The effects of dietary feeding of two flavonoids, chalcone and 2-hydroxychalcone on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of chalcone and 2-hydroxychalcone on the activities of detoxifying enzymes of glutathione S-transferase (GST) and quinone reductase (QR) in liver and colon. Rats were given subcutaneous injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce ACF. They also received an experimental diet containing 0.05% chalcone or 0.05% 2-hydroxychalcone for 5 weeks, starting one week before the first dosing of AOM. AOM exposure produced 90 ± 24 ACF/rat at the end of the study (week 5). Dietary administration of chalcone (44 ± 13, 51% reduction, p<0.01) or 2-hydroxychalcone (40 ± 16, 56% reduction, p<0.005) caused significant reduction in the frequency of ACF. Gavage with chalcone or 2-hydroxychalcone significantly elevated liver GST or QR activities in liver and colon. These findings might suggest the possible chemopreventive ability of chalcone and 2-hydroxychalcone, through induction of liver and colon GST and/or QR on colon tumorigenesis.

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In our previous study, uterine endometrial atypical hyperplasias and adenocarcinomas were induced in female transgenic mice harboring human proto type c-Ha-ras gene (rasH2 mice) within 22 weeks by a single intraperitoneal injection of N-ethyl-N-nitrosourea (ENU). In order to clarify the modifying effects of genistein (GE), 4-nonylphenol (NP), and methoxychlor (MXC) on uterine endometrial carcinogenesis, female rasH2 mice received an intraperitoneal injection of 120 mg/kg body weight (bw) of ENU, followed by no further treatment, diet containing 250 ppm GE, diet containing 250 ppm NP, or diet containing 1,000 ppm MXC for 24 weeks. Uterine proliferative lesions that were observed in treated groups were composed of endometrial hyperplasias, atypical hyperplasias of the endometrium, and adenocarcinomas. The incidence of adenocarcinomas in the ENU alone, ENU+GE, ENU+NP, and ENU+MXC groups was 55.6, 57.1, 47.1, and 0%, respectively, that in the ENU+MXC group being significantly depressed as compared to the ENU alone group (p<0.05). The incidence of atypical hyperplasias in the ENU+MXC group was also decreased. The results in the present study suggest that 1,000 ppm MXC, but not GE and NP, shows an inhibitory effect on the development of uterine adenocarcinomas in rasH2 mice initiated with ENU.

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Utility of Japanese White rabbit mutants with hypotrichosis (htr strain) was investigated in dermal toxicity studies. In the primary irritation study, the primary irritation indices (P.I.I.) by application of hexachlorophene and 3, 3’, 4’, 5-tetrachlorosalicylanilide (TCSA) were higher in the htr rabbits than in the control, haired rabbits. The P.I.I. by application of Tween 80 and sodium lauryl sulfate (SLS) were similar between the htr rabbits and the control rabbits. In the 16-day cumulative irritation study, irritation scores induced by SLS and sodium hydroxide were lower in the htr rabbits than in the control rabbits throughout the observation periods. However, approximately 30% of the dorsal skin of the control rabbits underwent the anagen phase of the hair cycle during the cumulative periods, resulting in difficulty to apply the chemicals and to estimate the skin reactions. In the phototoxicity study, irritation scores of the htr rabbits treated with 8-methoxypsoralen and TCSA were similar to those of the control rabbits. These results revealed advantages of the htr rabbits in the administration of test chemicals and the evaluation of skin reactions, suggesting the usefulness of htr rabbits for dermal toxicity studies.

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In the present study, effects of T-2 toxin, a kind of trichothecene mycotoxins produced by the genus Fusarium, on CCl₄-induced hepatic necrosis and expression of CYP2E1, a major metabolizing enzyme for CCl₄, were examined in the liver of mice. T-2 toxin treatment (4 mg/kg b.w.) at one day before CCl₄ inoculation (1 ml/kg b.w.) suppressed hepatic necrosis almost completely, and T-2 toxin treatment at one day after CCl₄ inoculation delayed the recovery of hepatic necrosis. Although not significant, T-2 toxin (4 mg/kg b.w.) lowered the total P450 contents until 48 hrs after treatment. In addition, Western blot analysis and immunohistochemical examinations revealed that T-2 toxin significantly suppressed CYP2E1 expression from 24 to 48 hrs after treatment while it did not influence CYP3A2 expression. These results suggest that pretreatment of T-2 toxin may suppress CCl₄-induced hepatic necrosis through suppression of CYP2E1 expression.

