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

描述（由申请人提供）：该提案是对批准号R01-ES01219的修订，标题为“甲基汞神经毒性的修饰因素”。该修订将扩大家长拨款，以创建一个转化/跨学科环境研究虚拟联盟（ViCTER）。最初拨款的目的是扩展塞舌尔儿童发育和营养研究（SCDNS），以更深入地研究研究者的新发现，即母体长链多不饱和脂肪酸（PUFA）状态对甲基汞神经毒性的明显调节。研究人员推测，在他们早期的研究中看到的明显的效果变化可能是由于母亲饮食中的抗氧化剂（硒和维生素E），以及食用鱼类中n-3 PUFA的抗炎作用。谷胱甘肽（GSH）对甲基汞的排泄至关重要，最近有证据表明，与谷胱甘肽代谢相关的基因变异是体内甲基汞滞留的决定因素。这种遗传关联尚未在一个特征鲜明的高食鱼人群中确定。此外，负责PUFA代谢的基因已被证明影响全身PUFA状态。这些遗传变异可能影响MeHg和PUFA剂量，从而强烈抵消MeHg的神经毒性，同样影响n-3 PUFA的保护性抗炎作用。了解这些基因对甲基汞、多聚脂肪酸和抗氧化代谢的影响，将首次阐明鱼类摄入风险效益比的种群差异是否可以用遗传变异来解释。拟议的项目将

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.