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.
A better understanding of the genetic factors influencing toxicity of MeHg and protection offered by beneficial nutrients in fish and the overall diet will result from the proposed expansion of the SCDNS under the ViCTER mechanism. Data on gene regulation of MeHg toxicity and metabolism of dietary PUFA and antioxidants will provide insights into the mechanisms underlying the interactions between nutrients and MeHg and, in turn, assist policymakers in formulating better targeted reference values to women of child-bearing age regarding fish consumption. The expanded scope of the SCDNS should also open new avenues for research clarifying the pathway between consuming fish and child development.
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