Dysregulation of gap junction intercellular communication (GJIC) is recognized as one of the key hallmarks for identifying non-genotoxic carcinogens (NGTxC). Currently, there is a demand for in vitro assays addressing the gap junction hallmark, which would have the potential to eventually become an integral part of an integrated approach to the testing and assessment (IATA) of NGTxC. The scrape loading-dye transfer (SL-DT) technique is a simple assay for the functional evaluation of GJIC in various in vitro cultured mammalian cells and represents an interesting candidate assay. Out of the various techniques for evaluating GJIC, the SL-DT assay has been used frequently to assess the effects of various chemicals on GJIC in toxicological and tumor promotion research. In this review, we systematically searched the existing literature to gather papers assessing GJIC using the SL-DT assay in a rat liver epithelial cell line, WB-F344, after treating with chemicals, especially environmental and food toxicants, drugs, reproductive-, cardio- and neuro-toxicants and chemical tumor promoters. We discuss findings derived from the SL-DT assay with the known knowledge about the tumor-promoting activity and carcinogenicity of the assessed chemicals to evaluate the predictive capacity of the SL-DT assay in terms of its sensitivity, specificity and accuracy for identifying carcinogens. These data represent important information with respect to the applicability of the SL-DT assay for the testing of NGTxC within the IATA framework.

• Keywords
• carcinogenesis, carcinogens, gap junction intercellular communication, scrape loading-dye transfer,
• MeSH
• Coloring Agents metabolism   MeSH
• Biological Assay methods   MeSH
• Cell Line MeSH
• Microscopy, Fluorescence methods   MeSH
• Liver pathology   MeSH
• Carcinogens MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Gap Junctions metabolism   MeSH
• Cell Communication drug effects   physiology   MeSH
• Carcinogenicity Tests methods   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Coloring Agents MeSH
• Carcinogens MeSH

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

• Keywords
• Airborne polychlorinated biphenyls, Endocrine disruption, HydroxyLated PCBs, Metabolism of xenobiotics, Tumor promotion,
• MeSH
• Cell Line MeSH
• Endocrine Disruptors metabolism   toxicity   MeSH
• Epithelial Cells drug effects   MeSH
• Hydroxylation MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants toxicity   MeSH
• Humans MeSH
• Neoplasms metabolism   MeSH
• Polychlorinated Biphenyls metabolism   toxicity   MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Receptors, Steroid metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endocrine Disruptors MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants MeSH
• Polychlorinated Biphenyls MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear MeSH
• Receptors, Steroid MeSH

As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

• MeSH
• Humans MeSH
• Neoplasms chemically induced   etiology   MeSH
• Hazardous Substances adverse effects   MeSH
• Signal Transduction drug effects   MeSH
• Environmental Exposure adverse effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Hazardous Substances MeSH