MODULATED GAP JUNCTIONAL INTERCELLULAR COMMUNICATION AS A BIOMARKER OF PAH EPIGENETIC TOXICITY - STRUCTURE-FUNCTION RELATIONSHIP

Cancer is a multistage multimechanism process involving gene and/or ch romosomal mutations (genotoxic events), altered gene expression at the transcriptional, translational, and posttranslational levels (epigene tic events), and altered cell survival (proliferation and apoptosis or necrosis), resulting in an imbalance of the organism's homeostasis. M aintenance of the organism's homeostasis depends on the intricate coor dination of genetic and metabolic events between cells via extracellul ar and intercellular communication mechanisms. The release of a quiesc ent cell, whether normal or premalignant, from the suppressing effects of communicating neighbors requires the downregulation of intercellul ar communication via gap junctions, thereby allowing factors that cont rol intracellular events to exceed a critical mass necessary for the c ell to either proliferate or undergo apoptosis. Therefore, determining the role an environmental pollutant must play in the multistage carci nogenic process includes mechanisms of epigenetic toxicity such as the effects of a compound on gap junctional intercellular communication ( GJIC). A classic example of a class of compounds in which determinatio n of carcinogenicity focused on genotoxic events and ignored epigeneti c events is polycyclic aromatic hydrocarbons (PAHs). The study of stru cture-activity relationships of PAHs has focused exclusively on the ge notoxic and tumor-initiating properties of the compound. We report on the structure-activity relationships of two- to four-ringed PAHs on GJ IC in a rat liver epithelial cell line. PAHs containing a bay or bayli ke region were more potent inhibitors of GJIC than the linear PAHs tha t do not contain these regions. These are some of the first studies to determine the epigenetic toxicity of PAHs at the epigenetic level.