This proposed research program will investigate genetic susceptibility to environmentally-induced orofacial clefts (ORFs) and neural tube defects (NTDs) using two transgenic mouse models. These two common human congenital defects are considered to be multi-factorial traits, having both a significant genetic and environmental component to their etiology. Given the complex pathophysiology of palatal and neural tube closure, the objective of the proposed research program is to utilize recently developed knock out mouse models lacking either a functional folate binding protein receptor (FBP-1) or a functional Ah receptor with which to test critical hypotheses concerning the role of susceptible genotypes on the development of environmentally-induced congenital malformations. Using the FBP-1 mice we will directly test the hypothesis that elevated levels of homocysteine cause OFCs and/or NTDs in the absence of folate depletion, especially when the embryo is exposed in utero to environmental toxicants. We intend to examine the morphological, biochemical and cellular processes that are compromised within embryos by either the absence of sufficient folate molecules or an increased exposure to high levels of homocysteine, as well as determining those processes that are aided by maternal folic acid supplementation. This include well-defined studies on the impact of the model compounds interacting with embryonic genotypes on cellular proliferation and/or cell death in the developing caraniofacies and neural tube. Additionally, the aryl hydrocarbon receptor (AhR) knockout mouse, which are resistant to aromatic hydrocarbon (TCDD) toxicity, will be similarly used to examine the genetic susceptibility to environmentally-induced birth defects using model environmental contaminants widely found in Texas' Rio Grande Valley as well as in the immediate environs of Sumqayit, Azerbaijan.
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