EVALUATION OF SUPERFUND CHEMICALS AS EPIGENETIC TOXICANTS

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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 this class of toxicants. To date, several rodent and human in vitro assays have been designed to 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 has evolved, based on the development of several human and rodent in vitro models, to detect chemicals which block GJIC and on advances in the molecular/biochemical understanding of mechanisms by which chemicals modulate GJIC, to the point where it will directly test chemicals from various remediation projects. Its primary aim will be to provide direct feedback to the remediation studies of Dr. Masten so that modification in the conditions for remediation can be improved. The second aim is to start examining the mechanisms by which mixtures of toxicants, before and after remediation efforts, might interact addititively, synergistically or antagonistically.