Dose-response analysis of short-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in three differentially susceptible rat lines.
Line A, B, and C rats were selectively bred from TCDD-resistant Han/Wistar (Kuopio; H/W) and TCDD-sensitive Long-Evans (Turku/AB; L-E) rats. Line A rats are the most resistant to TCDD acute lethality followed by line B and line C rats. The resistance in line A rats is associated with a mutated H/W-type aryl hydrocarbon receptor (Ahr) allele (Ahr(hw)) and in line B rats the resistance is associated with an allele of an unknown gene B (B(hw)), while line C rats are almost as sensitive to TCDD as L-E rats. The dose-responses of characteristic short-term effects (day 8 postexposure) of TCDD were used to evaluate the efficacy (magnitude of effect) and potency relationships between these lines. Line A rats showed similar efficacies as line C (line A:line C efficacy ratio more than 0.7) for thymus weight, EROD activity, and incisor tooth defects. In contrast, efficacies in line A were decreased (efficacy ratios 0.19-0.37) for body weight change, serum bilirubin, and FFA levels, and serum ASAT activity. For most endpoints the efficacies in line B rats seem to be lower than in line C rats. The potencies were close to each other in line A and B rats, but somewhat lower than in line C rats. The results support our previous concept of two different AHR-mediated signaling pathways leading to dioxin type I and type II endpoints. Rats with the Ahr(hw/hw) genotype show a markedly decreased efficacy for type II endpoints, but B(hw) allele had only a minor effect on efficacies for most endpoints. Both H/W-type resistance alleles also decreased the potency of TCDD. However, the potency differences in short-term toxicity seem not to explain, at least alone, the differences seen in acute lethality among the rat lines.
Simanainen
Ulla
U
National Public Health Institute, Department of Environmental Health, P.O. Box 95, FIN-70701 Kuopio, Finland. ulla.simanainen@ktl.fi
Tuomisto
Jouni T
JT
Tuomisto
Jouko
J
Viluksela
Matti
M
D000483:Alleles; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D003433:Crosses, Genetic; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D007180:Incisor / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D001219:Aspartate Aminotransferases; D001663:Bilirubin