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 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.
Upham
B L
BL
Department of Pediatrics and Human Development, Michigan State University, East Lansing 48824, USA. upham@pilot.msu.edu
Weis
L M
LM
Trosko
J E
JE
D000818:Animals; D015415:Biomarkers; D002273:Carcinogens; D002450:Cell Communication / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D004781:Environmental Exposure; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects; D009369:Neoplasms / Q000209:etiology; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D015415:Biomarkers; D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons