Journal of Toxicologic Pathology
Online ISSN : 1881-915X
Print ISSN : 0914-9198
ISSN-L : 0914-9198
Volume 7, Issue 3
Displaying 1-12 of 12 articles from this issue
  • Makoto Enomoto, Yasuhiko Hirouchi, Hijiri Iwata, Kasuke Nagano
    1994 Volume 7 Issue 3 Pages 317-328
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    Non-neoplastic findings obtained by detailed pathological examination of treated rodents utilized in subchronic studies up to 13 weeks in duration can contribute in determining the toxicity of chemicals and evaluate organ-specific injury. Pharmacokinetic and metabolic data on test chemicals are essential in elucidating organ specificity, the significance of the adverse effects on vital cellular functions in target organs, and in differentiating between effects which are “pathological”, “pharmacological” or “adaptive” in nature.
    Non-neoplastic lesions including proliferative changes observed in short- and mid-term studies (up to 26 weeks) may also provide a provisional basis for predicting tumor induction produced by prolonged exposure to test chemicals. Recent extensive work on the role of persistent, non-genotoxic tissue damage in rodents revealed that the carcinogenic potential of non-genotoxic chemicals might be considered to be conditional and the results of dose levels high enough to produce cell proliferation.
    The complexity of the non-neoplastic findings in rodents is known to increase with age, especially after one year. For proper evaluation of these data, analysis of causative effects, morphogenesis of each non-neoplastic change, and factors influencing the occurrence of these lesions are useful. General aspects of the pathological significance of these organ-specific, systemic lesions as age-associated background findings could contribute to understanding the susceptibility to chemicals as influenced by age-related alterations including the neoplastic process, in terms of bio-mechanistic and pharmacokinetic parameters.
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  • Kazuo Kobayashi, Yasuhiko Hirouchi, Hijiri Iwata, Seiki Yamakawa, Shin ...
    1994 Volume 7 Issue 3 Pages 329-343
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    A variety of spontaneous lesions found histologically in control Beagle dogs (males: 91, famales; 97) used in toxicity studies that were conducted at the Biosafety Research Center, Foods, Drugs and Pesticides during a 10 year period, are described. All animals were exsanguinated by incision of the axillary artery under sodium pentobarbital anesthesia at the end of each study.
    Neoplastic lesions included fibrosarcoma of the heart in a female dog at approximately 27 weeks of age (1.0%) and hemangioendothelioma of the spleen in a male dog, also at approximately 27 weeks of age (1.1%).
    The most common non-neoplastic changes in both male and famale dogs were deposits of amorphous masses at the renal papilla (males; 68.1%, females ; 80.4%) and fetal glomerulus in the kidney (males; 53.8%, females; 50.5%). Fatty changes in the renal tubular epithelium of female dogs occurred at an incidence of greater than 50%. Pigment deposition in the spleen, guranulation of the liver, atrophy in the thymus, C-cell hyperplasia of the thyroid gland, and pituitary cysts in male and female dogs were evident at an incidence of greater than 10%. In addition, multinucleated giant cells in the testes, eosinophilic bodies in the renal tubular epithelium in males, cellular infiltration of the parotid gland, and deposits of calcium in the spinal cord of females were seen at incidences of greater than 10%. Atrophy of the thymus and C-cell hyperplasia of the thyroid increased with age. Fetal glomerulus of kidney decreased with age.
    Other rare, but interesting lesions included: ectopic stomach tissue in the ileum, ductro-insular proliferation of the pancreas, deposits of calcium at the beginning portion of the aorta and in the spinal cord, and hemangiectasis at the atrioventriclar valve of the heart.
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  • Shunji Nakatsuji, Jyoji Yamate, Mitsuru Kuwamura, Takao Kotani, Sadasi ...
    1994 Volume 7 Issue 3 Pages 345-351
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    The kinetics of the proliferating cells in rat myocardial injury induced by isoproterenol was immunohistochemically observed using monoclonal antibodies against bromodeoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA). The number of PCNA-positive cells began to increase in necrotic areas of myocardium and its adjacent areas at as early as 12 hours after isoproterenol injection, reaching a maximum value on day 5. On the other hand, an increase in number of BrdU labelling cells was seen in similar areas at 24 hours and reached a peak on day 3. Thereafter, immunoreactive cells for both PCNA and BrdU gradually decreased along with scar tissue formation. The number of PCNA-positive cells was consistently greater than that of BrdU labelling cells. On day 3 when granulation tissues began to be formed, BrdU-positive cells dominated at the edge of the lesion, whereas PCNA-positive cells were found within the injured areas and in surrounding myocardium. These findings suggested that granulation tissue-constituting cells might be derived from interstitial connective tissue cells adjacent to myocardial lesions.
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  • Tomoyuki Watanabe, Yasunori Katsura, Akira Yoshitake, Hirokazu Masatak ...
