Superfund Research Program
Genotoxic and Cell Signaling Pathways of Arsenic in Mammalian Cells
Project Leader: Tom K. Hei (Columbia University Mailman School of Public Health)
Grant Number: P42ES010349
Funding Period: 2000 - 2011
Project Summary (2006-2011)
Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. Although arsenic induces various human cancers including skin, lung, bladder, kidney and liver, the carcinogenic mechanism remains unknown. Project investigators have shown, for the first time, that arsenic is a potent gene and chromosomal mutagen in mammalian cells and induces mostly multilocus deletions. These findings provide the first direct link between chromosomal abnormalities that have frequently been demonstrated in vitro and carcinogenicity in vivo. Furthermore, recent data have shown that mitochondria are a primary target in mediating arsenic induced genotoxicity. The overall goal of this project is to elucidate the contribution of mitochondrial DNA mutations and cell signaling pathways in mediating the genotoxicity and apoptosis of arsenic in mammalian cells. To achieve this goal, a series of eight inter-related specific tasks are used to address the testable hypotheses. The human-hamster hybrid (AL) cell assay is used to ascertain the role of mitochondrial DNA mutations and mitochondrial functions in modulating arsenic (sodium arsenite and methylated arsenic species) induced mutations at the CD59 locus. Since mitochondrial damage is often associated with induction of cell death, human melanocytes and melanoma cells are used to define the cell signaling pathways involved in mediating arsenic-induced apoptosis. There is a profound necessity to develop effective treatment strategy for this often fatal cancer. Furthermore, there is considerable interaction, both conceptually and in shared materials, between this project and other projects in the program. A better understanding of the genotoxic and apoptotic mechanisms of arsenic provide better interventional approach both in the treatment and prevention of arsenic-induced human diseases.