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We investigated the possibility of immunohistochemically identifying T- and B-lymphocytes in formalin-fixed, paraffin-embedded rat tissues as a basis for future pathological study. Spleens were removed from 8-week-old male Wister rats, and were fixed in 20% neutral-buffered formalin for 7, 30 or 90 days. After fixation, the specimens were embedded in ordinary paraffin by routine method. Paraffin sections were prepared and stained immunohistochemically using anti-CD3 (clone: G4.18) and -CD45RA (clone: OX-33) antibodies. Anti-CD3 and -CD45RA antibodies failed to stain without microwave heating pretreatment. The immunoreactivity of CD3 and CD45RA were both increased by microwave heating pretreatment. Consistent and specific immunostaining of CD3 was obtained throughout all formalin-fixation periods after 40 min or more of microwave heating pretreatment. CD45RA was clearly detected in the 7-day fixed tissues after 30 or 40 min of pretreatment. In the 30- and 90-day fixed tissues, identification of CD45RA was difficult at all lengths of microwave heating pretreatment. These findings suggest that CD3 and CD45RA are detectable in routine formalin-fixed, paraffin-embedded rat tissues although the immunoreactivity is influenced by formalin-fixation period, and that the present procedure, combining appropriate antibodies and pretreatment of microwave heating, is useful for retrospective analyses of rat lymphoid subtypes.

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A right mandible tumor was observed in a 10-year-old male Shih-Tzu dog. Histopathologically, neoplastic proliferation of polymorphic epithelial cells with abundant eosinophilic hyaline materials was observed in the gingival lamina propria. Eosinophilic materials were stained positively with Congo red and showed green birefringence under a polarising microscope, indicating amyloid. The amyloid was immunoreactive to anti-ameloblastin and -sheathlin antibodies. Amorphous or concentrically laminated calcification (Liesegang rings) was seen throughout the tumor tissue. This case was diagnosed as calcifying epithelial odontogenic tumor.

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The Working Group for the Proliferative Lesions of the Kidney in Rats and Mice was established by the Japanese Society of Toxicologic Pathology (JSTP) to discuss diagnostic problems on renal proliferative lesions in rodents. Members of the Working Group brought many histological specimen and literatures, and compared them with the nomenclatures of renal proliferative lesions in rats recommended by the groups of STP, WHO/IARC/RITA and NACAD proposed in 2000. The Working Group recognized that both of spontaneous and chemical-induced lesions could be categorized by the use of the same diagnostic criteria and classification based on histological and cytological characteristics. The results of histochemical and immunohistochemical examinations indicate that the origins of epithelial proliferative lesions are proximal tubules for basophilic cell type, either proximal or distal renal parts for their clear cell counterpart, and collecting ducts for oncocytic one, whereas the origin of clear cell type is still controversial. The Working Group proposed the modified classification of renal proliferative lesions that were slightly different from the recommendation of international harmonization of rat nomenclature of the kidney proposed by the groups of STP WHO/IARC/RITA and NACAD.

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We have generated a transgenic rat with the SV40 T antigen under probasin promoter control, allowing prostate specific gene expression. Males demonstrate atypical epithelial cell proliferation in the prostate from 4 weeks of age and develop prostate carcinomas at 100% incidence before they are 15 weeks old. These prostate caricnomas are completely androgen-dependent. Adequate materials of the prostate carcinomas, taking advantage of the rat transgenic model, allow us gene expression analysis for prostate carcinogenesis and involution process after castration. Male transgenic rats with a Sprague-Dawley genetic background were mated with wild-type females of F344, Wistar and ACI strains. F1 male transgenic hybrids with female Wistar and ACI rats had significantly lowered incidences of prostate carcinomas. However, the serum level of testosterone, and expression of the transgene, probasin, and the androgen receptor did not correlate with the strain variation in tumor development. These results clearly show that the transgenic rat is a good model for investigate prostate carcinogenesis and its modifying factors.

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