Dioxins and the Ah receptor: probes to uncover processes in neuroendocrine development

The developing neuroendocrine system is thought to be a sensitive target for a number of environmental chemicals. Many of these chemicals act, not by directly damaging macromolecules but through the inappropriate modulation of normal cellular processes that regulate cell growth and differentiation patterns. As our knowledge of the specific hormones and signaling pathways involving in these functions has advanced, so has our understanding that these chemicals may act by a number of different molecular mechanisms. The dioxin-like compounds are persistent environmental contaminants. The findings that they affect cell proliferation and differentiation, are tumor promoters, and are potent immuno-, developmental, and reproductive toxicants by mechanisms not dependent on cytotoxicity, are consistent with the hypothesis that these compounds act by modulating normal cell and tissue growth processes. Furthermore, findings in exposed experimental animals and humans suggest that the developing neuroendocrine system is a sensitive target for these chemicals. All evidence to data indicates that these compounds produce their biological and toxicology affects by binding to a gene regulatory protein, the Ah receptor, whose normal function has not been clearly delineated and whose normal endogenous ligand has not been identified. Yet data on the biochemistry and molecular biology of this transcription factor indicates that well regulated and conserved pathways exist for it to mediate the transduction of biochemical signals for the control of a number of hormones and growth factors. These and other data provide evidence to suggest that the Ah receptor may be necessary for the normal development of many tissues including those in the neuroendocrine system. Further research is necessary to understand if and how it may function in this system, what the normal endogenous ligand is, and how perturbations in its activity may affect normal development processes.