Polycyclic aromatic hydrocarbons with bay-like regions inhibited gap junctional intercellular communication and stimulated MAPK activity

Many polycyclic aromatic hydrocarbons (PAHs) are known carcinogens. A consi derable amount of research has been devoted to predicting the genotoxic, tu mor-initiating potential of PAHs based on chemical structure. However, info rmation on the correlation of structure with the non-genetoxic, epigenetic events of tumor promotion is sparse. PAHs containing a bay or bay-like regi on were shown to be potent inhibitors of gap-junctional intercellular commu nication (GJIC), an epigenetic event involved in the removal of an initiate d cell from growth suppression. We tested the epigenetic toxicity of PAHs c ontaining bay-like regions by comparing the effects of methylated vs. chlor inated isomers of anthracene on the temporal activation of mitogen-activate d protein kinase (MAPK) and the regulation of GJIC, Specifically, we used a nthracene, 1-methylanthracene, 2-methylanthracene, 9-methylanthracene, 9,10 -dimethylanthracene, 1-chloroanthracene, 2-chloroanthracene, and 9-chloroan thracene. We determined the effect of these compounds on GJIC and on the ac tivation of extracellular receptor kinase (ERK 1 and 2), a MARK, in F344 ra t liver epithelial cells. Results showed that bay or bay-like regions, form ed by either chlorine or a methyl group, reversibly inhibited GJIC at the s ame doses, time, and time of recovery, whereas the linear-planar isomers ha d no effect on GJIC. Similarly, the GJIC-inhibitory isomers also induced th e phosphorylation of ERK 1 and ERK 2, while the non-inhibitory isomers had no effect on the activation of these MAPKs. MARK activation occurred 10-20 min after the inhibition of GJIC, which indicates that MARK is not involved in the initial regulation of GJIC; instead altered GJIC may be affecting M APK activation. The present study revealed that there are structural determ inants of PAHs, which clearly affect epigenetic events known to be involved in the non-genetoxic steps of tumor promotion. These events are the releas e of a cell from growth suppression involving the reduction of GJIC, follow ed by the activation of intracellular mitogenic events.