Arsenic exposure via drinking water is associated with increased risk of human cancers, as well as a number of other dysfunctions. The investigators have demonstrated that although arsenite (the likely carcinogenic form of arsenic) is not a gene mutagen, it acts as a comutagen by interfering with DNA repair. However, DNA repair enzymes in vitro are not sensitive to arsenite implying that arsenite s effect on DNA repair in cells is not via enzyme inhibition. The investigators suggest that inhibition of DNA repair by arsenite results from an interference with p53-dependent pathways controlling cellular responses to DNA damage. Human exposure to arsenic, e.g. in drinking water, occurs over a long period of time. This proposal will address the effects of long term, low level arsenite treatment of a number of p53-related endpoints. Because they have found that rodent cells exposed to low levels of arsenite develop tolerance, whereas human cells do not, the emphasis will be on human cells.
The specific aims are first to determine the ability of arsenite and its metabolite dimethylarsinic acid (DMAA) to interfere with the cellular resoponse to x-ray-induced DNA damage in normal human diploid fibroblasts and keratinocytes. DNA-damage-in-ducible responses include transient cell cycle arrest, increase in p53 protein abundance, and the up-regulation of genes downstream of p-53(particularly gadd45 and p21). Second, the investigators will determine whether human cells which have undergone mutation, gene amplification, or transformation as a result of long term, low level arsenite or DMAA exposure(alone or with low doses of UVB) show increased frequencies of genomic instability compared with similarly treated cells which were not altered. Third, they will study the role of oxidant stress in arsenite's action by determining whether any effects seen in aims 1 (where p53-dependent fucntions are measured) and 2 (where genetic effects are measured) can be blocked by ascorbate, atocopherol, or N-acetyl-cysteine. Lastly, by expression cloning for genes which confer resistance to arsenite, they have cloned 2 cDNAs, fau (a purported tumor suppressor gene) and asr2 (whose product plays a role in apoptosis). The investigators will determine whether fau or asr2 will, when overexpressed, contribute to genomic instability in human cells.
|Uddin, Ahmed N; Burns, Fredric J; Rossman, Toby G et al. (2007) Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice. Toxicol Appl Pharmacol 221:329-38|
|Wu, Feng; Burns, Fredric J; Zhang, Ronghe et al. (2005) Arsenite-induced alterations of DNA photodamage repair and apoptosis after solar-simulation UVR in mouse keratinocytes in vitro. Environ Health Perspect 113:983-6|
|Komissarova, Elena V; Saha, Sam K; Rossman, Toby G (2005) Dead or dying: the importance of time in cytotoxicity assays using arsenite as an example. Toxicol Appl Pharmacol 202:99-107|
|Uddin, Ahmed N; Burns, Fredric J; Rossman, Toby G (2005) Vitamin E and organoselenium prevent the cocarcinogenic activity of arsenite with solar UVR in mouse skin. Carcinogenesis 26:2179-86|
|Burns, Fredric J; Uddin, Ahmed N; Wu, Feng et al. (2004) Arsenic-induced enhancement of ultraviolet radiation carcinogenesis in mouse skin: a dose-response study. Environ Health Perspect 112:599-603|
|Rossman, Toby G; Uddin, Ahmed N; Burns, Fredric J (2004) Evidence that arsenite acts as a cocarcinogen in skin cancer. Toxicol Appl Pharmacol 198:394-404|
|Rossman, Toby G (2003) Mechanism of arsenic carcinogenesis: an integrated approach. Mutat Res 533:37-65|
|Mure, Kanae; Uddin, Ahmed N; Lopez, Laura C et al. (2003) Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations. Environ Mol Mutagen 41:322-31|
|Rossman, Toby G; Visalli, Melissa A; Komissarova, Elena V (2003) fau and its ubiquitin-like domain (FUBI) transforms human osteogenic sarcoma (HOS) cells to anchorage-independence. Oncogene 22:1817-21|
|Rossman, Toby G; Uddin, Ahmed N; Burns, Fredric J et al. (2002) Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies. Environ Health Perspect 110 Suppl 5:749-52|
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