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

 描述(申请人提供)：鱼是主要的蛋白质来源和主要的营养来源，如对母婴健康至关重要的长链多不饱和脂肪酸(PUFA)。所有鱼类还含有甲基汞(MeHg)，这是一种已知的高暴露水平的神经毒物，日本和伊拉克的意外中毒证明了这一点。然而，尽管多年来的研究，在怀孕期间食用具有自然背景水平的甲基汞的鱼的安全性仍然存在很大的不确定性。确定这种不确定性的潜在原因很重要，因为对影响甲基汞毒性的因素了解有限，对颁布有关鱼类消费的公共政策是一项挑战。我们在塞舌尔共和国的研究表明，母亲食用鱼类造成的产前甲基汞暴露与儿童发育结果之间的联系比之前预期的要复杂得多，可能涉及伴随的饮食暴露和影响甲基汞毒性的遗传因素。为了检验这些复杂的关系，我们招募了1,536对母子对，并对他们在20个月大时的产前甲基汞暴露、母亲营养状况和发育结果进行了表征。此外，在我们的人类队列和果蝇模型中，我们研究了遗传因素对甲基汞代谢和毒性的调节作用。虽然我们继续发现甲基汞不影响独立于营养状态的神经发育结果，但我们的流行病学和实验遗传学发现支持一个新的生物学框架，该框架描述了谷胱甘肽依赖的途径和炎症在甲基汞中毒中的作用。我们计划审查这一框架，并将继续对儿童的发育跟踪以及对营养和遗传成分的探索。我们的目的是评估产前营养因素如何影响炎症，以及遗传因素如何影响GSH依赖途径影响产前甲基汞暴露和发育结果之间的关联。我们假设，出生前食用鱼类造成的甲基汞暴露与发育结果之间的关联在很大程度上受到内源性“保护性代谢途径”(毒物动力学)和外源饮食因素(毒物动力学、毒物动力学)的影响。我们将在7岁时重新检查儿童的发育结果，并将从母亲和儿童脐带血中提取储存的血液样本，以调查与甲基汞毒代动力学和毒物动力学有关的其他遗传因素，并测量炎症生物标志物，作为母亲炎症环境在改变甲基汞毒性中所起作用的指标。我们计划使用实验遗传学研究来确认在我们的队列中观察到的关联，并产生新的假设，然后可以用流行病学方法进行研究。我们的方法将解决新的假设，这些假设应该会澄清之前的队列研究的解释，但也会帮助公共政策制定者向育龄妇女提供关于怀孕期间食用鱼类的安全性的建议。

 DESCRIPTION (provided by applicant): 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. 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.