Despite the fact that nearly three percent of all newborns are affected by congenital malformations, our knowledge of the etiology of these defects is rudimentary. Recent advances in the understanding of the genetic control of normal development of the mammalian body plan have provided new opportunities to explore the basis of these defects. One particular family of homeobox genes that has been well characterized, the Hox genes, have been demonstrated to play an important role in pattern formation during embryogenesis. When their patterns of expression are perturbed by spontaneous or induced mutations, substantial alterations of the basic body plan can occur. Strikingly, many of these morphological changes have features in common with those observed in humans and animals exposed to specific environmental toxicants. We propose that certain teratogens, in particular ethanol, heat, and cadmium exert their teratogenic effects by altering Hox gene expression. Our goal is to test this hypothesis through a careful examination of the pattern of expression of certain Hox genes in mouse embryos after in utero exposure to these toxicants. We will focus on Hox genes that have been experimentally demonstrated to be involved in the development of those structures that are affected by exposure to ethanol, heat, or cadmium. Of particular interest is the Hoxc-8 gene which, in preliminary experiments, appears to be capable of mounting a transcriptional response to heat. Although the experiments proposed here will also contribute to our knowledge of Hox gene function in normal embryogenesis, our ultimate goal is to understand the role played by these genes in the development of congenital defects. Only after a solid foundation of information regarding the basis of malformations is in place can effective measures, both behavioral and therapeutic, be put in place to prevent their occurrence in humans.
