The AH receptor and a novel gene determine acute toxic responses to TCDD: segregation of the resistant alleles to different rat lines.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD),12 the most toxic congener of dioxins, exhibits wide sensitivity differences between a sensitive Long-Evans (L-E) rat and a resistant Han/Wistar (H/W) rat. The sensitivity is determined probably by two autosomal genes and it is highly end point dependent. The difference is more than 1000-fold for acute toxicity and negligible for CYP1A1 induction. The rat strains were recently shown to have differences in the size of AH receptor (AHR), which mediates most effects of TCDD. In the present study, the rat strains were crossed and the resistant alleles of genes determining TCDD sensitivity were segregated to new rat lines. Selection was based on AHR phenotype determined by Western blot and resistance to TCDD lethality. Two genes determining resistance were found: the Ahr and a novel gene designated "B." In homozygous rats, the H/W type Ahrhw allele prevented TCDD lethality up to 2000 microg/kg or more, and the H/W type "Bhw" allele also increased resistance to TCDD lethality but to a lesser extent. Heterozygous rats were only slightly more resistant to acute lethality than the respective sensitive homozygous rats. CYP1A1 induction was similar irrespective of the Ahr and "B" genotypes, but a substantial increase in serum bilirubin seen after low doses in sensitive rats occurred only after large doses in "Bhw/hw" and not at all in Ahrhw/hw rats. In conclusion, the Ahrhw allele is a major determinant of the exceptional resistance of H/W rats to TCDD lethality. There is also an additional gene, whose function remains to be characterized, conferring limited resistance to TCDD toxicity. These two H/W rat-derived alleles are separately expressed in the new rat lines created.
National Public Health Institute, Kuopio, FIN-70701, Finland.
J T
JT
Tuomisto
M
M
Viluksela
R
R
Pohjanvirta
J
J
Tuomisto
D000483:Alleles; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000502:physiology*
D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1