methylguanine-DNA methyltransferase contributes to chronic hexavalent chromium exposure-caused genotoxic effect and cell transformation

Abstract

Hexavalent chromium [Cr(VI)] is a common environmental pollutant and chronic exposure to Cr(VI) causes lung cancer and other types of cancer in humans, although the mechanism of Cr(VI) carcinogenesis remains elusive. Cr(VI) has been considered as a genotoxic carcinogen, but accumulating evidence indicates that Cr(VI) also causes various epigenetic toxic effects that play important roles in Cr(VI) carcinogenesis. However, it is not clear how Cr(VI)-caused epigenetic dysregulations contributes to Cr(VI) carcinogenesis. This study investigates whether Cr(VI) epigenetic toxic effect has an impact on its genotoxic effect. It was found that chronic low dose of Cr(VI) exposure time-dependently down-regulates the expression of a critical DNA damage repair protein O⁶-methylguanine-DNA methyltransferase (MGMT), leading to the increases of the levels of the highly mutagenic and carcinogenic DNA lesion O⁶-methylguanine (O⁶-MeG) in human bronchial epithelial BEAS-2B cells. Moreover, the levels of MGMT and O⁶-MeG in chronic Cr(VI) exposure-caused human lung cancer tissues are also significantly lower and higher than that in the adjacent normal lung tissues, respectively. It was further determined that chronic low dose of Cr(VI) exposure-transformed BEAS-2B cells display impaired DNA damage repair capacity and a high sensitivity to the toxicity of the alkylating chemotherapeutic drug Temozolomide. In contrast, stably overexpressing MGMT in parental BEAS-2B cells reverses chronic low dose of Cr(VI) exposure-caused DNA damage repair deficiency and significantly reduces cell transformation by Cr(VI). Further mechanistical studies revealed that chronic low dose of Cr(VI) exposure down-regulates MGMT expression through epigenetic mechanisms by increasing DNA methylation and histone H3 repressive modifications. Taken together, these findings suggest that epigenetic down-regulation of a crucial DNA damage repair protein MGMT contributes significantly to the genotoxic effect and cell transformation caused by chronic low dose of Cr(VI) exposure.

Keywords: DNA methylation; Epigenetic toxicity; Hexavalent chromium [Cr(VI)]; Histone H3 repressive modification; MGMT; O(6)-methylguanine (O(6)-MeG).