Water Resources Research Act Program

Details for Project ID 2007DC91B

Molecular Signaling by Environmental Arsenicals in Mammalian Cells

Institute: District of Columbia
Year Established: 2007 Start Date: 2007-03-01 End Date: 2008-02-29
Total Federal Funds: $14,960 Total Non-Federal Funds: $5,086

Principal Investigators: Deepak Kumar

Project Summary: Arsenic is a major contaminant in drinking water that is associated with skin lesions, peripheral vascular disease, hypertension and various cancers such as skin, lung and bladder cancer. Additionally, humans are exposed to organic arsenicals when used as pesticides and herbicides (e.g., monomethylarsonic acid, dimethylarsinic acid (DMAV) also known as cacodylic acid). The main sources of arsenic in drinking water are erosion of natural deposits; runoff from orchards, runoff from glass and electronics production wastes. Although, arsenic is a known human carcinogen in vitro, the mechanisms of arsenic toxicity and its carcinogenic effects are poorly understood. Unlike many other carcinogens, arsenical compounds do not directly induce gene mutations. Deregulation of cell cycle is the main event in cancer development. One hypothesis is that arsenic modulates key cell cycle regulatory proteins and induces transformation events in mammalian cells. In the present proposal, we will study the 3 checkpoints of the human cell cycle in response to low dose arsenic treatment. Arsenic primarily accumulates in the skin. We will study the use of cell-cycle patterns of normal human keratinocytes as well as expression of cell cycle regulatory proteins (cyclins and CDKs) as biomarkers of arsenic toxicity. We will also investigate the modulation (if any) of various oncogenic pathways such as AKT, MAPK and NFkB in response to arsenic. The signaling pathways modulated by Arsenic will help understand the arsenic toxicity at the molecular level and help make informed decisions about its exposure.