Hexavalent chromium [Cr(VI)] is firmly established as a human carcinogen by epidemiological studies in occupationally exposed groups from different countries. The presence of this toxic metal at numerous Superfund sites and in drinking water across many states has also raised significant public health concerns regarding cancer and other health risks associated with environmental exposures to Cr(VI). Ingestion of Cr(VI) through drinking water produced clear evidence of carcinogenicity in the small intestine of mice. The low-dose extrapolation of these animal data to environmental risks in humans requires knowledge of the mechanism of the carcinogenic action for Cr(VI), which dictates the use of specific extrapolation models. Cr(VI) generates Cr-DNA adducts as the most abundant form of DNA damage but these adducts are weakly duplex-distorting and do not induce classic DNA damage responses. This project will investigate a hypothesis on a major role of DNA repair products of the initially formed Cr-DNA damage in the activation of noncanonical branches of genotoxic stress signaling. We will also examine the biochemical processes governing the responsiveness of the stress-sensitive transcription factor p53 and a protective G1 checkpoint to Cr-DNA damage. The completion of this work is expected to provide mechanistic explanations for unusual genetic features of Cr(VI)-induced lung tumors and improve human risk assessment.
Hexavalent chromium (chromium-6, chrome-6) is a cancer-causing metal in humans and laboratory animals. It is commonly found in the workplace of many metal-processing occupations and is present in drinking water across many states in the country. This project is investigating how human cells respond to DNA damage by chromium-6, which can help explain the presence of specific genetic alterations in chromium-associated human lung tumors. A completion of the proposed work will improve assessment of human cancer risks resulting from Cr(VI) exposures.
|Luczak, Michal W; Zhitkovich, Anatoly (2018) Monoubiquitinated ?-H2AX: Abundant product and specific biomarker for non-apoptotic DNA double-strand breaks. Toxicol Appl Pharmacol 355:238-246|
|Krawic, Casey; Zhitkovich, Anatoly (2018) Toxicological Antagonism among Welding Fume Metals: Inactivation of Soluble Cr(VI) by Iron. Chem Res Toxicol 31:1172-1184|