Aryl hydrocarbon or dioxin receptor: biologic and toxic responses

Abstract

1. The AhR represents a ligand-activated transcription factor. Receptor agonists include planar aromatic compounds, a variety of heterocyclic plant constituents, and PCDD/PCDF. The latter lead to persistent activation of the receptor due to their strong binding affinity and long biologic half-life of over 10 years in human blood and fat. Practically every person on earth is exposed to these compounds via the diet (> 90%) and by high concentrations in mother's milk. PCDD/PCDF produced toxic responses in exposed people (primarily chloracne and immunosuppression) in the past. However, the present PCDD/PCDF levels (basal levels) in the general population are below those warranting toxicologic concern. 2. The AhR has been characterized as a helix-loop-helix transcription factor related to the Drosophila developmental genes sim and per. The cytosolic form of the receptor is present as an inactive complex with two subunits of HSP90. After ligand binding HSP90 is released and the receptor enters the nucleus as a heterodimer together with a related protein ARNT. It binds with high affinity to certain enhancer elements in the upstream region of several genes such as cytochrome P4501A1 (CYP1A1). The AhR transcriptionally activates several drug-metabolizing enzymes and proteins involved in growth/differentiation, such as the plasminogen activator inhibitor PAI-2 and IL-1 beta. In addition, it modulates the action of a number of other nuclear transcription factors such as receptors of the steroid hormone receptor superfamily and of cell surface receptors such as EGF. With the exception of CYP1A1 induction, little is known about the mechanism of transcriptional activation of the AhR-controlled genes. Many AhR-modulated biologic responses (such as modulation of the estrogen and EGF receptor) appear to be indirect. 3. Persistent activation of the AhR is probably responsible for toxic responses in experimental animals and humans. They are markedly tissue and species specific. In rodents a wasting syndrome, immunosuppression, teratogenicity, chloracne, and carcinogenicity/tumor promotion have been well studied. There is good evidence for an involvement for the AhR in these responses. However, the chain of events from receptor activation to the diverse toxic endpoints is largely unknown. Alteration of growth and differentiation of epithelial tissues may underlie most of the toxic responses. A lot has already been achieved, mostly by characterizing the AhR and transcriptional activation of CYP1A1. Still more work lies ahead of us, for example, elucidation of the physiologic roles of the AhR and of the chains of events from receptor activation to the various biologic and toxic endpoints.