Journal Article

A Truncation in the Aryl Hydrocarbon Receptor of the CRL:WI(Han) Rat Does Not Affect the Developmental Toxicity of TCDD

Tao Jiang, David R. Bell, Sally Clode, Ming Qi Fan, Alwyn Fernandes, Paul M. D. Foster, George Loizou, Alan MacNicoll, Brian G. Miller, Martin Rose, Lang Tran and Shaun White

in Toxicological Sciences

Volume 107, issue 2, pages 512-521
Published in print February 2009 | ISSN: 1096-6080
Published online December 2008 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfn252
A Truncation in the Aryl Hydrocarbon Receptor of the CRL:WI(Han) Rat Does Not Affect the Developmental Toxicity of TCDD

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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 ∼110 and ∼97 kDa in individual rats from both strains. The AhR cDNA from a CRL:WI(Han) rat with the ∼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 ∼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 ∼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.

Keywords: aryl hydrocarbon receptor; developmental toxicity; genetics; SNP; TCDD

Journal Article.  6918 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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