Critical roles of DNA repair and vitamin C in hexavalent chromium-induced toxicity.

摘要

Hexavalent chromium [Cr(VI] is one of the most potent carcinogenic chemicals. Several million industrial workers worldwide are exposed to Cr and Cr-containing compounds. Environmental contamination of soil and drinking water with Cr(VI) has become a significant concern due to continuous industrial emissions and the presence of heavily contaminated sites in the vicinity of residential areas. Currently, the molecular mechanisms of Cr(VI)-induced carcinogenesis remains unclear. However, due to the broad spectrum of Cr-lesions produced during Cr(VI) reduction and the complex nature of Cr genotoxicity, numerous components are thought to be involved. The studies presented in this thesis examine genetic and dietary factors which contribute to the cytotoxic and genotoxic effects of Cr(VI). In human cells, we demonstrate that nucleotide excision repair is responsible for the removal of Cr-induced DNA adducts and protection against chromate toxicity. We also provide genetic evidence for the role of monofunctional Cr-DNA adducts in the toxic effects of this metal. Vitamin C is considered to be a major antioxidant that usually protects cells against DNA damage. However, it is also a reducer of transition metals to their more reactive forms. We have shown that vitamin C enhances the cytotoxic, mutagenic, and genotoxic potential of Cr(VI) at otherwise nontoxic doses. Ascorbate-mediated toxicity was caused by aberrant mismatch repair of Cr damage in replicated DNA. This suggests that mismatch repair plays a major role in the cellular responses to Cr over a broad range of doses and therefore, it may represent an important factor in the individual susceptibility to genetic damage in Cr-exposed populations. Taken together, the results obtained in this thesis provide insights into genetic and dietary constituents which may increase Cr(VI)-induced carcinogenesis.