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

说明(由首席调查员提供)：这项申请是塞舌尔儿童发展和营养研究(SCDNS)竞争性更新的第一次重新提交，该研究最初于2000年获得资助，目的是审查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，当接触到高含量鱼类的饮食时。在SCDNS的最初阶段，测量了产前对甲基汞和选定的营养素的暴露，并评估了229名儿童在出生前30个月的神经发育。我们发现，在研究的甲基汞暴露范围内(母亲头发中的1-18ppm)，没有证据表明产前甲基汞对发育结果有独立的不利影响。然而，当统计模型根据母亲的饮食摄入量和营养状况进行调整时，产前接触甲基汞会对精神运动能力产生不利影响。这种影响是由于母体血清中长链多不饱和脂肪酸(LCPUFA)的水平造成的。-3LCPUFA水平对精神运动发育有积极影响，而甲基汞和-6LCPUFA都对精神运动发育有不利影响。因此，LCPUFA可能会对发育终点产生直接影响，并改变甲基汞效应。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以进行一项创新研究，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明显调节了甲基汞的神经毒性。最初的研究测量了鱼中存在的有限数量的候选营养物质，并根据我们早期研究的能量估计招募了一个队列。回过头来看，我们低估了营养对神经毒性和发育影响的复杂性。利用塞舌尔卫生部正在招募的一个更大、更强大的队列(n~1500人)，我们计划确认迄今发现的主要影响，并测试甲基汞和LCPUFA之间的相互作用。我们的计划还包括分析孕期维生素E和硒的状况，以此作为甲基汞和LCPUFA对发育的联合影响的可能修饰物。在我们最初的研究中，将使用显示单独使用甲基汞、单独使用LCPUFA或两者结合的方法来评估新的队列的发展情况。将增加社会沟通和行为的措施，以扩大评估的范围，继续使用更大的队列，并特别关注LCPUFA在甲基汞神经毒性暴露和儿童发育方面的作用，应使我们能够有效地解决我们最初五年研究提出的科学问题。它还将有助于确定怀孕期间食用鱼类的风险和好处。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。这些结果应该使监管机构能够发布以科学为基础的关于怀孕期间食用鱼类安全的建议。

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.