Epigenetic toxicology as toxicant-induced changes in intracellular signalling leading to altered gap junctional intercellular communication

Communication mechanisms [extra-, intra-, and gap junctional inter-cellular communication (GJIC)] control, from the fertilized egg, through embryogene sis to maturity and aging, whether a cell proliferates, differentiates, die s by apoptosis, or if differentiated, adaptively responds to endogenous and exogenous signals. From the egg to the 100 trillion cells in the human bod y, health is maintained when these communication processes between stem, pr ogenitor and terminally differentiated cells are integrated. Each cell choi ce involves 'epigenetic' mechanisms to alter the expression of genes at the transcriptional, translational or post-translational levels. Disruption of the communication mechanisms can be either adaptive or maladaptive. Modula tion of extra-cellular communication, either by genetic imbalances of growt h factors, hormones or neurotransmitters or by environmental, exogenous che micals can trigger signal transducing intra-cellular mechanisms. These intr a-cellular signals can modulate gene expression at the transcriptional, tra nslational or post-translational levels while also modulating GJIC. Untimel y or chronic disruption of GJIC during embryonic or fetal development could lead to embryonic lethality or teratogenesis. By modulation of GJIC, homeo static control of cell growth, differentiation or apoptosis could lead to s pecific diseases, such as neurological, cardiovascular, reproductive or end ocrinological dysfunction. Chemical modulation or oncogene downregulation o f GJIC in initiated tissues has been shown to lead to tumor promotion. Gene tic syndromes carrying a mutated gap junction gene, together with some tran sgenic and knock-out gap junction gene mice, provide evidence for the impor tance of this organelle found only in metazoans. Implications for 'threshol ds' to toxicants and for risk assessment are evident. (C) 1998 Elsevier Sci ence Ireland Ltd. All rights reserved.