The present study was undertaken to examine the susceptibility of catechol on the gastric mucosa of male rasH2 mice which have high susceptibility to genotoxic carcinogens. Mice were divided into 4 groups consisting of 7 to 15 per group, and given diets containing catechol at doses of 0, 0.2, 0.4 or 0.8% for 26 weeks. In the pyloric mucosa of the stomach, hyperplasias of gastric mucosa were significantly increased in the groups treated with 0.4% or more catechol, along with increased proliferating cell nuclear antigen (PCNA) positive rates, but no stomach tumors were induced. In the fundic mucosa of the stomach, the incidences of atrophic fundic glands with fewer and atrophic parietal cells were significantly increased in the groups treated with 0.4% or more catechol. In the forestomach, epithelial hyperplasias of the limiting ridge were observed in 5 of 15 mice given 0.8% catechol. These results suggest that rasH2 mice are not susceptible to glandular stomach carcinogenesis induced by catechol, although pyloric epithelial hyperplasias and increased proliferation activity of the pyloric mucosa were induced in rasH2 mice given the higher doses of catechol.

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The potential of hexachlorobenzene (HCB) to promote the development of glutathione S-transferase placental form (GST-P) positive foci in the male F344/DuCrj (F344) rat liver was evaluated with 11 different dietary doses, ranging from 0.002 to 75 ppm, using a medium-term liver bioassay system. No mortalities caused by HCB treatment were encountered, and no clinical changes were apparent. The numbers and areas of GST-P positive foci in the 0.002 ppm to 40 ppm groups were comparable with the control values, but those in the 75 ppm HCB group were slightly, albeit not significantly, increased. The present results indicate that HCB exerts weak promotion potential for rat liver carcinogenesis, but only at a dietary level of 75 ppm (5.27 mg/kg/day), thus providing evidence for the existence of a threshold.

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In order to establish an appropriate bioassay for detection of lung damage after fine particle inhalation, sequential histopathological changes were here examined after intratracheal instillation of quartz (DQ-12, 4 mg/rat), as a typical lung toxic agent, in F344 male rats. A total of 50, 10-week-old animals, were separated into two groups. Twenty five were exposed to the material suspended in saline (0.2 ml) using a specially designed aerolizer and subgroups were sacrificed 1, 3, 7, 14, and 28 days thereafter. The remaining 25 rats were exposed by intratracheal instillation to saline (0.2 ml) as a control group and were sacrificed on the same days. Both groups received intraperitoneal injections of BrdU before sacrifice, and both groups underwent assessment of lung histopathology with immunohistochemical demonstrations of BrdU, iNOS and MMP-3 as end-point markers. The results suggest that Days 1 and 28 after intratracheal instillation of test fine particles are the most appropriate for detection of acute and subacute inflammatory changes, respectively. Furthermore, BrdU on Day 1 and iNOS on Day 28 proved to be suitable end-point markers for this purpose. Although instillation and inhalation models are different, the present instillation model can be used for detection of acute or subacute lung toxicity due to inhaled fine particles.

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3,3'-Iminodipropionitrile (IDPN) is a potent neurotoxicant, which produces behavioral abnormalities and neuropathologic lesions in the central and peripheral nervous systems. Recently, 11 laboratories including ours carried out a collaborative neurotoxicity study using IDPN, and arterial hyalinization in the meninx of the brain and spinal cord was detected in 6 laboratories. Before that study, IDPN-induced vascular lesion had not been reported in any organ except the retina. The present study was undertaken to confirm the reproducibility of the IDPN-induced vascular lesion, to find out the onset of the lesion, and to determine the systemic distribution of the lesion. Male Crj:CD(SD)IGS rats were treated daily with IDPN 125 mg/kg and were sacrificed on days 15, 30, and 44. Behavioral abnormalities appeared from day 9 and thereafter, and axonal swelling in the central nervous system (CNS) was found on days 15, 30, and 44. Arterial hyalinization in the meninx was seen in 4 and 5 out of 6 rats on days 30 and 44, respectively. Almost all lesions were found in the small sized arteries in the basilar area of the brain and spinal cord, and near the dorsal roots of the spinal cord. Some affected vessels demonstrated fibrinoid degeneration, inflammatory cell infiltration or occluded lumina due to intimal thickening. In the organs and tissues other than the CNS, arterial hyalinization in the retina was found on days 30 and 44. Our results demonstrate the reproducibility of IDPN-induced vascular lesions and suggest that the lesions characterized by arterial hyalinization are restricted to the CNS and retina, and that vascular lesion occurred following neurotoxicity.

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To clarify the in vivo genotoxicity of cinnamaldehyde (CNMA) that is present in cigarette smoke, 8 organs and bone marrow of male mice given a single oral administration of 250 or 125 mg/kg body weight of CNMA were evaluated by an alkaline single-cell gel electrophoresis (comet) assay. The liver initiation activity of CNMA was also investigated by a short-term liver initiation assay. PH (Partially hepatectomized) male rats were given 1250 mg/kg body weight of CNMA by a single oral administration 12 hours after partial hepatectomy. In the comet assay, no significant differences of nuclear migration were observed in all tissues examined in mice treated with CNMA at 3 and 24 hours after administration. In the initiation assay, there were no significant increases in areas and numbers of glutathione S-transferase placental form (GST-P) positive foci in the livers of rats treated with CNMA. Based on these results, the possibility that CNMA has in vivo genotoxicity or liver initiation activity appears to be extremely low.

