{"title":"A case of spontaneous rete testis adenoma in a Sprague-Dawley rat.","authors":"Masako Imaoka, Tetsuya Osawa, Kiyonori Kai, Yoshimi Tsuchiya","doi":"10.1293/tox.2022-0018","DOIUrl":"https://doi.org/10.1293/tox.2022-0018","url":null,"abstract":"<p><p>A 104-week-old male CD (SD) rat exhibited enlargement of the left testis. Microscopically, this mass was demarcated from the testis by fibrous connective tissue and characterized by cystic dilatation with single-layered columnar cells and papillary proliferation connected to the solid growth area without clear boundaries. In the solid growth area, cells were dissected into irregular alveolar nests by scant fibrous tissue with small blood vessels. The nuclei of proliferating cells were variable in size and round- to oval-shaped, and their cytoplasm was pale or eosinophilic and sometimes contained vacuoles or eosinophilic granules. Immunohistochemically, the tumor cells were positive for vimentin and cytokeratin (CK) 7. Since CK7 was exclusively positive in the rete testis epithelium of the naïve rat, it was valuable to diagnose this tumor as rete testis-originated. Based on these results and the lack of apparent pleomorphism, mitotic figures, and metastasis, the present case was diagnosed as rete testis adenoma.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"263-268"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bc/38/tox-35-263.PMC9255997.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40503980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Satoshi Furukawa, Yuichiro Machida, Kazuya Takeuchi, Yumiko Hoshikawa, Kota Irie
{"title":"Failure to gulp surface air induces swim bladder adenomas in Japanese medaka (<i>Oryzias latipes</i>).","authors":"Satoshi Furukawa, Yuichiro Machida, Kazuya Takeuchi, Yumiko Hoshikawa, Kota Irie","doi":"10.1293/tox.2022-0030","DOIUrl":"https://doi.org/10.1293/tox.2022-0030","url":null,"abstract":"<p><p>In order to elucidate the effects of swim bladder inflation failure on swim bladder carcinogenesis, we investigated the sequential histopathological changes of swim bladders at 13, 24, 35, and 53 days post-hatch (dph) in medakas with an uninflated swim bladder, which was experimentally induced by denying access to the air-water interface between 0 and 6 dph. The reactive oxygen species (ROS) levels were measured at 24 dph. An uninflated swim bladder was induced in 47.3% of the fish denied access to the air-water interface (the denied group). The total incidence of swim bladder adenoma was 54.1% in the denied group; however, these tumors were observed in all fish with an uninflated swim bladder. In fact, these tumors were observed from 13 dph and onwards. The TBARS levels of the juveniles showed a 2.6-fold increase in fish with an uninflated swim bladder in the denied group compared to that in the control group. It is speculated that swim bladder inflation failure has some effects on the gas gland to produce ROS, leading to DNA damage in the gas glandular epithelium, which develops into swim bladder adenomas. Consequently, it is concluded that denying access to the air-water interface between 0 and 6 dph in medaka is an easy method of inducing swim bladder tumors in a short-term period, and is a useful method for producing tumor-bearing fish.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"237-246"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0b/a9/tox-35-237.PMC9255999.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40504086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Histopathology of acute colchicine intoxication: novel findings and their association with clinical manifestations.","authors":"Shojiro Ichimata, Yukiko Hata, Kojiro Hirota, Naoki Nishida","doi":"10.1293/tox.2022-0007","DOIUrl":"https://doi.org/10.1293/tox.2022-0007","url":null,"abstract":"<p><p>A 32-year-old woman attempted suicide by ingesting Gloriosa bulbs and died approximately 2 days later. Toxicological examination revealed a potentially fatal blood concentration of colchicine (0.096 mg/L). In addition to the increased mitotic figures in the gastrointestinal mucosa, a unique finding for acute colchicine intoxication, pathological examination showed microvesicular lipid droplets in the liver, kidney, heart, and conduction system. Furthermore, central chromatolysis of neurons was observed in the pontine nucleus, medial accessory olivary nucleus, nucleus of the solitary tract, and nucleus ambiguus. Grumose degeneration of the cerebellar dentate nucleus was also evident. These pathological findings may help identify colchicine intoxication, even in the absence of evidence suggesting ingestion during autopsy. Moreover, pathological changes in the heart and central nervous system may be associated with the development of serious complications of acute colchicine intoxication.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"255-262"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/73/8d/tox-35-255.PMC9255996.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40504087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A simple specimen preparation method for histopathological evaluation of vestibular organs.","authors":"Shinichi Onishi, Atsuko Murai, Aki Kito, Yuka Kawashima, Yusuke Ohmori, Atsuhiko Kato","doi":"10.1293/tox.2022-0008","DOIUrl":"https://doi.org/10.1293/tox.2022-0008","url":null,"abstract":"<p><p>Vestibular organs consist of the maculae staticae, which are located in both the utricle and saccule, as well as the semicircular ducts and their ampullas. There have been no reports on specimen preparation methods for vestibular organs, including maculae staticae or semicircular ducts. In this study, we investigated highly reproducible methods of preparing vestibular organ specimens for histopathological examinations. We established a method that allows researchers to observe the utricle and saccule, including otoliths, the ampulla of a semicircular duct, and parts of semicircular ducts. This highly reproducible method is useful for histopathological analysis of mice with symptoms of abnormal equilibrium caused by medical toxicity and genetic modification.