Abstract:A polycystic kidney rat model is being established from a Crj:CD (SD) rat strain. Unlike existing animal models of polycystic kidney disease, this mutant rat has a completely polycystic liver. Mating experiments revealed that the phenotype is controlled by an autosomal recessive gene. We propose that this gene be tentatively called the "rpc" gene. Key words: polycystic kidney, polycystic liver, rat Polycystic kidney disease (PKD) is a hereditary disorder that comes in two forms, adult polycystic kidney disease (APKD), and infantile polycystic kidney disease (IPKD). The adult type is an autosomal dominant polycystic kidney disease (ADPKD) and the infant type is an autosomal recessive polycystic kidney disease (ARPKD). Although many spontaneously occurring polycystic kidney mouse models have been established [1,3,4,8,10,12,13], the Cy rat [2,5,6,11] and the chin rat [9] are the only rat models. At Charles River Japan Inc., we have identified a female rat with polycysts on both the kidney and liver derived from an ongoing colony of Crj:CD (SD) rats. Development of a PKD model animal (hereinafter referred to as the PCK rat) with polycysts on both the kidney and liver was initiated by sib mating offspring of the female animal. Continuous sib mating since 1996 has led to the establishment of a rat model for PKD via an inbred strain originating from the Crj:CD (SD) rat, which is now in its twelfth generation. During this period, characteriza- (Received 27 April 1999 / Accepted 14 September 1999)Address corresponding: M. Katsuyama, Charles River Japan Inc., 10210-6, Tana, Sagamihara, Kanagawa 229-1124, Japan tion of the PCK rat and mating experiments with other strains were also performed, the results of which are reported here.The animal rooms were maintained at a temperature of 19-25°C, humidity of 40-80% with a 12 hr lightdark cycle (06:00-18:00). The animals were given ad libitum access to commercial feed CRF-1 (Oriental yeast Co., Ltd.) and tap-water. Body weight was measured every week from 3 to 111 weeks of age, and survival rate was documented during a general examination of the condition of the animals. The bilateral kidneys and liver were weighed at 5, 15, 25 and 35 weeks of age, and compared with that of the original Crj:CD (SD) rat strain. For histopathological examination, kidney and liver were fixed with 10% formalin, and according to standard procedures, were then paraffin sliced, HE stained, and examined by microscopy. In order to analyze the mode of inheritance, F3-F5 generation pck rats were mated with Crj:CD (SD) rats, bred in a room separate to that of PCK rats, and F344/DuCrj rats. Off-
To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of gamma-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study.
A single-dose oral toxicity lethal-dose study was conducted to examine the toxicity of capsinoids contained in CH-19 Sweet extract. CH-19 Sweet extract was administered once by gavage to SPF (Crl:CD(SD)) Sprague-Dawley male and female rats at dose levels of 0 (vehicle), 5, 10, or 20 ml/kg of body weight (BW). The concentration of capsinoids in the CH-19 Sweet extract was 71.25 mg/ml; this resulted in administered dose levels of capsinoids of 356.25, 712.5, and 1425 mg/kg BW, respectively. The toxicity of CH-19 Sweet extract by single oral administration was low; only transient salivation or decreased spontaneous movement was observed on the day of administration at > or =10 ml/kg BW. It was concluded that the lethal dose of CH-19 Sweet extract was estimated to be higher than 20 ml/kg (1425 mg/kg as capsinoids) for both males and females since no deaths were observed at any dose in this study. A bacterial reverse mutation test of CH-19 Sweet extract was performed employing Salmonella typhimurium and Escherichia coli and using the preincubation method. Treatment with CH-19 Sweet extract did not increase the number of revertant colonies compared with negative controls either in the presence (+S9) or absence (-S9) of metabolic activation. An in vitro chromosome aberration test was conducted using Chinese hamster lung cultured cells (CHL/IU). Treatment with CH-19 Sweet extract failed to induce chromosome aberrations in either short-term or continuous treatment scenarios, with or without metabolic activation (-S9, +S9). In an in vivo micronucleus test using BDF(1) male mice, CH-19 Sweet extract failed to increase the incidence of micronucleated polychromatic erythrocytes (MNPCEs) or decrease the ratio of polychromatic erythrocytes (PCEs) in any of the treatment groups. These results suggest the absence of mutagenicity as well as in vitro and in vivo clastogenicity of capsinoids contained in CH-19 Sweet extract.
A 26-week oral toxicity study of capsinoids-containing CH-19 Sweet extract was conducted in Sprague-Dawley rats (20 males and 20 females per group) at 6 weeks of age. The test substance was administered by gavage for 26 weeks at dose levels of 0 (vehicle), 1.25, 2.5, and 5.0 ml/kg/day. The concentration of capsinoids in the CH-19 Sweet extract employed was 71.25 to 73.15 mg/ml, resulting in dose levels of capsinoids of 89.06 to 91.44, 178.13 to 182.88, and 356.25 to 365.75 mg/kg, respectively. Adverse test article-related changes were only observed in males, not in females, and within the males, only at the high dose (5.0 ml/kg). Within that group (high-dose males), increases were observed in the numbers of segmented neutrophils, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, liver weights, and in the incidence and severity of hepatocellular focal necrosis. No test substance-related changes were detected in clinical signs, body weight, food consumption, water intake, ophthalmology, or urinalysis. No adverse test article-related changes were observed in low- or mid-dose males or in females at any dose. Based on the results of this chronic gavage study, the target organ was the liver and the no observed adverse effect level (NOAEL) for CH-19 Sweet extract in the rat was 2.5 ml/kg/day in males and 5.0 ml/kg/day in females (178.13 to 182.88 mg/kg and 356.25 to 365.75 mg/kg as capsinoids, respectively).
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