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

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%。本项目旨在探索性研究甲基汞（MeHg）暴露与胶质瘤风险和生存的关系。甲汞是一种强效神经毒素，对成人和产前暴露的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暴露源。中枢神经系统对甲基汞的毒性作用非常敏感，因为这种化合物能够穿过血脑屏障，在神经星形胶质细胞中积累，这种细胞是大脑中导致神经胶质瘤的细胞。甲基汞被认为会引发活性氧的过量产生，导致氧化应激和随后的细胞损伤。也有证据表明，甲基汞抑制谷胱甘肽和硒蛋白的抗氧化作用，这些酶介导硒的大部分抗氧化功能。该项目将基于一项由nci资助的多中心病例对照研究（R01 CA116174），该研究正在美国东南部主要医疗中心进行，旨在探索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，测量指甲剪下的甲基汞水平将比饮食评估提供更准确的甲基汞暴露测量。该项目的具体目的是：1)测量250例胶质瘤病例和250例匹配的社区对照者的趾甲甲汞含量；2) 1200例MeHg转运（SLC7A8、SLC7A5、SLC11A2）、生物转化（GCLC、GCLM）、分布（MT1A、MT1M、MT2A、MT4、MTF1）和消除（MRP1、MRP2）相关基因的基因型功能或标记单核苷酸多态性；3)评估趾甲甲基汞和汞代谢基因型与胶质瘤风险和患者预后的关系。据我们所知，这将是第一个将甲基汞暴露作为潜在神经胶质瘤危险因素的人群研究，并评估神经胶质瘤汞代谢的遗传变异。基于一项几乎完成的大型病例对照研究，拟议的试点调查可能为潜在的环境风险因素、胶质瘤发生的机制以及未来的研究方向提供新的信息。

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.