DIOXINS AND THE AH RECEPTOR - PROBES TO UNCOVER PROCESSES IN NEUROENDOCRINE DEVELOPMENT

The developing neuroendocrine system is thought to be a sensitive targ et for a number of environmental chemicals. Many of these chemicals ac t, not by directly damaging macromolecules, but through the inappropri ate modulation of normal cellular processes that regulate cell growth and differentiation patterns. As our knowledge of the specific hormone s and signaling pathways involved in these functions has advanced, so has our understanding that these chemicals may act by a number of diff erent molecular mechanisms. The dioxin-like compounds are persistent e nvironmental contaminants. The findings that they affect cell prolifer ation and differentiation, are tumor promters, and are potent immuno-, developmental, and reproductive toxicants by mechanisms not dependent on cytotoxicity, are consistent with the hypothesis that these compou nds act by modulating normal cell and tissue growth processes. Further more, findings in exposed experimental animals and humans suggest that the developing neuroendocrine system is a sensitive target for these chemicals. All evidence to date indicates that these compounds produce their biological and toxicological affects by binding to a gene regul atory protein, the Ah receptor, whose normal function has not been cle arly delineated and whose normal endogenous ligand has not been identi fied. Yet data on the biochemistry and molecular biology of this trans cription factor indicates that well regulated and conserved pathways e xist for it to mediate the transduction of biochemical signals for the control of a number of hormones and growth factors. These and other d ata provide evidence to suggest that the Ah receptor may be necessary for the normal development of many tissues including those in the neur oendocrine system. Further research is necessary to understand ii and how it may function in this system, what the normal endogenous ligand is, and how perturbations in its activity may affect normal developmen tal processes. (C) 1997 Inter Press, Inc.