Environmental exposure to organophosphates and onset of genotoxcity and oncogenes

有机磷酸酯的环境暴露以及基因毒性和癌基因的发生

基本信息

批准号：
7917436
负责人：
Robert W Sobol
金额：
$ 6.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7917436
关键词：
Acute Myelocytic Leukemia Aftercare Astrocytes Banana Birds Blast Cell Blood Carrots - dietary Cell Cycle Chemicals Chlorpyrifos Cholinesterase Inhibitors Chromosome Fragile Sites Chromosome abnormality Chronic Consumption DNA Damage DNA Repair DNA lesion Development Environment Environmental Carcinogens Environmental Exposure Environmental Health Exposure to Food Genetic Genome Genomic Instability Hand Health Human Incidence Individual Insecta Investigation Isoptera K-562 Link Livestock Lymphocyte Mediating Myelogenous Myeloid Metaplasia Oligodendroglia Oncogenes Oncogenic Organophosphates Pathway interactions Pesticide Residues Pesticides Phenotype Pilot Projects Poisoning Population Property Reaction Relative (related person)Risk Safety Sampling Soil System Techniques Toxic Environmental Substances Toxic effect Toxicology Universities University of Pittsburgh Cancer Institute Urine Water Work base carcinogenicity drinking water experience fruits and vegetables genotoxicity isofenphos leukemia leukemogenesis oncology pesticide exposure prevent repaired response soil sampling stem toxic organophosphate insecticide exposure tumorigenesis

项目摘要

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.

环境毒素已被证明会诱发基因毒性和基因组不稳定的 DNA 损伤，必须加以解决修复以防止肿瘤发生。最近，人们对这种药物的相对安全性产生了担忧。有机磷农药对环境的影响。人体血液和尿液中发现有机磷残留样品、牲畜、鸟类物种、土壤样品、饮用水和供人类消费的食品。慢性的接触农药，包括有机磷酸酯，会导致 DNA 损伤的发生率增加，染色体改变，表明农药可能是环境致癌物。本次试点项目因此，我们将研究有机磷酸酯异芬磷 (IFF) 引起的基因组不稳定性。慢性IFF 中毒与骨髓化生和急性髓性白血病有关。这种致癌特性可能源于在人类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 用于诱导染色体的假定机制来扩展这些观察结果损伤并造成淋巴细胞基因组不稳定。此外，我们将确定可能的 DNA 修复系统参与逆转 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：该试点项目将融合毒理学 Heyliger 博士的专业知识和 Sobol 博士的 DNA 损伤和修复专业知识来剖析机制与异苯磷等环境毒物相关的毒性和致癌性有关。