Environmental exposure to organophosphates and onset of genotoxcity and oncogenes

环境毒素已被证明会诱导遗传毒性和基因组不稳定的DNA损伤， 防止肿瘤发生。最近，人们开始关注 有机磷农药对环境的影响。人体血液和尿液中发现有有机磷残留物 样品、牲畜、鸟类物种、土壤样品、饮用水和人类消费食品。慢性 接触农药，包括有机磷，导致DNA损伤的发生率增加， 染色体改变，表明农药可能作为环境致癌物。这一试点项目 因此，将研究由有机磷异柳磷（IFF）诱导的基因组不稳定性。慢性IFF 中毒与骨髓化生和急性骨髓性白血病有关。这种致癌特性 可能源于在人淋巴细胞中观察到的IFF诱导的染色体畸变。在此，我们建议 通过确定IFF诱导染色体畸变的假定机制来扩展这些观察结果。 破坏并造成淋巴细胞的基因组不稳定性。此外，我们将确定DNA修复系统可能 参与逆转IFP诱导的DNA损伤，并定义DNA损伤反应途径， 介导细胞对农药暴露的反应。相关性：该试点项目将汇集毒理学 Heyliger博士的专业知识和Sobol博士的DNA损伤和修复专业知识来解剖机制 与环境毒物如异硫磷有关的毒性和致癌性。

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.