Environmental exposure to organophosphates and onset of genotoxcity and oncogenes

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Environmental toxins have been shown to induce genotoxic and genome-destabilizing DNA lesions that must be repaired to prevent oncogenesis. Recently, concerns have arisen regarding the relative safety of organophosphate pesticides to the environment. Organophosphate residues are found in human blood and urine samples, livestock, avian species, soil samples, drinking water and foods for human consumption. Chronic exposure to pesticides, including organophosphates, leads to an increased incidence of DNA damage and chromosomal alterations, suggesting that pesticides may act as environmental carcinogens. This pilot project will therefore study genomic instability induced by the organophosphate Isofenphos (IFF). Chronic IFF poisoning has been linked to myeloid metaplasia and acute myelogenous leukemia. Such oncogenic properties likely stem from IFF induced chromosomal aberrations observed in human lymphocytes. Here we propose to extend these observations by determining putative mechanism(s) utilized by IFF to induce chromosomal damage and create genomic instability in lymphocytes. In addition, we will identify DNA repair systems likely to be involved in reversing IFP-induced DNA damage and define the DNA damage response pathways that mediate the cellular reaction to pesticide exposure. Relevance: This pilot project will converge the toxicology expertise of Dr. Heyliger and the DNA damage and repair expertise of Dr. Sobol to dissect mechanisms associated with toxicity and carcinogenicity associated with environmental toxicants such as isophenfos.