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Parathyroid hormone related peptide (PTHrP) was discovered as a factor causing humoral hypercalcemia of malignancy (HHM). In the previous reports, HHM model rats showed “dentin niche” which is known as an odontoblastic reparative response to cytotoxic agents. In the present study, PTHrP and its receptor (PTHR1) detection patterns were evaluated, during the dentin niche formation process after treatment of a representative cytotoxic agent. Rats were injected with actinomycin D or saline, 9 rats each, and 3 rats from each group were sacrificed on days 1, 3, and 7. The incisors were subjected to immunohistochemical analysis for PTHrP, PTHR1 and ED-1 (macrophage marker), as well as histopathological analysis. On day 1, single cell necrosis and concomitant vesicles that contained necrotic cellular debris were observed. The latter vesicles were positive in the PTHrP, PTHR1 and ED-1 immunostainings. On day 3, depolarization of odontoblasts was observed and hypertrophied pulpal cells were formed osteodentin which stained positively stained for both PTHrP and PTHR1. On day 7, osteodentin had progressed to form dentin niche and the cells which comprised the lesion sustained positive reactions for both PTHrP and PTHR1. These observations suggest that the PTHrP/PTHR1 axis modulates odontoblastic repair and that the modulation might initiate proteins expression in activated macrophages.

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The present study was performed to assess the protective role of thioredoxin/adult T-cell leukemia-derived factor (TRX/ADF) on the liver and brain cell damages induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in ADF wild-type (WT) and transgenic (Tg) mice. The ADF WT and Tg mice were intraperitoneally injected with a single dose of TCDD (150 μg/kg body weight). One day after the treatment, the liver and brain tissues were examined electron microscopically to evaluate the cellular toxicity. In the ADF WT mice, marked reduction of subcellular components, such as mitochondria, rough endoplasmic reticula, and glycogen granules, as well as swelling of the remaining mitochondria, were evident in the liver cells. However, attenuation of these changes was evident in TCDD-treated TRX/ADF mice. Similar subcellular changes noted in the neuronal cells of TCDD-treated WT mice were also attenuated in Tg mice. The results suggest that oxidative cellular damage contributes to the acute toxicity induced by TCDD and that TRX/ADF protects against it.

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In human endometrium, α-smooth muscle actin (α-SMA)-positive stromal cells (SMA-SCs) surround endometrial glands, and the α-SMA expression is regulated by estrogen. The biological significance of these cells remains to be elucidated, and no information is available with regard to their animal counterparts. The present study, therefore, investigated SMA-SCs in the uteri of female Donryu rats and CD-1 mice. SMA-SCs with morphological similarities to those in the human were detected around the endometrial glands in normal cycling rats, but not in mice. Furthermore, the rat SMA-SCs disappeared after ovariectomy but returned with estrogen replacement in a duration-dependent manner, suggesting the regulatory role of estrogens similar to the human situation. Thus, SMA-SCs are present in rats, but not in mice, with characteristics close to their human counterparts. Their biological significance now needs to be elucidated by comparative studies.

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Modifying effects of docosahexaenoic acid (DHA) were examined using a medium-term multi-organ carcinogenesis model (DMBDD model). Groups of twenty F344 male rats were treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), 1,2-dimethylhydrazine (DMH, s.c.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, in drinking water) and dihydroxy-di-N-propylnitrosamine (DHPN, in drinking water) during the first 4 weeks (DMBDD treatment), and then DHA-ethyl ester (DHA-E), DHA-triglyceride (DHA-TG) and/or tocopherol were administered intragastrically 3 times a week for 31 weeks. Significant inhibition of the development of glutathione S-transferase placental form (GST-P) positive foci was observed in DMBDD treated 30% DHA-TG 404 mg and 128 mg + tocopherols groups and with tocopherol alone; however, this appeared to be due to the tocopherol. DHA treatment did not influence the development of aberrant crypt foci in the large intestine. Histopathologically, the incidences of preneoplastic and neoplastic lesions in other organs were also not increased or decreased by DHA treatment. Thus, the results indicate a lack of chemopreventive and tumor promotion effects of any type of DHA in male rats under the present experimental conditions.

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Pancreatic islet amyloidosis from a 15-year-old female greater white-nosed guenon is described. The monkey had been kept in an indoor exhibition facility at the Seoul Grand Park, Korea, and died 2 days after development of anorexia and lethargy. Histologically, amorphic homogeneous eosinophilic, hyalinized material was found deposited in the pancreatic islets and was positive for Congo red stain. The deposits were positive to amyloid A protein and P component by immunohistochemistry. Additionally, glucosuria and ketonuria were detected.

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Clonorchis sinensis (CS) infection combined with hepatocarcinogen treatment results in marked cholangiocarcinoma (CC) formation in hamsters. Hamsters were kept for 16 weeks with or without 1% aminoguanidine (AG) exposure through drinking water, and were treated with dimethylnitrosamine for 4 weeks, 2 days after being infected orally with 15 metacercariae of CS. Interestingly, of the 11 hamsters not treated with AG, 9 had malignant tumors, 1 had a benign tumor, and 1 was normal; however, of the 10 hamsters treated with AG, 5 had benign tumors, 4 had malignant tumors, and 1 was normal. Based on this result, AG has an inhibitory effect on the progression of CC. Further mechanistic study into the result of this morphological study is warranted.

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