State Water Resources Research Institute Program

Project ID: 2007DC91B
Title: Molecular Signaling by Environmental Arsenicals in Mammalian Cells
Project Type: Research
Start Date: 3/01/2007
End Date: 2/29/2008
Congressional District: District of Columbia
Focus Categories: Toxic Substances, Water Quality
Keywords: Arsenic, Cell cycle, Skin Cancer, Signaling
Principal Investigator: Kumar, Deepak
Federal Funds: $ 14,960
Non-Federal Matching Funds: $ 5,086
Abstract: 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.

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