Toxicogenomics of Lead, Mercury, and Cadmium

人类活动导致了许多有毒物质的环境分布 其中，重金属在我们的生活中随处可见。 生物圈除了对接触重金属的人产生急性毒性作用外， 长期接触金属对发育有更隐蔽的影响 所有有机体。 由此产生的发育过程的改变， 人类儿童的症状，如多动，感觉功能的变化， 以及认知能力（IQ）的变化。 果蝇是一个很有前途的模型 研究重金属暴露在发展过程中的影响 因为（1）对其遗传学的复杂理解， 操纵其基因组;（2）行为和形态学的可用性 对小剂量毒素敏感的检测。 人类和果蝇的细胞 被认为在暴露于某些环境中时， 有毒物质 这一建议的假设是，过度表达一些 重金属诱导的"保护基因"会使苍蝇对重金属产生抵抗力， 重金属暴露引起的行为和发育改变， 反过来说，敲除这些基因中的一些可能会使苍蝇 对重金属敏感。 为了验证这一假设，目标1是 将幼虫暴露于环境相关剂量的铅，汞， 镉，并提供有关其对认知，运动和 突触功能 目的二是进行DNA微阵列分析重金属- 暴露的幼虫（暴露将是NOAEL、LOAEL和LD 50，如 目标1，并确定哪些基因子集受影响最大，或者 积极或消极。 目标3是通过条件性上调 过度表达或下调，通过使用现有的突变， 表达中最显著的变化，并确定 测试化学品对认知，运动，和突触功能的这些 转基因苍蝇 这些研究的结果将确定候选人 对于在重金属暴露期间改变的最重要的基因， 人类，并可能导致生物测定或治疗重金属 等于或低于NOAEL和LOAEL值。

Human activity has resulted in the environmental distribution of many toxic substances, among them the heavy metals that are spread throughout our biosphere. In addition to acute toxic effects in the humans exposed to heavy metals there are more insidious effects of chronic exposure on the development of all organisms. The resulting altered developmental processes produce in human children symptoms such as hyperactivity, changes in sensory function, and changes in cognitive abilities (IQ). Drosophila is a promising model organism to study the effects of heavy metal exposure during development because of (1) the sophisticated understanding of its genetics, and the ease of manipulating its genome; (2) availability of behavioral and morphological assays sensitive to small doses of toxins. Both human and Drosophila cells are thought to induce expression of protective genes upon exposure to certain toxicants. The hypothesis of this proposal is that over-expressing some of the "protective genes" induced by heavy metals will make flies resistant to the behavioral and developmental alterations caused by heavy metal exposure, and conversely, that knocking out some of these genes might make flies more sensitive to heavy metal exposure. To test this hypothesis, Aim 1 is to expose the larvae to environmentally relevant doses of lead, mercury, and cadmium, and to provide data on their effects on cognition, locomotion and synaptic function. Aim 2 is to perform DNA microarray analysis heavy metal- exposed larvae (exposure will be to NOAEL, LOAEL, and LD50, as determined in the Aim 1, and determine what subsets of genes are most affected, either positively or negatively. Aim 3 is to upregulate, by conditional overexpression, or down regulate, by using existing mutations, the genes with the most significant changes in expression and to determine the effects of the test chemicals on cognition, locomotion, and synaptic function of these genetically altered flies. Results of these studies will identify candidates for the most important genes that are altered during heavy metal exposure in humans, and could well lead to bioassays or treatments for heavy metal exposure at or below NOAEL and LOAEL values.