Superfund Research Program
Mechanism of Stress-Induced Developmental Abnormalities
Project Leader: Jonathan H. Freedman (National Institute of Environmental Health Sciences (NIEHS))
Grant Number: P42ES010356
Funding Period: 2000-2011
Project Summary (2000-2005)
This project is investigating the mechanistic basis for cellular and molecular perturbations and associated health effects that are due to exposure to hazardous substances. Exposure to metals (cadmium, copper) 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 also been shown that ROS increases AP-1 binding by activating c-jun N-terminal kinase (JNK) or extracellularly responsive kinases (ERK). Ultimately, the generation of intracellular oxidative stress disrupts normal development by "inappropriately" activating these signal transduction cascades to induce the transcription of genes that affect cell growth and differentiation. To explore these effects, two model systems will be used: cultured mammalian cells and zebrafish. The studies using cultured cell lines are investigating the 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.