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INSIGHTS FROM AHR AND ARNT GENE KNOCKOUT STUDIES REGARDING RESPONSES TO TCDD AND REGULATION OF NORMAL EMBRYONIC DEVELOPMENT
Citation:
Abbott, B D. INSIGHTS FROM AHR AND ARNT GENE KNOCKOUT STUDIES REGARDING RESPONSES TO TCDD AND REGULATION OF NORMAL EMBRYONIC DEVELOPMENT. International Federation of Teratology Societies, Satellite Symposium on Reproductive & Developmental Effects of Dioxins & Endocrine Disruptors, Matsue and Hiroshima, Japan, July 12-18, 2000.
Description:
The aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT) are members of the Per-ARNT-Sim (PAS) family of proteins. The AhR binds members of the chemical family that includes dioxins, furans and coplanar polychlorinated biphenyls (PCBs). A ligand-AhR-ARNT complex forms and binds to DNA response elements in the nucleus to regulate gene transcription, producing a diverse range of biological effects including reproductive and developmental toxicity. The most potent ligand for the AhR is the compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is often used as a model compound in mechanistic studies. The roles of the AhR and ARNT in response to TCDD and in normal embryonic development have been evaluated using knockout mice in which the AhR or ARNT gene was inactivated. The AhR null mice survive and are fertile, but an increased number of deaths was noted for implanted embryos, pregnant and lactating females and weaned pups. There were also deleterious effects observed in aging animals, particularly in liver and immune system function. The ARNT null embryos died in utero and examination of the phenotypes revealed deficits in vascularization of embryo, yolk sac, and in formation of the placental labyrinth. ARNT heterodimerizes with other PAS proteins including the hypoxia induction factor 1-alpha. This complex regulates responses to hypoxia through up regulation of vascular endothelial cell growth factor (VEGF), promoting formation of vasculature. The ARNT null conceptus expressed VEGF abundantly in trophoblastic giant cells, suggesting that constitutive, rather than hypoxia-induced, expression of VEGF predominates at this stage of development in extracellular tissues. The phenotype of the ARNT null conceptus may be related to disruption of VEGF binding, expression of VEGF receptors or both. Further study of the AhR and ARNT knockout mice could provide insight into the developmental roles of these PAS proteins.