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

甲基汞暴露、汞代谢基因型和成人神经胶质瘤的风险

• 批准号: 8582978
• 负责人: Kathleen M. Egan
• 金额: $ 8.43万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8582978
• 关键词: ABCC1 gene; Accounting; Adult; Adult Glioma; Adverse effects; Antioxidants; Astrocytes; Blood - brain barrier anatomy; Brain; Case-Control Studies; Cells; Central Nervous System Neoplasms; Child; Clip; Communities; Consumption; DNA; Development; Dietary Assessment; Environmental Pollution; Environmental Risk Factor; Enzymes; Etiology; Evaluation; Excess Mortality; Fishes; Funding; Future; GCLC gene; GCLM gene; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Glioblastoma; Glioma; Glutathione; Grant; Human; Individual Differences; Investigation; MMP2 gene; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Mediating; Medical center; Mercury; Metabolic Biotransformation; Metabolism; Methylmercury Compounds; Nail plate; Nervous System Physiology; Neuraxis; Neurotoxins; Oral; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Population Study; Reactive Oxygen Species; Resources; Risk; Risk Factors; Sampling; Selenium; Shellfish; Single Nucleotide Polymorphism; Source; Structure of nail of toe; Toxic effect; Trace Elements; Variant; abstracting; base; cancer epidemiology; methylmercury exposure; mortality; prenatal exposure; programs; public health relevance; relating to nervous system; response; selenoprotein; tumor; uptake

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.

描述（由申请人提供）：抽象神经胶质瘤是一种高度致命的恶性肿瘤，病因未知，占成人恶性脑肿瘤的近80％。该项目的目的是对甲基汞（MEHG）与神经胶质瘤风险和生存的关系进行探索性研究。 MEHG是一种有效的神经毒素，与成人和儿童在产前暴露的儿童中对神经功能的不良影响相关。 MEHG是一种无处不在的环境污染物，其鱼类和贝类消耗包括主要的暴露来源。中枢神经系统非常容易受到MEHG的毒性作用，因为该化合物能够越过血脑屏障并积聚在神经星形胶质细胞中，这会引起胶质瘤。有人建议MEHG触发活性氧的过量生产，从而导致氧化应激和随后的细胞损伤。也有证据表明，MEHG抑制了谷胱甘肽和硒蛋白的抗氧化作用，这些酶介导了大多数硒的抗氧化剂功能。该项目将基于由NCI资助的（R01 CA116174）病例对照研究，该研究探讨了美国东南部主要医疗中心成人神经胶质瘤的遗传和环境危险因素。所有研究参与者都可以使用指甲剪接以测量痕量元素和口服DNA样品的水平以研究遗传敏感性。鉴于鱼类中的MEHG含量很高，并且在汞代谢中的个体差异中，测量指甲剪发中的MEHG水平将比饮食评估更准确地测量MEHG暴露。该项目的具体目的是：1）在250例胶质瘤病例和250个匹配的社区控制中测量脚趾甲MEHG； 2）在1200例病例中的基因型功能或标记单核苷酸多态性和传输基因的1200个对照（SLC7A8，SLC7A5，SLC11A2），生物转化（GCLC，GCLM）（GCLM，GCLM），分布MEHG的消除（MRP1，MRP2）； 3）评估脚趾甲MEHG和汞代谢基因型与神经胶质瘤风险和患者预后的关联。据我们所知，这将是首次研究MEHG暴露为潜在神经胶质瘤危险因素并评估与神经胶质瘤汞代谢的遗传变异的人群研究。基于一项大型，几乎完成的病例对照研究，拟议的试点研究可能会提供有关潜在环境风险因素，神经胶质瘤肿瘤发育机制的新信息以及未来研究的方向。