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ToxSci Advance Access published online on December 4, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn252
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Published by Oxford University Press 2008.

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*,1, Sally Clode{dagger}, Ming Qi Fan*, Alwyn Fernandes{ddagger}, Paul M D Foster§, George Loizou, Alan MacNicoll{ddagger}, Brian G. Miller||, Martin Rose{ddagger}, Lang Tran|| and Shaun White{ddagger}

* School of Biology, University of Nottingham, University Park, Nottingham NG7 2RD, UK {dagger} Covance Laboratories Ltd., Otley Road, Harrogate, North Yorkshire, HG3 1PY, UK {ddagger} Central Science Laboratory, Environment, Food and Health, Sand Hutton, York YO41 1LZ, UK § NIEHS, PO Box 12233 (MD E1-06), 111 TW Alexander Drive, Research Triangle Park, NC 27709 USA Health & Safety Laboratory, Harpur Hill, Buxton, Derbyshire SK17 9JN, UK || Institute of Occupational Medicine, Research Park North, Riccarton, Edinburgh, EH14 4AP, UK

1 to whom correspondence should be addressed. Phone (44) 115 9513210, email david.bell{at}nottingham.ac.uk, Fax (44) 115 9513251

Received October 23, 2008; revision received November 26, 2008; accepted November 26, 2008


  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 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 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 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.

Key Words: Aryl hydrocarbon receptor; genetics; SNP; TCDD; developmental toxicity.


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