2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), commonly called dioxin, is a highly toxic environmental contaminant. The toxicity of dioxin has been studied extensively, and one of the most characteristic effects is its action on the immune system, and particularly the thymus. The thymus is especially sensitive to TCDD during development, and prenatal exposure to TCDD has been shown to cause thymic atrophy in all species studied at doses far below those toxic in adults. However, the mechanism by which TCDD induces thymic atrophy following prenatal exposure is unclear. We hypothesize that TCDD upregulates genes involved in apoptosis, in particular Fas and FasL, and that thymic atrophy seen following prenatal TCDD exposure results from FasL based apoptosis of T-cells. The experiments proposed here will characterize and quantify the expression of Fas and FasL following prenatal TCDD exposure. This hypothesis will be tested using Fas deficient (lpr) and FasL defective (gld) mice. In addition, we propose to determine the mechanism by which TCDD induces apoptosis by differentiating between the mitochondrial and death receptor pathways. Whether Fas/FasL expression and induction of apoptosis is regulated by the AhR will be tested using AhR KU mice. Also, caspase inhibitors will be used in vivo in an attempt to abrogate the prenatal immunotoxicity of TCDD.
