Abstract
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.
Highlights
RECETOX, Faculty of Science, Masaryk University, 625-00 Brno, Czech Republic; Department of Pediatrics and Human Development, Institute for Integrative Toxicology, Michigan State
“With respect to cancer causation, integration of the analyses suggest that the inhibition of gap junctional intercellular communication is involved in non-genotoxic cancer induction or in the non-genotoxic phase of the carcinogenic process” [1]
We found that only 27 compounds assessed using the scrape loading-dye transfer (SL-dye transfer (DT)) assay in WBF344 cells are included in databases of negative or positive chemicals in the Ames bacterial assay [315,316]
Summary
“With respect to cancer causation, integration of the analyses suggest that the inhibition of gap junctional intercellular communication is involved in non-genotoxic cancer induction or in the non-genotoxic phase of the carcinogenic process (such as inflammation, cell toxicity, cell proliferation, inhibition of cell differentiation, and apoptosis)” [1]. Extracellular matrix interactions, nutrients, catabolites, pH and temperature) (Figure 2) In this way, GJIC plays a central role in integrating signaling mechanisms controlling gene expression and coordinating cell behavior across the solid tissues of a multicellular organism, where gap junctions join virtually all differentiated cells, except free-flowing cells [28]. GJIC-dependent integration of various extra-, intra- and inter-cellular signals across the cells within a tissue is a key component of the systems control of cellular events that allows coordinating cell metabolism, gene expression and cell behavior between contiguous syncytium of cells organized into a hierarchal multicellular system (Figure 2) This mechanism is critical for maintaining tissue homeostasis via balanced cell proliferation, differentiation and apoptosis within a tissue [27,28,30,31,32]. That requires availability and accessibility of (a) suitable cell lines or in vitro cellular models with either basal (GJIC-competent cells) or inducible (GJIC-deficient cells) and measurable levels of GJIC, as well as (b) techniques for GJIC evaluation with acceptable operability and sufficient throughput
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