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

 描述（由申请人提供）：鱼类是一种主要的蛋白质来源，也是长链多不饱和脂肪酸（PUFA）等营养素的主要来源，这些营养素对母亲和胎儿的健康至关重要。所有鱼类都含有甲基汞，这是一种已知的神经毒物，在日本和伊拉克发生的意外中毒事件证明，甲基汞的暴露量很高。然而，尽管经过多年的研究，在怀孕期间食用含有天然背景甲基汞水平的鱼类是否安全仍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，这对颁布有关鱼类消费的公共政策构成了挑战。我们在塞舌尔共和国进行的研究表明，孕妇食用鱼类导致的产前甲基汞暴露与儿童发育结果之间的关系比以前预期的要复杂得多，可能涉及同时发生的饮食暴露和影响甲基汞毒性的遗传因素。为了研究这些复杂的关系，我们招募了一组1,536对母子，并对他们进行了产前甲基汞暴露，母亲营养状况和20个月大的发育结果的特征。此外，我们研究了修饰作用的遗传因素对甲基汞的代谢和毒性在我们的人类队列和果蝇模型。虽然我们继续发现，甲基汞不影响神经发育的结果独立的营养状况，我们的流行病学和实验遗传学研究结果支持一种新的生物学框架，描述了谷胱甘肽依赖性途径和炎症的甲基汞毒性的作用。我们计划研究这一框架，并将继续对儿童的发育进行跟踪，并探索营养和遗传成分。我们的目的是评估产前营养因素如何影响炎症，影响谷胱甘肽依赖途径的遗传因素影响产前甲基汞暴露和发育结果之间的关联。我们假设，产前甲基汞暴露从鱼类消费和发育结果之间的关联，在很大程度上是由内源性的“保护性代谢途径”（toxicokerma）和外源性的饮食因素（toxicokerma，toxicodynamics）的影响。我们将在7岁时重新检查儿童的发育结果，并将利用储存的母亲和儿童脐带血样本，以调查涉及甲基汞毒代动力学和毒代动力学的其他遗传因素，并测量炎症生物标志物作为母体炎症环境在修饰甲基汞毒性中的作用的指标。我们计划使用实验遗传学研究来证实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，这些假设应该澄清以前的队列研究的解释，但也有助于公共政策制定者为育龄妇女制定关于怀孕期间食用鱼类安全的建议。

 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.