Methylmercury exposure, mercury metabolism genotypes, and risk of adult glioma

描述（由申请人提供）：摘要胶质瘤是一种病因不明的高致死性恶性肿瘤，占成人恶性脑肿瘤的近80%。本项目的目的是对甲基汞（MeHg）暴露与神经胶质瘤风险和生存率的关系进行探索性研究。甲基汞是一种强效神经毒素，对产前接触的成人和儿童的神经功能都有不良影响。甲基汞是一种普遍存在的环境污染物，食用鱼类和贝类是主要的接触源。由于甲基汞化合物能够穿过血脑屏障，并在神经星形胶质细胞中积累，而神经星形胶质细胞是大脑中产生神经胶质瘤的细胞，因此，中枢神经系统极易受到甲基汞的毒性影响。甲基汞被认为会引发活性氧的过度产生，造成氧化应激和随后的细胞损伤。还有证据表明，甲基汞会抑制谷胱甘肽和硒蛋白的抗氧化作用，而这些酶介导硒的大部分抗氧化功能。该项目将基于一项多中心NCI资助的（R 01 CA 116174）病例对照研究，该研究探索了美国东南部主要医疗中心正在进行的成人胶质瘤的遗传和环境风险因素。所有研究参与者都可以获得用于测量微量元素水平的指甲剪和用于研究遗传易感性的口腔DNA样本。鉴于鱼类中甲基汞含量的高度可变性和汞代谢的个体差异，测量指甲屑中的甲基汞水平将比饮食评估更准确地测量甲基汞暴露。本项目的具体目标是：1）测量250例新发胶质瘤患者和250例匹配的社区对照者的趾甲甲基汞; 2）1200例病例和1200例对照中参与转运的基因的基因型功能或标记单核苷酸多态性（SLC 7A 8、SLC 7A 5、SLC 11 A2），生物转化（GCLC，GCLM），分发（MT 1A、MT 1 M、MT 2A、MT4、MTF 1）和消除（MRP 1，MRP 2）的甲基汞;和3）评估趾甲甲基汞和汞代谢基因型与神经胶质瘤的风险和患者的结果。据我们所知，这将是第一个人口研究调查甲基汞暴露作为一个潜在的神经胶质瘤的危险因素，并评估遗传变异的汞代谢与神经胶质瘤。基于一个大型的，几乎完成的病例对照研究，拟议的试点调查可能会提供新的信息，一个潜在的环境危险因素，神经胶质瘤肿瘤的发展机制，以及未来的研究方向。

DESCRIPTION (provided by applicant): Abstract Glioma is a highly lethal malignancy with unknown etiology that accounts for nearly 80% of adult malignant brain tumors. The aims of this project are to conduct an exploratory investigation of the relationship of methylmercury (MeHg) exposure with glioma risk and survival. MeHg is a potent neurotoxin associated with adverse effects on neurologic function both in adults and in children exposed prenatally. MeHg is a ubiquitous environmental contaminant with fish and shellfish consumption comprising the major source of exposure. The central nervous system is highly susceptible to the toxic effects of MeHg since the compound is able to cross the blood-brain barrier and accumulates in neural astrocytes, the cells in the brain which give rise to glioma. MeHg has been suggested to trigger the overproduction of reactive oxygen species causing oxidative stress and subsequent cellular damage. There is also evidence that MeHg inhibits the antioxidant effects of glutathione and selenoproteins, enzymes which mediate most of the antioxidant functions of selenium. The project will be based on a multicenter NCI-funded (R01 CA116174) case-control study exploring genetic and environmental risk factors for adult glioma underway at major medical centers in the Southeastern US. Nail clippings to measure levels of trace elements and oral DNA samples to study genetic susceptibility are available for all study participants. Given the high variability o MeHg content in fish and individual differences in mercury metabolism, measuring MeHg levels in nail clippings will provide a more accurate measurement of MeHg exposure than dietary assessment. Specific aims of this project are to: 1) Measure toenail MeHg in 250 incident glioma cases and 250 matched community controls; 2) Genotype functional or tagging single nucleotide polymorphisms in 1200 cases and 1200 controls for genes involved in the transport (SLC7A8, SLC7A5, SLC11A2), biotransformation (GCLC, GCLM), distribution (MT1A, MT1M, MT2A, MT4, MTF1), and elimination (MRP1, MRP2) of MeHg; and 3) Evaluate associations of toenail MeHg and mercury metabolism genotypes with glioma risk and patient outcome. To our knowledge this will be the first population study to investigate MeHg exposure as a potential glioma risk factor and to evaluate genetic variation in mercury metabolism with glioma. Based on a large, nearly completed case-control study, the proposed pilot investigation may provide new information on a potential environmental risk factor, mechanisms for glioma tumor development, and directions for future study.