Mechanism of Stress-Induced Developmental Abnormalities

点击翻译按钮获取中文摘要

Exposure to transition metals is associated with a variety of human diseases and developmental abnormalities. The Superfund chemicals copper (No. 141) and inorganic mercury (No. 3) have the potential to affect transcription by modulating the activity of a variety of intracellular signal transduction pathways. We propose that exposure to transition metals disrupts normal development by "inappropriately" activating signal transduction pathways. In situations where these metals "appropriately" activate a pathway, defense and repair genes are expressed and the metals are detoxified. However, "inappropriate" or uncontrolled activation of these pathways may lead to metal-induced developmental abnormalities. We will investigate the hypothesis that mercury and copper modulate the activity of intracellular signal transduction pathways to affect transcription, which ultimately disrupts normal development. The research outlined in this application will test this hypothesis using DNA microarrays and gene knockout technologies using the model organism, Caenorhabditis elegans (C. elegans) and cultured mammalian cells. In the studies outlined in this application, the ability of copper and inorganic mercury to affect gene expression and the activity of cognate transcription factors will be assessed. The goals of the research outlined in this application are to (a) characterize the changes in C. elegans and liver cell transcriptomes associated with copper and inorganic mercury exposure, and identify the genes that are essential for defense against metal toxicity; (b) identify metal-responsive signal transduction pathways; (c) link pathways identified through genomic analyses to metal-induced alterations in transcription factor function; and (d) apply the information and technologies developed during the studies of mercury and copper to other environmental toxicants, including, organophosphate insecticides, polychlorinated biphenyls, and polyaromatic hydrocarbons. The information gained in the proposed studies will help to elucidate the molecular pathways by which metals induce their toxic response. This information may be directly applied to the clinical intervention and possible prevention of metal-induced pathologies.