Influence of human gene variants on the effects of developmental MeHg exposure

说明(申请人提供)：甲基汞(MeHg)是一种普遍存在的环境污染物。甲基汞的神经毒性和大脑发育的高度敏感性在人类和实验动物中都得到了很好的证实。产前暴露的儿童表现出一系列的影响，从严重的脑瘫到轻微的发育迟缓。发育中的甲基汞暴露的许多更微妙的影响可能是永久性的，包括行为异常和智商下降，并给整个社会带来巨大的代价。据估计，多达15%的美国育龄妇女的血液总汞浓度高于与其子女智商丧失相关的水平。最近，谷胱甘肽相关基因的遗传多态与血汞水平升高相关，这表明这些多态可能在甲基汞所致神经发育障碍的易感性中起作用。我们设计了一种策略，利用人源化斑马鱼来确定谷胱甘肽S转移酶pI1、谷氨酸半胱氨酸连接酶催化亚基和谷氨酸半胱氨酸连接酶修饰亚基(分别为GSTP1、GCLC和GCLM)基因多态性在甲基汞所致神经发育障碍易感性中的功能作用。我们之前已经证明，斑马鱼在发育期间暴露于低到中等水平的甲基汞，在发育期间和成年后表现出神经缺陷，类似于人类的情况。这一实验室模型将使我们能够有效地探索基因与环境的相互作用以及特定基因变体单独和组合的作用。如果我们正在调查的基因多态被证明影响对发育中的甲基汞的敏感性，那么甲基汞暴露的社会影响可能被严重低估。 与公众健康相关：甲基汞(MeHg)是一种普遍存在的环境污染物。在人类和实验动物中，高水平甲基汞的神经毒性和发育中大脑的易感性增加都是众所周知的。产前暴露的儿童表现出一系列的影响，从严重的脑瘫到轻微的发育迟缓(Castoldi等人，2001年)。发育中的甲基汞暴露的许多更微妙的影响可能是永久性的，包括行为异常和智商下降。据估计，多达15%的美国育龄妇女的血液总汞浓度高于与其子女智商丧失相关的水平。因此，每年有多达637,233名儿童出生时脐带血汞水平高于与智商丧失相关的水平(Trasande等人，2005年)。据估计，美国每年因此而损失的生产力超过80亿美元(Trasande等人，2005年)。如果我们正在调查的基因多态被证明影响了对发育中的甲基汞的敏感性，那么其社会影响可能被严重低估。

DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a ubiquitous environmental pollutant. The neurotoxicity of MeHg and the high susceptibility of the developing brain are well established both in humans and experimental animals. Prenatally exposed children display a range of effects varying from severe cerebral palsy to subtle developmental delays. Many of the more subtle effects of developmental MeHg exposure can be permanent, including behavioral abnormalities and loss of IQ, and impart a significant cost to society as a whole. It is estimated that as many as 15% of American women of childbearing age have total blood mercury concentrations at a level above that associated with loss of IQ (> 3.5 <g/L) in their children. Recently, genetic polymorphisms in glutathione-related genes have been associated with higher blood mercury levels which suggests that these polymorphisms may play a role in the susceptibility to MeHg-induced neurodevelopmental dysfunction. We have designed a strategy to determine the functional role of polymorphisms in glutathione S-transferase pi 1, glutamate-cysteine ligase catalytic subunit, and glutamate-cysteine ligase modifier subunit (GSTP1, GCLC and GCLM, respectively) in susceptibility to MeHg-induced neurodevelopmental dysfunction using humanized zebrafish. We have previously demonstrated that zebrafish exposed during development to low-to-moderate levels of MeHg show neurological deficits, during development and as adults, similar to those seen in humans. This laboratory model will allow us to efficiently explore gene-environment interactions and the role of specific gene variants individually and in combination. If the genetic polymorphisms we are investigating are shown to influence sensitivity to developmental MeHg, the societal impact of MeHg exposures may be dramatically underestimated. PUBLIC HEALTH RELEVANCE: Methylmercury (MeHg) is a ubiquitous environmental pollutant. The neurotoxicity of high levels of MeHg and the increased susceptibility of the developing brain are well established both in humans and experimental animals. Prenatally exposed children display a range of effects varying from severe cerebral palsy to subtle developmental delays (Castoldi et al., 2001). Many of the more subtle effects of developmental MeHg exposure can be permanent, including behavioral abnormalities and loss of IQ. It is estimated that as many as 15% of American women of childbearing age have total blood mercury concentrations at a level above that associated with loss of IQ (> 3.5 <g/L) in their children. As a result, as many as 637,233 children are born each year with cord blood mercury levels above that which is associated with loss of IQ (Trasande et al., 2005). The associated loss of productivity in the United States is estimated to be greater than $8 billion annually (Trasande et al., 2005). If the genetic polymorphisms we are investigating prove to influence sensitivity to developmental MeHg, the societal impact may be dramatically underestimated.