Many of the toxic responses to TCDD (particularly in targets such as the skin and the immune system) are a consequence of altered growth and differentiation, presumably mediated by the Ah receptor-dependent control of the expression of specific growth regulatory and differentiation genes. Previous studies from this laboratory have shown that TCDD induces terminal differentiation in cultures of normal human keratinocytes and blocks the thymic epithelial cell (TEC)-dependent maturation of prothymocytes in vitro. Subsequent research by others confirms that TCDD affects thymocyte maturation in vivo and suggests that thymic epithelium is altered by in vivo exposure to TCDD. We propose that the inhibition of thymocyte development is mediated by a functional impairment of the epithelial component of the thymic microenvironment (TME), and that the effect on thymic epithelium results from the induction of terminal differentiation by TCDD. This mechanism is analogous to the actions of this compound on human epidermal cells (keratinocytes). The common embryological origin, expression of differentiation antigens and functional overlap of skin and thymus epithelium support the relevance of the findings in keratinocytes to the proposed studies of the actions of TCDD on thymic epithelium. Both a biological and potential pathological role can be envisioned for the Ah receptor in the thymus. The Ah receptor may be an important developmental protein, controlling the expression of genes required for the differentiation of the thymic primordium into a functional TME. The activation signal for this Ah receptor may initiate from signal transduction pathways triggered by the seeding of the primordium by prothymocytes. The metabolically persistent receptor agonist, TCDD, would produce a sustained activation of the Ah receptor and gene expression, pushing the differentiation of the thymic primordium beyond a functional state and into terminal differentiation. The proposed research using early gestation C57BL/6 and neonatal SCID mice, and fetal thymic organ cultures as models will examine the role of the Ah receptor and its battery of known differentiation and growth regulatory genes in the development and function of the TME. Cloning strategies will be implemented in these thymus developmental models to identify novel TCDD- responsive developmental genes. A detailed study of the molecular biology of TCDD actions on the development and function of the epithelial component of the TME should provide a prototype model for other developmental targets and new information on the biological function of the Ah receptor system.
