This Article Free Full Text Free Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Hall, W. C. Articles by Borzelleca, J. F. Search for Related Content PubMed PubMed Citation Articles by Hall, W. C. Articles by Borzelleca, J. F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Kidney Cancer Social Bookmarking                         What's this?

Spontaneous Renal Tubular Hyperplastic and Neoplastic Lesions in Three Sprague-Dawley Rats from a 90-Day Toxicity Study

¹ Hall Consulting, Inc., Mount Airy, MD 21771, USA
² Rodent Genetics, Charles River Laboratories, Troy, NY 12180, USA
³ Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
⁴ Covance Laboratories, Inc., Vienna, Virginia 22182, USA (DGG, BMU) and Madison, WI 53704 (DGP)
⁵ Professor Emeritus, Dept. of Pharmacology and Toxicology, VA Commonwealth University, Richmond, VA 23229, USA

Correspondence: Address correspondence to: William C. Hall, Hall Consulting, Inc. 12337 Sherwood Forest Drive, C26, Mount Airy, MD 21771, USA; e-mail:hallconsulting{at}earthlink.net

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague–Dawley (Crl:CD®(SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague–Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3–13) of the Bhd gene was sequenced, and a guanine (nt106^G) to adenine (nt106^A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106^G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.

Key Words: Tumor suppressor gene • Birt-Hogg-Dubé • tuberous sclerosis • Nihon rat • Eker rat • kidney neoplasm • Microsatellite loci • laser capture microdissection

Abbreviations: Bhd, Birt-Hogg-Dubé • Tsc-2, Tuberous sclerosis 2 • LCM, Laser capture microdissection • PCR, Polymerase chain reaction • bp, base pair • cM, CentiMorgan • NT, nucleotide • NTP, National Toxicology Program • A, Adenine • C, Cytosine • G, Guanine • T, Thymine

Toxicologic Pathology, Vol. 35, No. 2, 233-241 (2007)
DOI: 10.1080/01926230601156252


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				G. C. Hard, J. C. Seely, G. E. Kissling, and L. J. Betz Spontaneous Occurrence of a Distinctive Renal Tubule Tumor Phenotype in Rat Carcinogenicity Studies Conducted by the National Toxicology Program Toxicol Pathol, April 1, 2008; 36(3): 388 - 396. [Abstract] [Full Text] [PDF]