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A truncation in the Aryl Hydrocarbon Receptor of the\ud CRL:WI(Han) rat does not affect the developmental\ud toxicity of TCDD

By tao Jiang, David Robert Bell, Sally Clode, MingQi Fan, Alwyn Fernandes, Paul M.D. Foster, George Loizou, Alan MacNicoll, Brian G. Miller, Martin Rose, Lang Tran and Shaun White

Abstract

The Aryl Hydrocarbon Receptor (AhR) is required for the toxicity of TCDD, and so the AhR of CRL:WI and CRL:WI(Han) rats was characterised. 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 ~110kDa 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 ~97kDa protein revealed a point mutation, and\ud 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 ~97kDa; the recombinant\ud AhR bound TCDD with an affinity that was not statistically different from the full-length protein. A single-nucleotide polymorphism (SNP) assay was developed, and showed that\ud 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\ud 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

Publisher: Oxford University Press
Year: 2009
OAI identifier: oai:eprints.nottingham.ac.uk:1066
Provided by: Nottingham ePrints

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