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，可选择性地破坏胎儿大脑的发育。人类主要通过食用鱼类接触甲基汞，导致美国约6%的育龄妇女血液中汞含量达到或高于EPA设定的参考剂量。血液中汞含量升高的母亲所生的孩子表现出认知缺陷。尽管甲基汞持续存在健康风险，但使发育中的神经系统对甲基汞毒性最敏感的离散机制尚不清楚。此外，对甲基汞中毒产生耐药性的因素也不完全清楚。在这个提议中，我们将研究甲基汞是如何干扰神经发生的最早事件的。我们的总体假设是MeHg在神经系统中通过克服内源性防御机制来改变细胞信号通路的活性。通过果蝇模型，我们发现MeHg可以激活Notch受体信号，这是果蝇和人类正常神经发生所必需的高度保守的途径。我们还发现，对甲基汞的整体抗性是通过神经系统中谷胱甘肽合成的上调来实现的。因此，我们将研究这些基本机制是如何运作的，以破坏或保护神经系统的发育，有三个目的。首先，我们将描述胚胎神经发生中三种不同的细胞分化事件，其中Notch信号可能受到MeHg的干扰。其次，我们将确定并表征MeHg与Notch通路中蛋白靶点的直接相互作用。最后，我们将通过人工选择和表达谱鉴定赋予甲基汞抗性的基因产物。这些数据将促进我们对胚胎神经系统对甲基汞毒性易感性的基本分子机制的理解。

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.