Fish is a major protein source and a primary source of nutrients such as long chain polyunsaturated fatty acids (PUFA) which are essential for maternal and fetal health. All fish also contain methylmercury (MeHg), a known neurotoxicant at high levels of exposure as demonstrated by accidental poisonings in Japan and Iraq. However, despite many years of research, there is still substantial uncertainty regarding the safety of eating fish with natural background levels of MeHg during pregnancy. Identifying the potential reasons for this uncertainty is important, as limited understanding of factors influencing MeHg toxicity represents a challenge for promulgating public policies on fish consumption. Our studies in the Republic of Seychelles have revealed that the association between prenatal MeHg exposure from maternal fish consumption and child developmental outcomes is far more complex than previously anticipated, and likely involve concomitant dietary exposures and genetic factors influencing MeHg toxicity. To examine these complex relationships, we enrolled a cohort of 1,536 mother-child pairs and characterized them for prenatal MeHg exposure, maternal nutritional status, and developmental outcomes at 20 months of age. Further, we examined the modifying role of genetic factors on MeHg metabolism and toxicity in our human cohort and in a Drosophila model. While we continue to find that MeHg does not influence neurodevelopmental outcomes independent of nutritional status, our epidemiological and experimental genetics findings support a novel biological framework that describes the role of GSH-dependent pathways and inflammation in MeHg toxicity. We plan to examine this framework, and will continue both developmental follow-up of the children and the exploration of nutritional and genetic components. We aim to evaluate how prenatal nutritional factors affecting inflammation, and genetic factors affecting GSH-dependent pathways influence associations between prenatal MeHg exposure and developmental outcomes. We hypothesize that the association between prenatal MeHg exposure from fish consumption and developmental outcomes is largely influenced by endogenous "protective metabolic pathways" (toxicokinetics) and exogenous dietary factors (toxicokinetics, toxicodynamics). We will re-examine the children at seven years of age for developmental outcomes, and will draw upon stored blood samples from both mothers and child's cord to investigate additional genetic factors involved in MeHg toxicokinetics and toxicodynamics, and measure inflammatory biomarkers as indicators of the role of the maternal inflammatory milieu in modifying MeHg toxicity. We plan to use experimental genetic studies to confirm the associations observed in our cohort and generate new hypotheses that can then be studied with an epidemiologic approach. DNA genotyping was determined for mothers and offspring. Polymorphisms of genes important to transfer of MeHg across the blood-brain barrier (ATP binding cassette family C: ABC) and for the metabolism of PUFA (fatty acid desaturase: FADS) were associated with maternal MeHg and maternal PUFA levels but not clearly with developmental endpoints. The project also includes a series of experiments using the Drosophila model which will examine the role of ABC and glutathione S-Transporters: GST genes for MeHg tolerance. Our approach will address novel hypotheses that should bring clarity to the interpretation of previous cohort studies, but also assist public policy makers in crafting advice to women of child-bearing age regarding the safety of consuming fish during pregnancy. ExpandCollapse Abstract