A truncation in the aryl hydrocarbon receptor of the CRL:WI(Han) rat does not affect the developmental toxicity of TCDD.
The aryl hydrocarbon receptor (AhR) is required for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and so the AhR of CRL:WI and CRL:WI(Han) rats was characterized. Western blot showed AhR proteins of approximately 110 and approximately 97 kDa in individual rats from both strains. The AhR cDNA from a CRL:WI(Han) rat with the approximately 110-kDa protein revealed a sequence that was identical to that of the CRL:WI and SD rat. However, cloning of the AhR from a rat with the approximately 97-kDa protein revealed a point mutation, and five variants encoding two C-terminally truncated variants of the AhR protein, arising from a point mutation in the intron/exon junction and consequent differential splicing. These C-terminally truncated variants were expressed and shown to give rise to a protein of approximately 97 kDa; the recombinant AhR bound TCDD with an affinity that was not statistically different from the full-length protein. A single-nucleotide polymorphism assay was developed, and showed that both alleles were represented in a Hardy-Weinberg equilibrium in samples of CRL:WI and CRL:WI(Han) populations; both alleles are abundant. Rats from two studies of TCDD developmental toxicity were genotyped, and the association with toxicity investigated using statistical analysis. There was no plausible evidence that the AhR allele had a significant effect on the toxic endpoints examined. These data show that the two AhR alleles are common in two strains of Wistar rat, and that the AhR alleles had no effect on TCDD-induced developmental toxicity in two independent studies.
Jiang
Tao
T
School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
Bell
David R
DR
Clode
Sally
S
Fan
Ming Qi
MQ
Fernandes
Alwyn
A
Foster
Paul M D
PM
Loizou
George
G
MacNicoll
Alan
A
Miller
Brian G
BG
Rose
Martin
M
Tran
Lang
L
White
Shaun
S
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D005838:Genotype; D006130:Growth Disorders / Q000139:chemically induced* / Q000235:genetics*; D008024:Ligands; D010957:Plasmids / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics
D018076:DNA, Complementary; D004785:Environmental Pollutants; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins