Persistent Organochlorines and Testicular Cancer Risk

说明： 睾丸生殖细胞癌(TGCC)的发病率最高， 自20世纪50年代以来，恶性肿瘤在年轻人中的发展已经增加了几倍。 在动物系统中的实验和观察研究引起了人们的关注。 人口增长率的上升部分是由于全人口范围内的、持续的 接触工农业生产中的内分泌干扰物 申请。人类接触此类化学物质是否与TGCC有关 风险尚未被直接研究。我们建议确定是否存在 TGCC与血清中持久性有机氯的水平有关，重点是 P，p‘-DDE、多氯联苯(PCbs)和其他化合物(例如， 狄氏剂、六氯环己烷、六氯苯)。我们还将检查 与这些化合物相关的TGCC风险是否由基因改变 对这些化合物可能改变TGCC风险的机制的敏感性。 例如，我们将确定TGCC风险是否与互动有关 1)血清p，p‘-DDE和多谷氨酰胺重复序列多态性升高 在雄激素受体(AR)基因中，以及2)血清PCb水平升高和 氧化应激防御酶基因的多态性。 为了达到这些目的，我们将对男性进行辅助调查 雄激素研究(MARS)，一个最近发起的，由NCI资助的， TGCC分子遗传危险因素的人群病例对照研究 MARS资助包括基于人口的标准病例和控制确定 和招募，详细的面谈，抽血和分子 雄激素合成、代谢和基因多态的遗传分析 信号基因(包括AR)。辅助研究将包括大约 250例TGCC和750例对照作为MARS的一部分。提供资金予 辅助性研究将提供1)快速查明和招募病例 减少化疗对血清有机氯测定影响的系统 TGCC患者体内残留情况；2)有机氯农药和多氯联苯 高分辨气相色谱/同位素稀释法高分辨质量 光谱分析；以及3)常见的基因多态分析 氧化应激防御系统(锰超氧化物歧化酶、谷胱甘肽 S-转移酶M1、M3、T1和P1)。将有足够的统计力量来 检测相对较弱的总体关联，以及不到3倍的关联 相互作用的影响。这一结果应该会为我们的 对环境污染物在致病机制中作用的认识 TGCC。

DESCRIPTION: The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy developing in young men, has increased several-fold since the 1950s. Experimental and observational studies in animal systems have raised concern that the increasing rates are due in part to population-wide, persistent exposure to endocrine disrupting compounds from industrial and agricultural applications. Whether human exposure to such chemicals is associated with TGCC risk has not been directly studied. We propose to determine whether the risk of TGCC is related to serum levels of persistent organochlorines, focusing on p,p'-DDE, polychlorinated biphenyls (PCBs), and other compounds (e.g., dieldrin, hexachlorocyclohexanes, hexachlorobenzene). We also will examine whether the risk of TGCC associated with these compounds is modified by genetic susceptibility to mechanisms through which these compounds may alter TGCC risk. For example, we will determine whether TGCC risk is related to interactions between 1) elevated serum p,p'-DDE and polyglutamine repeat tract polymorphisms in the androgen receptor (AR) gene, and 2) elevated serum PCB levels and polymorphisms in oxidative stress defense enzyme genes. To address these aims, we will conduct an ancillary investigation to the Male Androgen Research Study (MARS), a recently-initiated, NCI-funded, population-based case-control study of molecular genetic risk factors for TGCC. MARS funding includes standard population-based case and control ascertainment and recruitment, a detailed in-person interview, blood draw, and molecular genetic analyses of polymorphisms in androgen synthesis, metabolism, and signaling genes (including AR). The ancillary study will include approximately 250 cases of TGCC and 750 controls recruited as part of MARS. Funding for the ancillary study will provide for 1) a rapid case ascertainment and recruitment system to minimize effects of chemotherapy on serum measures of organochlorine residues among TGCC patients; 2) assay of organochlorine pesticides and PCBs by high resolution gas chromatography/isotope dilution high resolution mass spectometry; and 3) assays for common polymorphisms in genes involved in oxidative stress defense systems (manganese superoxide dismutase, glutathione S-transferases M1, M3, T1, and P1). There will be adequate statistical power to detect relatively weak overall associations, as well as less than 3-fold interaction effects. The results should add significant new information to our understanding of the role of environmental contaminants to the pathogenesis of TGCC.