| Due to its persistent nature and demonstrated toxicity at excessive levels, copper poses a concern as an environmental contaminant. Although copper is an essential metal, its redox properties allow for the potential to cause oxidative stress through the formation of reactive oxygen species. Oxidative stress can activate mitogen-activated protein kinase (MAPK) pathways, which ultimately converge upon nuclear transcription factors responsible for regulating the expression of genes involved in detoxification/repair, cell differentiation and proliferation, cell movement, inflammation, and apoptosis. These evolutionarily conserved signaling systems present in eukaryotes play a central role in transducing signals to the nucleus. While the MAPK pathways are responsible for mediating normal physiological functions, these pathways are also implicated in a variety of pathologic conditions. Sustained cellular stress has the potential to overwhelm the protective capacity of cellular detoxification mechanisms, leading to prolonged or inappropriate activation of genes regulated by MAPK pathways.; The process of development involves a highly orchestrated series of events in which numerous genes involved in cell growth, division, and differentiation are expressed in a temporally and/or spatially-regulated manner. Perturbations of the signaling systems that regulate these genes, from exposure to toxicants that induce oxidative stress, may lead to a number of adverse developmental abnormalities. While there are a number of studies that have examined the effects of excessive copper in various organisms and tissues, few studies address the molecular mechanisms involved in copper toxicity and the mechanistic basis of developmental toxicity as a result of copper exposure during the early stages of development.; Our studies investigated the hypothesis that exposure to elevated levels of copper causes oxidative stress resulting in the formation of stable lipid peroxidation by-products, which results in activation of the MAPK cascades, phosphorylation and activation of nuclear transcription factors and proto-oncogenes, and increased AP-1 activity, ultimately culminating in developmental abnormalities due to changes in the expression of genes involved in development. The results of our study demonstrated that in COS-7 cells, exposure to copper results in increased production of the lipid peroxidation by-product 4-hydroxynonenal, along with phosphorylation and activation of the JNK/SAPK and p38 pathways. (Abstract shortened by UMI.)... |
