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

说明（由主要研究者提供）：本申请是塞舌尔儿童发育和营养研究（SCDNS）竞争性延期的首次重新提交，该研究最初于2000年获得资助，以检验以下假设：当接触源自食用高含量鱼类的饮食时，孕妇的营养和饮食状况可能会改变甲基汞的毒性。在SCDNS的初始阶段，产前暴露于甲基汞和选定的营养素进行了测量和神经发育的队列的229名儿童进行了评估，通过前30个月的生活。我们发现，在所研究的甲基汞暴露范围内（母体头发中1-18 ppm），没有证据表明产前甲基汞对发育结果产生独立的不良影响。然而，有一个不利的影响，产前甲基汞暴露的心理能力时，统计模型进行了调整，母亲的饮食摄入量和营养状况。这种影响是由于母体血清中的）-3和）-6长链多不饱和脂肪酸（LCPUFA）水平。）-3 LCPUFA水平对精神发育有有利影响，而甲基汞和）-6 LCPUFA对精神发育有不利影响。因此，LCPUFA可能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。我们的目的是扩展SCDNS，以进行创新研究，更深入地测试我们最近发表的新发现的参数，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效估计招募了一个队列。回顾过去，我们低估了营养对神经毒性和发育影响的复杂性。我们计划利用塞舌尔卫生部招募的一个更大的更强大的队列（n~ 1 500）来确认迄今为止发现的主要影响，并测试甲基汞和LCPUFA之间的相互作用。我们的计划还包括检测怀孕期间维生素E和硒的状况，作为甲基汞和LCPUFA对发育综合影响的可能修饰剂。在我们的初步研究中，将使用显示单独甲基汞、单独LCPUFA或两者结合之间相关性的措施来评估新队列的发展。将增加社会沟通和行为的措施，以扩大评估的范围。继续SCDNS，利用更大的队列，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追求我们的第一个五年的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益处。此外，我们将开始研究饮食如何与甲基汞接触相互作用这一更广泛的问题。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依据。 公共卫生相关性：人类接触甲基汞几乎完全来自食用鱼类，所有鱼类都含有一定的甲基汞。鱼类还提供其他营养素，如长链多不饱和脂肪酸（LCPUFA），这是大脑发育所必需的，对儿童发育有有益的影响。迄今为止，我们的研究结果表明，LCPUFA对神经发育的有益影响可能会调节甲基汞的不良影响。这项拟议的研究将确定其他膳食营养素是否可以减少甲基汞的神经毒性，并增加LCPUFA的影响。这些结果不仅对建议公众食用鱼类的机构，而且对有关怀孕期间营养摄入的公共卫生政策都具有直接和重要的公共卫生意义。

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.