Persistent, low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effect on aryl hydrocarbon receptor expression in a dioxin-resistance model.
Most toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated by the aryl hydrocarbon receptor (AHR). A single, acute dose of TCDD can alter its own receptor levels thus complicating evaluation of dose-response relationships for AHR-mediated events. Since environmental exposure to dioxins is typically of a repeated low-dose nature, we examined the effect of such exposure on AHR expression. Three rat strains differing greatly in their sensitivity to acute TCDD lethality, Long-Evans (Turku AB) (L-E) (LD50 approximately 10 microg/kg); Sprague Dawley (SD) (LD50 approximately 50 microg/kg); and Han/Wistar (Kuopio) (H/W) (LD50 > 9600 microg/kg), were administered TCDD intragastrically, biweekly for 22 weeks producing doses equivalent to 0, 10, 30, and 100 ng/kg/day. Changes in hepatic AHR levels were quantitated at the protein level by radioligand binding and immunoblotting and at the mRNA level by RT-PCR. Cytosolic AHR protein was elevated at 10 or 30 ng/kg/day TCDD in SD and L-E rats; AHR mRNA was also elevated at these doses, suggesting a pretranslational mechanism. There was no apparent relationship between TCDD-induced AHR regulation and strain sensitivity to TCDD. Overall, "subchronic" TCDD did not greatly perturb AHR expression. The maintenance of relatively constant receptor levels in the face of persistent agonist stimulation is in contrast to the sustained depletion of AHR by TCDD observed in cell culture and to the fluctuations in AHR observed hours to days following acute TCDD exposure in vivo. Changes in AHR levels may affect dose-response relationships; the effect of TCDD on its own receptor at environmentally relevant dosing schemes is therefore important to risk assessment.
Franc
M A
MA
Department of Pharmacology, University of Toronto, Ontario, Canada, M5S 1A8.
Pohjanvirta
R
R
Tuomisto
J
J
Okey
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AB
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004147:Dioxins / Q000633:toxicity; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013723:Teratogens / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects / Q000502:physiology
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D013723:Teratogens