The mechanisms by which chemicals can induce toxicities, such as teratogenesis, carcinogenesis, reproductive and neuro-toxicities, include mutagenesis (genotoxicity), cell killing (cytotoxicity) and/or altered gene expression, (epigenesis). Since many important environmental toxicants are not mutagenic (genotoxic), it is important that assays be developed and characterized which can detect chemicals which modulate gap junctional intercellular communication (GJIC). These chemicals which block GJIC have been shown in vivo in a number of organisms, including humans, to be teratogens, tumor promoters, reproductive- and neuro-toxicants. The objective of this project is to integrate three disciplines: biochemistry, molecular/cell biology and environmental engineering to determine if remediation of several classes of mixtures of environmental toxicants (PCB's, HAH's, PAH's) decreases the toxicities of the parent mixtures or actually enhances the toxicities. To achieve this goal, several primary aims are proposed: namely, to determine if Superfund toxicants which activate protein kinase C can be predicted to be potential tumor promoters; to assess the ability of various types of remediation/bioremediation techniques to remove or enhance the toxicities of mixtures of toxicants as measured by their ability to modulate GJIC; and to understand how mechanisms of mixtures of these chemicals might differentially activate the PKC second messenger system and affect GJIC in different cell strains. This subproject will study the role of cellular signal transduction systems and, in particular, the role of protein kinase C in the toxicity of various epigenetic toxicants. A variety of molecular/biochemical studies on remediated PCBs and other epigenetic toxicants will be done to determine how they might mediate their toxicities on GJIC through various cellular signal transduction pathways.
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