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

改变甲基汞对吃鱼人群的毒性的因素

• 批准号: 9285799
• 负责人: PHILIP W DAVIDSON
• 金额: $ 87.72万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-21 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285799
• 关键词: 7 year old; Address; Affect; Age-Months; Biological; Biological Markers; Blood specimen; Child; Child Development; Child health care; Cohort Studies; Communication; Complex; Consumption; Data; Development; Diet; Dietary Factors; Dose; Drosophila genus; Eating; Enrollment; Epidemiology; Experimental Genetics; Experimental Models; Exposure to; Female of child bearing age; Fishes; Funding; Genes; Genetic; Genetic study; Glutathione; Grant; Health; Human; Inflammation; Inflammatory; Intake; Iraq; Japan; Kinetics; Language; Language Development; Longitudinal cohort study; Maternal Exposure; Measures; Metabolic Pathway; Metabolism; Methylmercury Compounds; Modeling; Mothers; Nervous System Physiology; Neurotoxins; Nutrient; Nutritional; Nutritional status; Oceans; Outcome; Oxidative Stress; Pathway interactions; Policy Maker; Polyunsaturated Fatty Acids; Population; Positioning Attribute; Pregnancy; Pregnant Women; Property; Proteins; Public Health; Public Policy; Recommendation; Research; Risk; Role; Safety; Seychelles; Source; Toxic effect; Toxicokinetics; Uncertainty; Vision; cohort; fetal; follow-up; immune function; inflammatory marker; inflammatory milieu; methylmercury exposure; novel; nutrition related genetics; parent grant; prenatal; prenatal exposure; public health relevance; repository; skill acquisition; skills; sound; toxicant; trend; virtual

 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.

 描述（由申请人提供）：鱼是主要的蛋白质来源和营养物质的主要来源，例如长链多不饱和脂肪酸（PUFA），这对母体和胎儿的健康至关重要。所有鱼还含有甲基汞（MeHg），这是一种已知的神经毒物。日本和伊拉克的意外中毒事件表明，甲基汞的暴露水平很高。 然而，尽管经过多年的研究，怀孕期间食用具有天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。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的了解有限，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的研究表明，孕产妇食用鱼类导致的产前甲基汞接触与儿童发育之间存在关联。结果比之前预期的要复杂得多，并且可能涉及伴随的饮食暴露和影响甲基汞毒性的遗传因素。为了研究这些复杂的关系，我们招募了 1,536 对母子对，并对其进行产前特征分析。甲基汞暴露、母亲营养状况和 20 个月大时的发育结果 此外，我们在人类队列和果蝇模型中研究了遗传因素对甲基汞代谢和毒性的影响，同时我们继续发现甲基汞并没有影响。独立于营养状况影响神经发育结果，我们的流行病学和实验遗传学研究结果支持一个新的生物学框架，该框架描述了 GSH 依赖性途径和炎症在甲基汞毒性中的作用。我们旨在评估影响炎症的产前营养因素和影响 GSH 依赖性途径的遗传因素如何影响产前甲基汞暴露与发育结果之间的关联。产前因食用鱼类而接触的甲基汞和发育结果在很大程度上受到内源性“保护性代谢途径”（毒代动力学）和外源性饮食因素（毒代动力学、毒动力学）的影响。我们将在七岁时重新检查儿童的发育情况。我们计划使用来自母亲和孩子脐带的储存血液样本来研究与甲基汞毒代动力学和毒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体炎症环境在改变甲基汞毒性中的作用的指标。实验遗传学研究，以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，这些假设应该使以前的队列研究的解释更加清晰，但也可以帮助公众。政策制定者为育龄妇女制定有关怀孕期间食用鱼类安全的建议。