Effects of pesticides on prostate cancer progression in PTEN mutant mice

农药对 PTEN 突变小鼠前列腺癌进展的影响

• 批准号: 7814051
• 负责人: Michael D Henry
• 金额: $ 31.89万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814051
• 关键词: Acute; Address; Adenocarcinoma; Affect; Agriculture; Androgens; Animal Model; Apoptosis; Area; Biological Markers; Biology; Bioluminescence; Cancer Etiology; Cell Proliferation; Cellular biology; Chemicals; Chlorpyrifos; Chronic; Clinical; Cohort Studies; Data; Detection; Diagnosis; Disease; Disease Outcome; Disease Progression; Environmental Exposure; Environmental Pollution; Environmental Risk Factor; Epidemiologic Studies; Epithelial Cells; Epithelium; Etiology; Exposure to; Family history of; Follow-Up Studies; Fostering; Future; General Population; Genetic; Genetic Predisposition to Disease; Goals; Grant; Health; Herbicides; Human; Image; Imaging technology; Indolent; Iowa; Laboratories; Lesion; Life; Link; Malignant neoplasm of prostate; Modeling; Mus; Mutant Strains Mice; North Carolina; Occupational; Occupational Exposure; Outcome; PC3 cell line; PTEN gene; Pesticides; Phenotype; Premalignant; Prevention; Process; Prostate; Risk; Signal Pathway; Skin Neoplasms; Testing; Time; Translational Research; Tumor Suppressor Genes; Work; base; cancer cell; cancer risk; cell motility; farm worker; farmer; gene environment interaction; human disease; in vivo; interest; male; malignant state; mouse model; novel strategies; pesticide exposure; prevent; prospective; public health relevance; tumor progression

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- ES-101*: Effects of Environmental Exposures on Phenotypic Outcomes Using Non-Human Models. Farmers as a group have the highest occupational risk for prostate cancer, but the causes for this are unknown. The Agricultural Health Study associated exposure to certain organophosphorothioate pesticides with increased prostate cancer risk in farmers and professional pesticide applicators with a first-degree family history of prostate cancer. These findings indicate that exposure to these environmental contaminants may interact with a genetic predisposition toward prostate cancer, but the biologic mechanism(s) by which this might occur remain unclear. This information is critical not only for better defining the risks posed by these pesticides for farm workers and others exposed to these chemicals, but also may advance our understanding of prostate cancer progression in the general population. Experimental exploration of the mechanistic links between pesticide exposure and prostate cancer progression will be difficult in humans. Therefore, the objective of this proposal is to test the hypothesis that exposure to organophosphorothioates accelerates prostate cancer progression in a mouse model genetically predisposed to develop premalignant prostate lesions (B6:PTEN/luc) in order to establish an experimental platform for exploring these links. Our model employs sophisticated imaging technology which can be used to rapidly assess the effects of exposures to environmental challenges on prostate cancer progression. This model is generally applicable to evaluating other environmental exposures and can be used in ways not possible in humans to understand the mechanistic links between environmental exposures and the etiology of prostate cancer. PUBLIC HEALTH RELEVANCE: Epidemiologic studies indicate that farmers and others occupationally exposed to certain organophosphorothioate pesticides may have further increased risk for prostate cancer when there is a first degree family history of this disease. Because the mechanistic basis of this finding will be difficult to determine in humans, here we will explore whether exposure of mice genetically predisposed to develop prostate cancer to these pesticides affects disease progression. Elucidating the mechanisms by which certain pesticides influence prostate cancer progression may impact the prevention, detection, and treatment of this disease.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）转化科学和特定的挑战主题，15- ES-101*：环境暴露对使用非人类模型的表型结果的影响。农民作为一个群体，患前列腺癌的职业风险最高，但其原因尚不清楚。农业健康研究将接触某些有机硫代磷农药与具有一级前列腺癌家族史的农民和专业农药施用者的前列腺癌风险增加联系起来。这些发现表明，暴露于这些环境污染物可能与前列腺癌的遗传易感性相互作用，但这种情况可能发生的生物学机制仍不清楚。这些信息不仅对于更好地确定这些农药对农场工人和其他暴露于这些化学品的人构成的风险至关重要，而且还可以促进我们对一般人群中前列腺癌进展的理解。在人类中，对农药暴露与前列腺癌进展之间的机制联系进行实验探索将是困难的。因此，本提案的目的是检验暴露于有机硫代磷酸酯加速前列腺癌进展的假设，在遗传上倾向于发展癌前前列腺病变（B6：PTEN/luc）的小鼠模型中，以建立探索这些联系的实验平台。我们的模型采用了先进的成像技术，可用于快速评估暴露于环境挑战对前列腺癌进展的影响。该模型通常适用于评估其他环境暴露，并且可以以人类不可能的方式使用，以了解环境暴露与前列腺癌病因之间的机制联系。 公共卫生相关性：流行病学研究表明，农民和其他职业接触某些有机硫代磷农药的人，如果有一级前列腺癌家族史，患前列腺癌的风险可能会进一步增加。由于这一发现的机制基础将难以在人类中确定，在这里，我们将探讨暴露于遗传上易患前列腺癌的小鼠是否会影响疾病的进展。阐明某些农药影响前列腺癌进展的机制可能会影响这种疾病的预防，检测和治疗。