The role of modulated gap junctional intercellular communication in epigenetic toxicology.

The normal development and health of all multicellular organisms, including the human being, depend on the adaptive maintenance of the integrity of the genetic information (e.g., DNA protective and repair mechanisms), as well as of the homeostatic and cybernetic regulatory systems within and between tissues. The primary focus of the past and current toxicological studies and risk assessment practices has been to ascertain and predict the "genotoxicity" of various physical and chemical agents. The paradigm of "carcinogen as mutagen," while valuable for stimulating studies of the detection of mutagens and of their potential role in "causing" somatic and germ line diseases, has tended to blunt research on the role of nongenotoxic mechanisms in disease causation. This brief analysis will emphasize the need to consider the role of modulated gap junctional intercellular communication (GJIC) in any biological risk assessment model. It is based on the following assumptions and facts. Because gap junctions exist in all metazoans, they have been associated with the regulation of cell proliferation, development, differentiation, and the adaptive function of both excitable and nonexcitable coupled cells. A highly evolutionarily conserved family of genes codes for proteins (connexins), which, as hexameric units (connexons), form membrane-associated channels of gap junctions. Cells coupled by gap junctions will have their ions and small regulatory molecules equilibrated. Regulation of GJIC can be at the transcriptional, translational, or posttranslational levels. Transient down or up regulation of GJIC can be induced by endogenous or exogenous chemicals via many mechanisms at any of these three levels. Stable abnormal regulation has been associated with activated oncogenes, and normal regulation has been associated with several tumor suppressor genes. The dysfunction of these gap junctions might play a role in the actions of various toxic chemicals that have cell type/tissue/organ specificity. This could bring about distinct clinical consequences, such as embryo lethality or teratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the central nervous system, hyperplasia of the skin, and tumor promotion of initiated tissue. Modulation of GJIC should be viewed as a scientific basis of "epigenetic toxicology" because the alteration of intercellular communication would alter the internal physiological state of the cell. The inhibition of GJIC is a necessary component of mitogenesis (a necessary component of the multistage carcinogenic process). The modulation of GJIC can have both toxicological, as well as therapeutic potential.