    1994 Volume 7 Issue 3 Pages 353-361
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    The Image Processor for Analytical Pathology (IPAP), is a computer-based image analysis instrument which uses current technology to provide valuable information to the pathologist. Our own studies using the IPAP system are focussed on the fields of tumor pathology and toxicologic pathology. The spectrum of methods for the characterization of histologic patterns in these fields consists of karyometric and histometric measurements. This paper describes the hardware configuration of the IPAP and the software system which has been developed to allow a flexible and interactive analysis of microscopical images with minimal computer training and experience. Some examples are given to illustrate the possibilities of the IPAP.
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  • Mikinori Torii, Satoshi Inoue, Shuuichi Matsushima, Satoshi Fuji, Tosh ...
    1994 Volume 7 Issue 3 Pages 363-370
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    To study how free radicals affect the vascular endothelium of spontaneously hypertensive rats (SHR), the aorta of 13-week-old male SHR and Wistar-Kyoto rat (WKY) were perfused tert-butyl hydroperoxide (t-BOOH) and the resulting hydrogen peroxide was morphologically examined using cerium lanthanide. The spin trap method revealed a hydroxyl radical adduct at 5 min after t-BOOH perfusion. In t-BOOH-perfused SHR, cauliflower-like blebs were frequently seen on the endothelial cell surface, sometimes with prominent microvilli and marginal folds. Fine granular materials were found clumped or scattered on the surface. On the other hand, blebs and fine granular materials were rarely seen on the cellular surface in t-BOOH-perfused WKY. Transmission electron microscopy accidentally showed a few blebs with electron-dense material only in the intercellular junction in t-BOOH-perfused WKY endothelium. In t-BOOH-perfused SHR, membrane blebs and intracytoplasmic edema were seen in the endothelium. Electron-dense materials were abundant on the surface of the intact and the degenerated endothelium. X-ray spectra showed the cerium peaks, corresponding to the electron dense-material. These findings clearly indicate that free radical injury, especially hydroxyl radical injury, is much more intense in the endothelial cells of SHR than in those of WKY.
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  • Masaharu Tanaka, Yoshiya Aze, Tsuneo Fujita
    1994 Volume 7 Issue 3 Pages 371-377
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    To investigate the relationship between the frequency of megakaryocytic emperipolesis and the number of hematopoietic cells, the animals were administered lipopolysaccharide (LPS) intravenously at a daily dose of 0.5mg/kg body weight for up to 7 days, and histopathology of bone marrow and hematology of peripheral bloods were examined on Hour 2, 8, and 24 and Day 3, 5, and 7 of LPS-treatment. Mature neutrophils appeared to be the most common hematocytes engulfed by megakar-yocytes. Engulfed blood cells were observed in the demarcation membrane system of mature megakar-yocytes. Cell membranes of both megakaryocytes and entering cells were intact. Although megakar-yocytic emperipolesis was also found in control rats, its incidence increased markedly in LPS-treated rats which showed hyperplasia of granulocytes and megakaryocytes in their bone marrows. The index of emperipolesis showed a minimal change from 2.25 to 3.04 during the experimental period in control rats, whereas it rose from Hour 8 (9.78) and peaked on Day 3 (46.04) in LPS-treated rats. Hyperplasia of hematopoietic cells such as megakaryocytes and segmented neutrophils also peaked on Day 3 of LPS-treatment. These changes suggest that emperipolesis is a phenomenon closely related to severe hematopoietic hyperplasia in the bone marrow.
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  • Akiyoshi Yoshida, Takanori Harada, Toshiaki Kitazawa, Toshinori Yoshid ...
    1994 Volume 7 Issue 3 Pages 379-385
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    The effects of prolonged treatment with ovarian steroid hormones on the development of endometrial adenocarcinoma were investigated in ICR mice. For the tumor induction, a mixed solution of ethylenethiourea (ETU, 100mg/kg body weight) and sodium nitrite (NaNO2, 70mg/kg body weight) was administered weekly to 60 mice by stomach tube for 26 weeks. Additional 40 animals received distilled water in the same manner. At 45 weeks of study, a silastic or polyethylene tube loaded with progesterone or 17β-estradiol was implanted in the dorsal subcutis of animals. The animals were killed at 52 weeks of study and subjected to pathological examinations including immunohistochemical staining for nuclear estrogen receptors on paraffin section. Prolonged treatment with progesterone for 8 weeks (45-52 weeks) suppressed the development of atypical hyperplasia slightly but not of adenocarcinoma. The incidences of these lesions were not affected by 17β-estradiol. Immunohistochemical staining for nuclear estrogen receptors denoted positive reaction in glandular cells of atypical hyperplasia but the intensity of staining was less than that in the normal endometrial gland. The nucleus in the endometrial adenocarcinoma was generally negative for the staining or showed heterogenous distribution of faintly positive reaction. These evidences indicate that effacement or functional impairment of nuclear steroid receptors are likely to be important in malignant transformation of the precursor lesions into adenocar-cinoma in the endometrium of mice.
