Epigenetic Disease: Teratogenesis

Abstract In contrast to germline mutations, which are hereditable and result in malformation syndromes, and somatic mutations, which are nonheredit able and contribute to oncogenesis, teratogenesis can be viewed as resulting from changes in gene expression that are induced by in utero exposure of the developing embryo to an exogenous compound or to increased amounts of an endogenous compound. This differs from the traditional view of teratogenesis as representing the effect of toxins that cause cell death. Although teratogens undoubtedly cause cell death, they may do so not by nonspecific toxic effects on cellular metabolism but by activating specific genetic pathways that lead to an active form of cell death, termed apoptosis, which is an essential process of normal development. Teratogenic exposure of mouse embryos to ethanol or retinoic acid (RA) results in an increased area and density of dying cells at sites of developmentally programmed cell death (Kotch and Sulik, 1992a, b; Sulik et al., 1988). In this chapter, evidence will be presented indicating that the effects of two well-studied teratogens, retinoic acid and ethanol, may be mediated by specific changes in gene expression.