Mechanisms of methylmercury toxicity in neural development

描述（由申请人提供）：甲基汞（MeHg）是一种持久性环境毒素，可选择性破坏胎儿大脑发育。人类主要通过食用鱼类接触甲基汞，导致美国约6%的育龄妇女血液中的汞含量达到或超过美国环保署规定的参考剂量。母亲血汞水平升高所生的孩子表现出认知缺陷。尽管甲基汞对健康构成了持续的风险，但使发育中的神经系统对甲基汞毒性最敏感的独立机制尚不清楚。同样，对甲基汞中毒产生抵抗力的因素也没有完全了解。在这个建议中，我们将调查如何甲基汞干扰神经发生的最早期事件。我们的总体假设是，甲基汞通过克服内源性防御机制，改变细胞信号通路的活性，在神经系统中发挥特异性作用。使用果蝇（果蝇）模型，我们发现甲基汞可以激活Notch受体信号，这是一种高度保守的途径，是苍蝇和人类正常神经发生所必需的。我们还发现，对甲基汞的全面抵抗是通过上调神经系统中特定的谷胱甘肽合成来实现的。因此，我们将研究这些基本机制如何运作，以破坏，或者保护，神经系统的发展有三个目标。首先，我们将描述三个不同的细胞分化事件在胚胎神经发生中的Notch信号可能受到甲基汞的干扰。其次，我们将确定和表征直接相互作用的甲基汞与蛋白质的目标在Notch途径。最后，我们将通过人工选择和表达谱分析来鉴定赋予甲基汞抗性的基因产物。这些数据将促进我们的基本分子机制的理解，决定胚胎神经系统的易感性，甲基汞毒性。

DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a persistent environmental toxin that selectively disrupts development of the fetal brain. Human exposure to MeHg, which occurs predominantly through fish consumption, contributes to an estimated 6% of women of child-bearing age in the U.S. having blood mercury levels at or above the reference dose set by the EPA. Children born to mothers having elevated blood mercury levels show cognitive deficits. Despite the ongoing health risks posed by MeHg the discrete mechanisms that make the developing nervous system most sensitive to MeHg toxicity are not clear. As well, factors that confer resistance to MeHg intoxication are not fully understood. In this proposal we will investigate how MeHg interferes with the earliest events in neurogenesis. Our overall hypothesis is that MeHg acts specifically in the nervous system by overcoming endogenous defense mechanisms to alter activity of cell signaling pathways. Using the Drosophila (fruit fly) model, we have discovered that MeHg can activate Notch receptor signaling, a highly conserved pathway required for normal neurogenesis in flies and humans. We also find overall resistance to MeHg is achieved by upregulation of glutathione synthesis specifically in the nervous system. We will therefore investigate how these fundamental mechanisms operate to disrupt, and alternatively protect, nervous system development with three Aims. First, we will characterize three distinct cell differentiation events in embryonic neurogenesis where Notch signaling is potentially perturbed by MeHg. Second, we will identify and characterize direct interactions of MeHg with protein targets in the Notch pathway. Finally, we will identify gene products that confer MeHg resistance by artificial selection and expression profiling. These data will advance our understanding of the fundamental molecular mechanisms dictating the susceptibility of the embryonic nervous system to MeHg toxicity.