Spontaneous renal tubular hyperplastic and neoplastic lesions in three Sprague-Dawley rats from a 90-day toxicity study

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 (nt106G) to adenine (nt106A) 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 nt106G-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.