Note, following abstract from 1994. It was later determined that TCDD
levels in general population was sufficient to warrant concern.
[Aryl hydrocarbon or dioxin receptor: biologic and toxic responses]
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. PMID: 7984872
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