Oxidative Stress, Signal Transduction, Cell-Cell Communication

摘要

Human exposure to chemicals is rarely limited to genotoxic agents but also to nongenotoxic chemicals. Nongenotoxic agents alter a cell's phenotype through epigenetic mechanisms at the transcriptional, posttranscriptional, translational, or posttranslational level. The integration of intercellular communication through gap junctions and intracellular pathways plays a role in maintaining the homeostasis by controlling the expression of genes that control cell proliferation, apoptosis, and differentiation. Our results showed that a series of USAFOSR-toxicants, such as polycyclic aromatic hydrocarbons and perfluorinated fatty acids were toxic by inhibiting gap junctional intercellular communication (GJIC). Specific structure-activity relationships of various PAH and PFFA isomers were the first structure-activity results reported for nongenotoxicants. The tumor promoting oxidants dicumyl peroxide, benzoylperoxide and H2O2 reversibly inhibited GJIC at noncytotoxic doses but only in the presence of the antioxidant glutathione, whereas, the non-tumor promoting oxidant t-butylperoxide had no effect on these cell-signaling pathways. Ceramides reversibly inhibited GJIC only if they had an acyl group of 6-8 carbons. The C2-ceramide was a strong inducer of apoptosis while the GJIC inhibitory ceramides also inhibited apoptosis. In conclusion, epigenetic toxicants can alter intracellular signaling pathways that control mitogenesis and apoptosis and GJIC plays a role in modulating these pathways.