Factors Modifying the Toxicity of Methylmercury in a Fish-Eating Population

描述（由申请人提供）：本提案是授权号R 01-ES 01219的修订版，标题为“改变甲基汞神经毒性的因素”。该修订将扩大母基金，以创建一个翻译/跨学科环境研究虚拟联盟（ViCTER）。最初赠款的目的是扩大塞舌尔儿童发育和营养研究，以更深入地研究研究人员的新发现，即母体长链多不饱和脂肪酸（PUFA）状况对甲基汞神经毒性的明显调节作用。研究人员假设，在他们早期的研究中观察到的明显效果改变可能是由于母体饮食中的抗氧化剂（硒和维生素E），以及食用鱼类的n-3 PUFA的抗炎作用。谷氨酰胺（GSH）是排泄甲基汞所必需的，最近有证据表明，与GSH代谢相关的基因变体是体内甲基汞滞留的决定因素。这种遗传关联尚未确定在一个良好的特点高吃鱼的人口。此外，已显示负责PUFA代谢的基因影响全身PUFA状态。这些遗传变异可能会影响甲基汞和多不饱和脂肪酸的剂量，反过来又强烈抵消甲基汞的神经毒性，并同样影响n-3多不饱和脂肪酸的保护性抗炎作用。了解这些基因对甲基汞、多不饱和脂肪酸和抗氧化剂代谢的影响，将首次澄清鱼类摄入风险-效益比的人口差异是否可以通过遗传变异来解释。 拟议项目将 创建一个虚拟联盟，主题为：汞毒性和营养代谢的遗传修饰剂。该联盟将包括两个新的合作伙伴。隆德大学的遗传流行病学家Karin Broberg博士多年来一直在研究人类人群中与金属毒物相关的单核苷酸多态性（SNP），并将分析SCDNS队列母亲的DNA样本。一旦母体血液样本的甲基汞和多不饱和脂肪酸相关的单核苷酸的特点，统计分析将被用来调查遗传变异如何可能修改个人甲基汞暴露和多不饱和脂肪酸的状态，反过来，解释单核苷酸如何修改甲基汞毒性（毒理动力学）在母研究。佛蒙特大学的发育神经生物学家Matthew兰德博士利用果蝇平台鉴定了与发育过程中对甲基汞耐受性相关的基因。这两项新的调查增加了新颖和创新的机制研究，以表征人类遗传变异对甲基汞的动力学和毒性以及多不饱和脂肪酸和膳食抗氧化剂的有益影响。他们以前的合作已经证明了创新的跨学科和翻译协同作用，例如Broberg博士确定的基因可以在兰德博士的实验室进行测试，而兰德博士与果蝇的甲基汞耐受性相关的基因和基因变异可以帮助Broberg博士将工作重点放在对甲基汞的神经毒性特别重要的单核苷酸多态性上。

DESCRIPTION (provided by applicant): This proposal is a revision of grant number R01-ES01219, entitled "Factors modifying the Neurotoxicity of Methylmercury". The revision will expand the parent grant to create a Virtual Consortium for Translational/Transdisciplinary Environmental Research (ViCTER). The aim of the original grant is to extend the Seychelles Child Development and Nutrition Study (SCDNS) to study in more depth the investigators' novel finding of an apparent modulation of MeHg neurotoxicity by maternal long- chain polyunsaturated fatty acid (PUFA) status. The investigators hypothesize that the apparent effect modification seen in their earlier study may have been due to anti- oxidants (selenium and vitamin E) in the maternal diet, as well as the anti-inflammatory effects of n-3 PUFA from fish consumption. Glutathione (GSH) is essential for excretion of MeHg and there is recent evidence that variants of genes associated with GSH metabolism are determinants of MeHg retention in the body. This genetic association has yet to be determined in a well-characterized high fish eating population. Furthermore, genes responsible for PUFA metabolism have been shown to influence the systemic PUFA status. These genetic variations may influence MeHg and PUFA dose that in turn strongly offset MeHg neurotoxicity and similarly influence the protective anti-inflammatory effect of n-3 PUFA. Understanding these genes' influence on MeHg, PUFA and antioxidant metabolism would clarify, for the first time, whether population differences in the ris-benefit ratio for fish intake can be accounted for by genetic variation. The proposed project will create a Virtual Consortium with the theme: Genetic Modifiers of Mercury Toxicity and Nutrient Metabolism. The consortium will include two new partners. Dr. Karin Broberg, a genetic epidemiologist at the University of Lund, has studied single nucleotide polymorphisms (SNPs) related to metal toxicokinetics in human populations for several years and will analyze DNA samples from the SCDNS cohort mothers. Once maternal blood samples have been characterized for MeHg and PUFA related SNPs, statistical analyses will be used to investigate how genetic variation may modify individual MeHg exposure and PUFA status and, in turn, explain how the SNPs modify MeHg toxicity (toxicodynamics) in the parent study. Dr. Matthew Rand, a developmental neurobiologist at the University of Vermont, has used a Drosophila platform to identify genes associated with tolerance to MeHg during development. Both new investigations add novel and innovative mechanistic studies to characterize human genetic variations that impact on the kinetics and toxicity of MeHg as well as beneficial effects of PUFA and dietary antioxidants. Their previous collaborations have demonstrated innovative transdisciplinary and translational synergies such that genes identified by Dr. Broberg can be tested in Dr. Rand's laboratory while genes and genetic variations in those genes linked to MeHg tolerance in Drosophila by Dr. Rand can help focus Dr. Broberg's work on SNPs that appear particularly important to the neurotoxicity of MeHg.