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（由适用提供）：鱼是主要的蛋白质来源，也是养分的主要来源，例如长链多不饱和脂肪酸（PUFA），这对于材料和胎儿健康至关重要。所有鱼类还含有甲基汞（MEHG），这是一种高水平暴露的神经毒性，如日本和伊拉克的意外中毒所证明。但是，多年来的研究，关于在怀孕期间以天然背景水平的鱼类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，因为对因素的有限理解影响MEHG毒性是颁布有关鱼类消费的公共政策的挑战。我们在塞舌尔共和国的研究表明，产前MEHG摄入量和儿童发育效果的关联比以前预期的要复杂得多，并且可能涉及饮食中的饮食暴露和遗传因素影响MEHG毒性。为了检查这些复杂的关系，我们招募了1,536个母子对的队列，并将其特征为在20个月大时的产前MEHG暴露，孕产妇营养状况和发育结果。此外，我们研究了遗传因素对人类队列和果蝇模型中MEHG代谢和毒性的修改作用。尽管我们继续发现MEHG不影响与营养状况无关的神经发育结果，但我们的流行病学和实验遗传学发现支持了一种新的生物学框架，该框架描述了MEHG毒性中GSH依赖性途径和注射的作用。我们计划检查该框架，并将继续对儿童的发展随访以及营养和遗传成分的探索。我们的目的是假设，鱼类食用和发育结果的产前MEHG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”（毒性动物学）（毒性）（毒性）和外源饮食因素（毒性，毒性，毒性，毒性动力学）的影响。我们将在七岁的发育结果中重新检查儿童，并将利用母亲和儿童绳索的储存血样，以研究MEHG毒性和毒性动力学涉及的其他遗传因素，并衡量炎症生物标记物，并指示母体炎症性乳房乳房在修饰MEHG毒性中的作用。我们计划使用实验性遗传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，然后可以通过流行病学方法对其进行研究。我们的方法将介绍新的假设，这些假设应该使对以前的队列研究的解释具有清晰度，同时也可以帮助公共决策者向拥有儿童年龄的妇女制定有关怀孕期间食用鱼类安全的建议。