Effects of pesticides on prostate cancer progression in PTEN mutant mice

描述（由申请人提供）：该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*：使用非人类模型的环境暴露对表型结果的影响。作为一个群体，农民患前列腺癌的风险最高，但原因尚不清楚。农业健康研究将有一级前列腺癌家族史的农民和专业农药施药人员接触某些有机磷硫代农药与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，但其可能发生的生物学机制尚不清楚。这些信息不仅对更好地确定这些农药对农场工人和其他接触这些化学品的人构成的风险至关重要，而且还可能促进我们对普通人群中前列腺癌进展的理解。农药暴露与前列腺癌进展之间的机制联系的实验探索在人类中是困难的。因此，本提案的目的是在遗传易发前列腺癌前病变的小鼠模型（B6:PTEN/luc）中验证暴露于有机磷硫酸盐加速前列腺癌进展的假设，从而为探索这些联系建立实验平台。我们的模型采用复杂的成像技术，可用于快速评估暴露于环境挑战对前列腺癌进展的影响。该模型一般适用于评估其他环境暴露，并可用于人类无法理解的环境暴露与前列腺癌病因之间的机制联系。

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.