Superfund Research Program
Epigenetic Effects of Pre- and Post-Remediated Environmental Toxicants
Project Leader: James E. Trosko
Grant Number: P42ES004911
Funding Period: 1995 - 2006
Final Progress Reports
Year: 2004 1999
These studies are based on the researchers' hypothesis that gap junctional intercellular communication is necessary for maintaining homeostatic control of cell proliferation, cell differentiation, apoptosis and adaptive responses of differentiated cells. Using an in vitro normal rat liver epithelial cell system, various known remediated chemicals have been tested for their ability to inhibit GJIC (a functional marker for potential teratogenic, tumor promoting, reproductive and neurotoxic consequences). In addition, the structure/activity relationships of several PAHs were identified. The researchers found for the first time that PAHs containing bay regions formed by an angular benzo-ring or containing bay-like regions formed by an angular methyl group were more inhibitory of GJIC than were PAHs that did not contain either bay or bay-like regions. Moreover, anthracene isomers were used to probe which signal transduction pathways have common receptors with, or are directly involved in, regulating GJIC. Results showed that the anthracenes containing bay-like regions induced mitogen-activated phosphokinases (MAPK) ERK1 and ERK2, whereas the linear isomers did not activate MAPK. Dr. Masten (an Environmental Engineer) and Dr. Trosko (a geneticist/toxicologist/cell biologist) worked together in an interdisciplinary fashion, whereby, after engineering various remediation processes to eliminate the toxicities of chemicals in Dr. Masten's lab, the by-products were tested in Dr. Trosko's lab for either a reduction or increase in toxicity. When products showed more toxicity than the parent compound, the remediation protocols were modified to reduce the toxicities. Equally important, this interdisciplinary project allowed the unique training of Dr. Masten's graduate students by having them do the in vitro toxicology assays and to understand the techniques and concepts needed to perform these assays. These studies and their associated publications are the first of their kind assessing the epigenetic toxicities of chemically-remediated products.