Modulated gap junctional intercellular communication as a biomarker of PAH epigenetic toxicity: structure-function relationship.

Abstract

Cancer is a multistage multimechanism process involving gene and/or chromosomal mutations (genotoxic events), altered gene expression at the transcriptional, translational, and post-translational levels (epigenetic events), and altered cell survival (proliferation and apoptosis or necrosis), resulting in an imbalance of the organism's homeostasis. Maintenance of the organism's homeostasis depends on the intricate coordination of genetic and metabolic events between cells via extracellular and intercellular communication mechanisms. The release of a quiescent cell, whether normal or premalignant, from the suppressing effects of communicating neighbors requires the downregulation of intercellular communication via gap junctions, thereby allowing factors that control intracellular events to exceed a critical mass necessary for the cell to either proliferate or undergo apoptosis. Therefore, determining the role an environmental pollutant must play in the multistage carcinogenic 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 determination of carcinogenicity focused on genotoxic events and ignored epigenetic events is polycyclic aromatic hydrocarbons (PAHs). The study of structure-activity relationships of PAHs has focused exclusively on the genotoxic and tumor-initiating properties of the compound. We report on the structure-activity relationships of two- to four-ringed PAHs on GJIC in a rat liver epithelial cell line. PAHs containing a bay or baylike region were more potent inhibitors of GJIC than the linear PAHs that do not contain these regions. These are some of the first studies of determine the epigenetic toxicity of PAHs at the epigenetic level.ImagesFigure 1

Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles

“…Numerous studies have been performed to determine the correlation between mutagenicity in the Ames test and carcinogenicity, with results differing based on which chemical database was used (Tennant and Ashby 1991). Inhibition of GJIC has been shown to be associated with the effect of tumor promoters and nongenotoxic carcinogens (Rosenkranz et al 2000;Swierenga and Yamasaki 1992;Upham et al 1998).…”

Bioavailability and Risk Assessment of Orally Ingested Polycyclic Aromatic Hydrocarbons

“…Many PAHs were reported to cause epigenetic toxicity (Upham, Weis, and Trosko 1998). Epigenetic chemicals alter the genetic phenotype of a cell is by interacting with a finite number of intracellular biochemical pathways that turn genes on and off.…”

Site Contamination Health Risk Assessment Case Study Involving Tenant Relocation from a Former Gasworks Site

“…Attention was then directed to the PAHs in soil as risk drivers, since they were not found in significant amounts in drinking water or indoor dusts and textiles. Several PAH compounds (1) act as carcinogens in animal studies (IARC, 1973;Rubin, 2001), (2) are probably carcinogenic to humans (IARC, 1987;Boffetta et al, 1997), and (3) exert genotoxic and nongenotoxic effects that may relate to tumor initiation and tumor promotion activities (Upham et al, 1998;Rubin, 2001). In addition, coal tars and coal-tar pitches have been causally associated with cancer in humans (IARC, 1985).…”