Mechanisms of methylmercury toxicity in neural development

描述(申请人提供)：甲基汞(MeHg)是一种持久的环境毒素，选择性地干扰胎儿大脑的发育。人类主要通过食用鱼类接触到甲基汞，估计有6%的美国育龄妇女的血液汞水平达到或超过美国环保局设定的参考剂量。血汞水平升高的母亲所生的孩子会出现认知缺陷。尽管甲基汞带来了持续的健康风险，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，对甲基汞中毒产生抵抗力的因素还不完全清楚。在这项提案中，我们将研究甲基汞是如何干扰神经发生的早期事件的。我们的总体假设是，甲基汞通过克服内源性防御机制来改变细胞信号通路的活动，从而在神经系统中特异地发挥作用。利用果蝇(果蝇)模型，我们发现甲基汞可以激活Notch受体信号，这是果蝇和人类正常神经发生所需的一种高度保守的途径。我们还发现，对甲基汞的总体抵抗是通过上调谷胱甘肽的合成实现的，特别是在神经系统。因此，我们将研究这些基本机制是如何运作的，以扰乱神经系统发育，或者保护神经系统发育，目的有三个。首先，我们将描述胚胎神经发生中三个不同的细胞分化事件，其中Notch信号可能被甲基汞干扰。其次，我们将确定和表征甲基汞与Notch途径中的蛋白质靶标的直接相互作用。最后，我们将通过人工选择和表达谱来鉴定与甲基汞抗性有关的基因产物。这些数据将促进我们对决定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.