Orofacial clefts are among the most common birth defects in humans and are associated with significant life- long morbidity and mortality. There is considerable epidemiological evidence to suggest that the interaction of genes and the environment contributes to the pathophysiology of cleft palate (CP). In order to study these gene-environment interactions, CP in murine models can be induced with the pollutant 2, 3, 7, 8-tetrachloro- dibenzo-p-dioxin (dioxin). A locus, chemically mediated teratogenesis 1 (Cmt1), which is genetically linked to CP susceptibility was identified using this murine model. This proposal aims to identify genes involved in CP pathophysiology through both genetic and genomic approaches. First, Cmt1 will be physically mapped using interval-specific congenic mice and haplotype comparisons of common inbred mouse strains to identify the underlying gene(s) involved in modifying susceptibility. Genetic variants that affect gene expression are pre- dicted to underlie a majority of biological variation, including disease susceptibility. Therefore, as a second approach, temporal gene expression profiles will be generated to compare molecular palatogenesis in sensi- tive and resistant strains of mice. Since dioxin teratogenesis is mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, it is likely that the molecular mechanism of CP induction involves alterations in gene expression. Therefore, differentially expressed AHR responsive genes will be identified throughout palatogenesis and the downstream effects on palate development will be characteri- zed.' Genes involved in dioxin-induced CP may be common to CP caused by a variety of genetic and/or environmental insults and point to a common pathophysiologic mechanism of clefting. Thecharacterized gene expression profiles associated with mammalian CP could be used in the future to screen pharmaceuti- cals and environmental contaminants for teratogenic activity. Relevance: The goal of this proposal is to understand how genes of an individual interact with environmental exposures to cause cleft palate. This research can be used to test chemicals for toxic potential, as well as identify people at risk for cleft palate. By understanding the risk factors that can lead to cleft palate, treat- ment and prevention strategies can be developed.
| Stevens, Emily A; Mezrich, Joshua D; Bradfield, Christopher A (2009) The aryl hydrocarbon receptor: a perspective on potential roles in the immune system. Immunology 127:299-311 |
