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

描述（由主要研究者提供）：该申请是塞舌尔儿童发育和营养研究（SCDNS）的竞争性更新的第一次重新提交，该研究最初于2000年资助，目的是研究孕妇在怀孕期间的营养和饮食状况可能会改变甲基汞的毒性的假设，如果甲基汞的暴露源于食用富含鱼类的饮食。在SCDNS的初始阶段，测量了产前接触甲基汞和选定营养素的情况，并评估了229名儿童在出生后30个月的神经发育情况。在研究的甲基汞暴露范围内（母体头发中1-18 ppm），我们没有发现产前甲基汞对发育结果的独立不利影响的证据。然而，当对统计模型进行孕妇饮食摄入和营养状况调整时，产前甲基汞暴露对精神运动能力有不利影响。这种影响是由于母体血清中（3和）6长链多不饱和脂肪酸（LCPUFA）的水平。-3 LCPUFA水平对精神运动发展有有益影响，而MeHg和)-6 LCPUFA水平对精神运动发展有不利影响。因此，LCPUFA可能直接影响发育终点并改变MeHg效应。其他营养协变量也可能进一步改变甲基汞的毒性。我们的目标是扩展SCDNS，进行一项创新研究，以更深入地测试我们最近发表的新发现的参数，该发现显示LCPUFA对甲基汞神经毒性的明显调节。最初的研究测量了鱼类中存在的有限数量的候选营养素，并根据我们早期研究的功率估计登记了一个队列。回顾过去，我们低估了营养对神经毒性和发育的影响的复杂性。我们计划利用塞舌尔卫生部招募的一个更大、更有力的队列（n~1,500）来确认迄今为止发现的主要效应，并测试MeHg和LCPUFA之间的相互作用。我们的计划还包括分析妊娠期维生素E和硒的状态，作为MeHg和LCPUFA对发育的联合影响的可能调节因素。在我们最初的研究中，新的队列将通过测量显示单独MeHg、单独LCPUFA或两者结合之间的关联来评估其发展。将增加社会沟通和行为的测量，以扩大评估的范围，继续使用更大的队列进行SCDNS，并特别关注LCPUFA在甲基汞神经毒性暴露和儿童发育之间的作用，这将使我们能够有效地追求我们前五年研究中提出的科学问题。它还将有助于确定怀孕期间食用鱼类的风险和益处。此外，我们将开始研究更广泛的问题，即饮食如何与甲基汞暴露相互作用。这些结果应使监管机构能够颁布有关怀孕期间食用鱼类安全的科学建议。

DESCRIPTION (provided by principal investigator): This application is the first resubmission of a competing renewal of the Seychelles Child Development and Nutrition Study (SCDNS), initially funded in 2000 to examine the hypothesis that maternal nutritional and dietary status during pregnancy might modify the toxicity of MeHg when exposure stems from consumption of a diet high in fish. During the initial period of the SCDNS, prenatal exposure to MeHg and selected nutrients were measured and neurodevelopment of cohort of 229 children was evaluated through the first 30 months of life. We found no evidence of independent adverse effects of prenatal MeHg on developmental outcomes within the range of MeHg exposure studied (1-18 ppm in maternal hair). However, there was an adverse effect of prenatal MeHg exposure on psychomotor ability when statistical models were adjusted for maternal dietary intake and nutritional status. This effect was due to maternal serum levels of )-3 and )-6 long-chain polyunsaturated fatty acids (LCPUFA). )-3 LCPUFA levels had a beneficial influence on psychomotor development while both MeHg and )-6 LCPUFA adversely affected psychomotor development. Thus, LCPUFA might have a direct impact on developmental endpoints and modify the MeHg effect. It is also likely that other nutritional covariates might further modify the toxicity of MeHg. Our aim is to extend the SCDNS to pursue an innovate study to test in more depth the parameters of our recently published novel finding showing an apparent modulation of MeHg neurotoxicity by LCPUFA. The initial study measured a limited number of candidate nutrients present in fish and enrolled a cohort based on power estimates from our earlier studies. In retrospect, we underestimated the complexity of nutrient effects on neurotoxicity and development. Using a larger more powerful cohort (n~1,500) being recruited by the Seychelles Ministry of Health, we plan to confirm the main effects found to date and test interactions between MeHg and LCPUFA. Our plan also includes assaying vitamin E and selenium status in pregnancy as possible modifiers of the combined effects of MeHg and LCPUFA on development. The new cohort will be assessed for development using measures that showed an association between either MeHg alone, LCPUFA alone or the combination of both in our initial study. Measures of social communication and behavior will be added to increase the scope of the assessment Continuing the SCDNS utilizing a larger cohort and focusing specifically on the role of LCPUFA in relation to MeHg neurotoxic exposures and child development should allow us to efficiently pursue the scientific questions raised by our first five years of study. It will also contribute to establishing the risks and benefits of fish consumption during pregnancy. In addition we will begin to study the broader question of how diet may interact with MeHg exposure. These results should enable regulators to promulgate scientifically based advisories concerning safety of consuming fish during pregnancy. PUBLIC HEALTH RELEVANCE: Public Health Significance Human exposure to MeHg is almost exclusively from fish consumption and all fish contain some MeHg. Fish also provide other nutrients such as Long chain Polyunsaturated Fatty Acids (LCPUFA) that are essential for brain development and exert a beneficial influence on child development. Our results to date suggest that the beneficial influence of LCPUFA on neurodevelopment may modulate adverse effects of MeHg. The proposed study will determine if other dietary nutrients can reduce the neurotoxicity of MeHg and increment the effects of LCPUFA. The results should have immediate and important public health implications not only for agencies that advise the public about fish consumption, but also for public health policies regarding nutrient intake during pregnancy.