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

Communication mechanisms [extra-, intra-, and gap junctional inter-cellular communication (GJIC)] control, from the fertilized egg, through embryogenesis to maturity and aging, whether a cell proliferates, differentiates, dies by apoptosis, or if differentiated, adaptively responds to endogenous and exogenous signals. From the egg to the 100 trillion cells in the human body, health is maintained when these communication processes between stem, progenitor and terminally differentiated cells are integrated. Each cell choice 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. Modulation of extra-cellular communication, either by genetic imbalances of growth factors, hormones or neurotransmitters or by environmental, exogenous chemicals can trigger signal transducing intra-cellular mechanisms. These intra-cellular signals can modulate gene expression at the transcriptional, translational or post-translational levels while also modulating GJIC. Untimely or chronic disruption of GJIC during embryonic or fetal development could lead to embryonic lethality or teratogenesis. By modulation of GJIC, homeostatic control of cell growth, differentiation or apoptosis could lead to specific diseases, such as neurological, cardiovascular, reproductive or endocrinological dysfunction. Chemical modulation or oncogene down-regulation of GJIC in initiated tissues has been shown to lead to tumor promotion. Genetic syndromes carrying a mutated gap junction gene, together with some transgenic and knock-out gap junction gene mice, provide evidence for the importance of this organelle found only in metazoans. Implications for 'thresholds' to toxicants and for risk assessment are evident.