Exposure to metals (cadmium, cooper) and organic pesticides (dieldrin, chlorpyrifos) disrupts normal cellular development and differentiation. These hazardous chemicals have been shown to induce intracellular oxidative stress and produce reactive oxygen species (ROS). ROS in turn can stimulate activating protein-1 (AP-1) binding, as well as increase c- jun and c-fos protein and mRNA levels. It has been shown that ROS increases in AP-1 binding activating c-jun N-terminal kinase (JNK) or extracellularly responsive kinases (ERK). Ultimately, the generation of intracellular oxidative stress can disrupt normal development by """"""""inappropriately"""""""" activating these signal transduction cascades to induce the transcription of genes that affect cell growth and differentiation. The hypothesis that cadmium, copper, dieldrin and chlorpyrifos increase the intracellular levels of ROS to affect c-jun levels, and increase AP-1 binding activity will be investigated. To explore this hypothesis two model system two model systems will be used: cultured mammalian cells and zebrafish. The studies proposed using cultured cell lines will investigate molecular and cellular aspects of hazardous chemical exposure on development. As a physiologic end-point, the effects of cadmium and copper exposure on zebrafish development will be examined. There are four specific aims in this project: (1) Characterize the effects of metals and pesticides on metallothionein and proto-oncogene expression. (2) Identify upstream regulatory elements that mediate chemically induced transcription. (3) Determine the effects of hazardous chemical exposure on the activities of (a) AP-1 and (b) signal transduction cascades that regulate Ap-1 pathways that regulate development in zebrafish. The information and concepts obtained from the proposed studies directly address several of the goals outlined in the Superfund Research Program, which is to understand the human health and environmental effects associated with hazardous waste. Specifically, the research outlined in this project will address the mechanistic basis for cellular and molecular perturbations and associated health effects that are due to exposure to hazardous substances.
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