In order to evaluate a short-term carcinogenicity testing system using CB6F1 -Tg rasH2 (rasH2-Tg) mice carrying a human prototype c-Ha-ras gene, 26-week studies were conducted in 12 different facilities as a part of an International Life Science Institute Health and Environmental Science Institute (ILSI HESI) international collaborative project. In each study N-methyl-N-nitrosourea (MNU) was administered to a separate group of rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. We herein have summarized the mortality, body weight change, and neoplastic and nonneoplastic lesions detected in these positive control groups as representative historical positive control data. Also, we performed an interlaboratory comparison of the response of rasH2-Tg mice to MNU based on the data of 11 positive control groups from these studies. Although the body weight of rasH2-Tg mice showed lower values than that of non-Tgmice during the experimental period, body weight gain in the rasH2-Tg mice was similar to that in non-Tg mice. The mortality of rasH2-Tg mice during the study period was very low, the same as for the non-Tg mice. Incidences of spontaneous alveolar/bronchiolar adenomas and splenic hemangiomas/hemangiosarcomas were also low in the rasH2-Tg mice. Nonneoplastic lesions detected in the rasH2-Tg mice were similar to those in non-Tg mice, excluding the incidence of myopathy. There were interlaboratory differences in mortality and incidence of some lesions in the MNU-treated groups. However, the causes of death were common among the 11 laboratories and almost all the MNU-treated rasH2-Tg mice developed forestomach squamous cell papillomas/carcinomas or malignant lymphomas. This suggests that there is no appreciable difference in the response of the rasH2-Tg mouse to MNU used as a positive control. Therefore, it is concluded that MNU would be an adequate positive control compound in this testing system.

Abstract. We investigated the chronic functional and histopathological changes in the sciatic nerve and lens of streptozotocin (STZ)-diabetic rats and evaluated the preventive effects of ranirestat (AS-3201), a potent aldose reductase inhibitor, on these changes. Sorbitol levels in the sciatic nerve and lens, motor nerve conduction velocity (MNCV), and development of cataracts were measured in STZ-diabetic rats given a ranirestat-admixed diet (0.0005%) for 35 weeks. Ranirestat reduced sorbitol accumulation in the sciatic nerve and improved the decrease in MNCV of STZ-diabetic rats. Morphological and morphometric examination of changes in sural nerve revealed that treatment with ranirestat prevented both the deformity of myelinated fibers and the decrease in their axonal and myelin areas (atrophy). Ranirestat also averted the changes in the size frequency histogram of myelinated fibers. Finally, STZ-diabetic rats developed early lens opacities 8 weeks after STZ injection and had cataract by the end of the experimental period. However, in the ranirestat-treated diabetic rats, no lens opacity was observed in any rat throughout the entire experimental period. This study suggests that the polyol pathway plays an important role in the progress of diabetic neuropathy and cataract formation in STZ-diabetic rats. Ranirestat should be a promising agent for the treatment of complications associated with diabetes, especially neuropathy.

A novel rat model of hereditary renal cell carcinoma (RC) was found in a rat colony of the SpragueDawley strain in Japan, and named the "Nihon" rat. In this strain, RCs develop from early preneoplastic lesions, which begin to appear at 4 weeks of age, forming adenomas by the age of 16 weeks. The RCs are predominantly of clear cell type. Southern blot, northern blot and SSCP analyses revealed no change in the Tsc1, Tsc2, VHL, and c-Met genes. Thus, the Nihon rat should be a valuable experimental model for understanding renal carcinogenesis, especially clear cell type, which is common among human RCs.Key words: Nihon rats -Tsc2 gene mutant (Eker) rats -Renal carcinogenesis -Hereditary cancer Hereditary cancer was first described in the rat by Eker in 1954.1) The Eker rat model of hereditary renal carcinoma (RC) was the first example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. In 1994, Hino and colleagues identified a germline mutation in the rat homologous to the human tuberous sclerosis gene (TSC2) as the predisposing Eker gene.2-4) Recently, we found a novel hereditary RC model in the Sprague-Dawley rat in Japan. We have named this novel RC model the Nihon rat. In this report, we described the origin, transmission mode, and phenotypic and molecular features of Nihon rats.All animals were housed individually in stainless steel cages with wood chip bedding in a room controlled at a temperature of 23±2°C, humidity of 55±10%, with a 12 h lighting cycle (from 6 a.m. to 6 p.m.). The rats were fed a standard diet (CR-LPF, Oriental Yeast Co., Ltd., Tokyo) and were allowed tap water ad libitum. Animals were killed by exsanguination under pentobarbital sodium anesthesia. After necropsy, tissues were fixed in 10% neutral buffered formalin, processed to paraffin-embedded blocks, and sectioned at 5 µm using standard procedures. Sections were stained with hematoxylin and eosin for microscopical examination. Midsagittal sections of each kidney were also stained with periodic acid-Schiff (PAS), and with alcian blue for acid mucopolysaccharides. Tail and kidney DNAs from the original (parent) female rat were extracted as reported. [4][5][6][7][8][9] We used Southern blot, northern blot and SSCP analyses to search for mutations of the Tsc1, Tsc2, VHL, and c-Met genes. The gene-specific primers for Tsc1, Tsc2, VHL, and c-Met [Accession No. AB012279 (primer for exon 17), AB012280 (primer for exon 18) and AB012281 (primer for exon 19), kindly provided by Dr. Y. Kikuchi] were described previously. [4][5][6][7][8][9] Bilateral, multicentric renal tubule tumors were found in 15 out of 343 rats during 5 toxicity studies during the safety evaluation of 3 unrelated chemicals in our laboratory, although renal tumors were found in both treated and non-treated rats (Table I). The age of the rats ranged from 7 to 16 weeks at termination of the treatment period in each of the studies (Table I). The rats had all obtained from the same supplier (Clea Japan Inc., Shiga). At necropsy, bilatera...

The mechanism by which the specific ␤ 3 -adrenoceptor agonist AJ-9677 relieves insulin resistance in vivo was investigated by studying its effects in the white and brown adipose tissues of the KK-A y /Ta diabetic obese mouse model. AJ-9677 reduced the total weight of white adipose tissues by reducing the size of the adipocytes, an effect associated with the normalization of tumor necrosis factor-␣ (TNF-␣) and leptin expression levels. The levels of uncoupling protein (UCP)-1 mRNA in brown adipose tissue were increased threefold. AJ-9677 caused a marked increase (20-to 80-fold) in the expression of UCP-1 in white adipose tissues. The levels of UCP-2 mRNA were increased in both the white and brown adipose tissues of diabetic obese mice, and AJ-9677 further upregulated UCP-2 mRNA levels in brown adipose tissue, but reduced its levels in white adipose tissue. UCP-3 mRNA levels were not essentially changed by AJ-9677. However, AJ-9677 significantly (two-to fourfold) upregulated the GLUT4 mRNA and protein levels in white and brown adipose tissues and the gastrocnemius. The generation of small adipocytes, presumably mediated by increased expression of UCP-1 in addition to increased lipolysis in response to AJ-9677, was associated with decreased TNF-␣ and free fatty acid production and may be the mechanism of amelioration of insulin resistance in KK-A y /Ta diabetic obese mice. Diabetes 50:113-122, 2001