In vivo up-regulation of aryl hydrocarbon receptor expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a dioxin-resistant rat model.
The aryl hydrocarbon receptor (AHR) mediates toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and regulates expression of several genes such as CYP1A1. Little is known about what regulates expression of the AHR itself. We tested the ability of TCDD to alter in vivo expression of its own receptor in rat strains that are susceptible to TCDD lethality [Long-Evans (Turku AB) (L-E) and Sprague Dawley (SD)] and in a rat strain that is remarkably resistant to TCDD lethality [Han/Wistar (Kuopio) (H/W)]. Rats were administered a single, intragastric dose of 5 or 50 microg/kg of TCDD. Hepatic cytosol, nuclear extract, and RNA were prepared at 1, 4, and 10 days after TCDD exposure. AHR expression was assessed at three levels: ligand binding function, immunoreactive protein and mRNA. TCDD at 5 microg/kg produced a 2- to 3-fold increase in cytosolic AHR in all strains; 50 microg/kg produced depletion at day 1 followed by recovery in SD and H/W but not L-E rats. Both the increase in AHR above basal levels and the recovery from initial depletion were accompanied by elevations in steady-state AHR mRNA, suggesting a pre-translational mechanism for AHR regulation by its own ligand. This up-regulation in vivo is in contrast to the sustained depletion of AHR caused by TCDD in cell culture. There was no clear relationship between AHR regulation and strain sensitivity; thus, the large inherent strain differences in susceptibility to TCDD lethality probably are not explained by differential regulation of AHR by TCDD.
Franc
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MA
Department of Pharmacology, University of Toronto, Medical Sciences Building, 1 King's College Circle, M5S 1A8, Toronto, Ontario, Canada.
Pohjanvirta
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R
Tuomisto
J
J
Okey
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AB
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004147:Dioxins / Q000494:pharmacology; D005260:Female; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D013723:Teratogens / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens