Arsenic is an important environmental carcinogen that affects millions of people worldwide throughcontaminated water supplies. Although arsenic induces various human cancers including skin, lung, bladder,kidney and liver, the carcinogenic mechanism remains unknown. With the funding support of this grant, theapplicant has shown, for the first time, that arsenic is a potent gene and chromosomal mutagen inmammalian cells and induces mostly multilocus deletions. These findings provide the first direct link betweenchromosomal abnormalities that have frequently been demonstrated in vitro and carcinogenicity in vivo.Furthermore, our recent data have shown that mitochondria are a primary target in mediating arsenicinducedgenotoxicity. The overall goal of this application is to elucidate the contribution of mitochondrial DNAmutations and cell signaling pathways in mediating the genotoxicity and apoptosis of arsenic in mammaliancells. To achieve this goal, a series of eight inter-related specific aims are proposed to address the fourtestable hypotheses. The human-hamster hybrid (A-L) cell assay will be used to ascertain the role ofmitochondrial DNA mutations and mitochondrial functions in modulating arsenic (sodium arsenite andmethylated arsenic species) induced mutations at the CD59 locus. Since mitochondrial damage is oftenassociated with induction of cell death, human melanocytes and melanoma cells will be used to define thecell signaling pathways involved in mediating arsenic-induced apoptosis. There is a profound necessity todevelop effective treatment strategy for this often fatal cancer. Furthermore, there is considerable interaction,both conceptually and in shared materials, between this project and that of Projects 2, 3 and 4. A betterunderstanding of the genotoxic and apoptotic mechanisms of arsenic will provide better interventionalapproach both in the treatment and prevention of arsenic-induced human diseases.
Showing the most recent 10 out of 333 publications