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  • EFFECTS OF TESTOSTERONE AND TESTOSTERONE PLUS ESTROGEN
    Masanori Murakoshi, Rie Inada, Masashi Tagawa, Minoru Suzuki, Atsushi ...
    1994 Volume 7 Issue 3 Pages 387-395
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    The effects of testosterone and 17β-estradiol (E2) on the dorsolateral prostate of castrated rats were investigated by histopathological and immunohistochemical procedures. Male Sprage-Dawley rats were divided into four experimental groups. Group 1 consisted of intact controls. The other animals were castrated. In group 2, rats were sacrificed 2 days after castration. The castrated animals were treated for 6 weeks with 1) testosterone I mg/head (Group 3) and 2) testosterone I mg/head plus E2 10 μg/head (Group 4). A significant increase in the dorsolateral prostatic weight occurred after 6 weeks treatment with testosterone plus E2 (Group 4). Histopathologically, glandular hyperplasia with fibro-muscular stromal proliferation was clearly observed, and the number of bromo-deoxyuridine (BrdU)-positive cells showed a significant increase over that induced by testosterone alone. Immunohisto-chemical localization of glutathione peroxidase (GSH-PO) which effectively reduces the lipid peroxides, was clearly observed in the glandular epithelial cells of the dorsolateral prostate following testosterone alone or testosterone plus E2-treatment. Therefore, it appeared that GSH-PO protein synthesis in the glandular epithelium of the dorsolateral prostate can be enhanced (induced?) by sex hormones such as testosterone and E2. In the dorsolateral prostate of intact rats, positive staining for androgen receptor (AR) was observed in nuclei of the glandular epithelial cells. In addition, immunodetectable AR decreased within 2 days after castration, but returned to intact levels after administration of testosterone. These findings agree with previous work on the ventral prostate. Furthermore, in group 4, AR was also detected in the nuclei of the proliferated stromal fibro-muscular cells. It is concluded that immunohisto-chemical analysis, using GSH-PO and AR, may be a useful method for predication of the effects of androgen. action on the rat prostate.
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  • Tetsuro Sugimoto, Shuichi Chiba, Yasuyuki Misawa, Rikio Niki
    1994 Volume 7 Issue 3 Pages 397-402
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    We have invented a simple screening method of detecting drug-induced lipidosis mor-phologically by using cultured rat blood monocytes. In this method, rat blood is centrifuged in iodinated gradient medium to separate monocytes, and these cells are then incubated on chamber slides. These slides are treated with 4, 4'-Diethylethoxyhexestrol at concentrations of 10-4, 10-5, and 10-6 M for 24 hours. Upon examination, light microscopic examination reveals dark blue granules in the cytoplasm of monocytes by acid hematein stain. Lamellar myeloid body formation can be detected in the electron microscopic specimens prepared with the inverted embedding method. This cultured monocyte system, using chamber slides, is considered to be a suitable tool for screening out potent lipidosis-inducing amphiphilic compounds and to be useful for studying structure-activity relationships, because of the simple and fast processes.
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  • Tetsuro Sugimoto, Maya Kajiwara, Shuichi Chiba, Yasuyuki Misawa, Rikio ...
    1994 Volume 7 Issue 3 Pages 403-407
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
    Drug-induced lipidosis is characterized ultrastructurally by the occurrence of myeloid bodies, which are probably due to the formation of drug-lipid complexes. Histochemical acid hematein tests are currently applied to detect lipidosis. In order to clarify the differences in these stainings, three acid hematein techniques were compared ; Baker's original method, a modified method of AFIP, and a simplified method devised by Hori. Liver tissues were obtained from rat treated orally with 4, 4'-Diethylaminoethoxy-hexestrol. The procedures of dichromate treatment are critically different between Baker's and the other two methods. Dark blue stained granules were clearly observable in the cytoplasm of hepatocytes and Kupffer cells with Baker's method. The appearances of staining were confirmed by the results of electron microscopic examination. Positive reactions were eliminated by a pyridine extraction test. The other two methods yielded only diffused dark blue reactants. These results indicate that dichromate treatment before the freezing of the samples as done in Baker's method may be an important process for the simultaneous oxidation, chromation, and fixation of lipids, particularly for demonstrating the presence of myeloid bodies. We also examined the effects of fixation periods with 20% neutral buffered formalin in Baker's method. The reaction products were still detectable even after six months, although the color intensity was weaker.
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  • Tomoko Kaneko-Ishino, Fumitoshi Ishino, Hiroyuki Nakayama, Mokbul Hoss ...
    1994 Volume 7 Issue 3 Pages 409-412
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
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  • Kazuo Kobayashi, Seiki Yamakawa
    1994 Volume 7 Issue 3 Pages 413-416
    Published: September 30, 1994
    Released on J-STAGE: January 22, 2009
    JOURNAL FREE ACCESS
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