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"275-279"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0d/5e/tox-35-275.PMC9256003.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40504083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Response biomarkers of inhalation exposure to cigarette smoke in the mouse lung.","authors":"Shugo Suzuki, Kazuhisa Asai, Min Gi, Kazuya Kojima, Anna Kakehashi, Yuji Oishi, Taisuke Matsue, Nao Yukimatsu, Kazuto Hirata, Tomoya Kawaguchi, Hideki Wanibuchi","doi":"10.1293/tox.2021-0077","DOIUrl":"https://doi.org/10.1293/tox.2021-0077","url":null,"abstract":"<p><p>Cigarette smoking is known to increase the risk of cancer and chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of short-term nose-only inhalation exposure to cigarette smoke in mice. Male 10-week-old C57BL mice were exposed to clean air (control) or mainstream cigarette smoke for 1 h/day, 5 days/week, for 2 or 4 weeks. Exposure to cigarette smoke increased the number of inflammatory cells, especially neutrophils, in the bronchoalveolar lavage fluid, increased inflammatory cell infiltration foci, and caused an increase in the thickness of the peripheral bronchial epithelium. Microarray gene expression analysis indicated that smoke exposure induced inflammatory responses, including leukocyte migration and activation of phagocytes and myeloid cells, as early as two weeks after the initiation of exposure. Importantly, chemokine (C-C motif) ligand 17, resistin-like alpha, and lipocalin 2 were upregulated and may serve as useful markers of the toxic effects of exposure to cigarette smoke before pulmonary histological changes become evident.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"247-254"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3d/29/tox-35-247.PMC9256000.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40504082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Masakatsu Nohara, Mayo Iwasaki, Mahiro Nishio, Akihiko Sugiyama
{"title":"Histopathologic effect of in ovo exposure to methotrexate at early embryonic stage on optic tectum of Japanese quail (<i>Coturnix japonica</i>).","authors":"Masakatsu Nohara, Mayo Iwasaki, Mahiro Nishio, Akihiko Sugiyama","doi":"10.1293/tox.2022-0011","DOIUrl":"https://doi.org/10.1293/tox.2022-0011","url":null,"abstract":"The optic tectum of Japanese quail embryos with in ovo exposure to methotrexate 100 ng/g egg on embryonic day 4 was examined from 3 to 24 hour after treatment. At 9 hour after methotrexate exposure, several apoptotic neuroepithelial cells appeared in the ventricular zone of the optic tectum; these increased in number and were diffusely distributed throughout all layers of the ventricular zone of the optic tectum at 12 hour. At 24 hour, neuroepithelial cells in the ventricular zone of the optic tectum were eliminated and showed sparse cell density. Throughout the experimental period, proliferation of neuroepithelial cells in the ventricular zone of the optic tectum of methotrexate-treated embryos was inhibited. These results suggest that neuroepithelial cells in the ventricular zone of the optic tectum in Japanese quail embryos can be affected by folic acid antimetabolites, methotrexate, at an early embryonic stage.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"269-274"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ca/28/tox-35-269.PMC9256001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40504085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The potential of organoids in toxicologic pathology: Histopathological and immunohistochemical evaluation of a mouse normal tissue-derived organoid-based carcinogenesis model.","authors":"Rikako Ishigamori, Mie Naruse, Akihiro Hirata, Yoshiaki Maru, Yoshitaka Hippo, Toshio Imai","doi":"10.1293/tox.2022-0021","DOIUrl":"https://doi.org/10.1293/tox.2022-0021","url":null,"abstract":"Recently, we introduced an organoid-based chemical carcinogenesis model using mouse normal tissue-derived organoids. In the present review article, the histopathological and immunohistochemical characteristics of mouse normal tissue-derived organoids and tumors derived from these organoids after their in vitro treatment with genotoxic carcinogens and injection into nude mouse are reviewed. In organoids treated in vitro with genotoxic carcinogens, we confirmed macroscopic tumorigenicity and histopathological findings, including neoplastic characteristics, such as multilayered epithelia and/or invasion of epithelia into the surrounding interstitium. In contrast glandular/cystic structures with monolayered epithelia were clearly demarcated from the surrounding Matrigel/interstitium in the untreated control groups. In addition to macroscopic tumorigenicity, these microscopic epithelial changes, which are characteristic of the early stages of carcinogenesis, are included in the requirements for carcinogenicity-positive judgement of the organoid-based carcinogenesis model. Immunohistochemistry of cytokeratins (CKs), used to determine the origin of epithelia and distribution of extraductal invasive lesions, or oncogenic kinases, which reflect molecular activation in epithelia following chemical treatment, is helpful for accurate diagnosis and molecular evaluation in the early stages of carcinogenesis. This information improves our biological understanding of organoid-based chemical carcinogenesis models.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 3","pages":"211-223"},"PeriodicalIF":1.2,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/80/5b/tox-35-211.PMC9255998.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40503981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thania R. R. Lima, Nathália P. Souza, Ana P. Ferragut Cardoso, Lígia M. M. Gomide, Merielen G. Nascimento e Pontes, Hélio A. Miot, Lora L. Arnold, Samuel M. Cohen, João Lauro V. de Camargo
{"title":"Testicular alterations in cryptorchid/orchiopexic rats chronically exposed to acrylamide or di-butyl-phthalate","authors":"Thania R. R. Lima, Nathália P. Souza, Ana P. Ferragut Cardoso, Lígia M. M. Gomide, Merielen G. Nascimento e Pontes, Hélio A. Miot, Lora L. Arnold, Samuel M. Cohen, João Lauro V. de Camargo","doi":"10.1293/tox.2021-0045","DOIUrl":"https://doi.org/10.1293/tox.2021-0045","url":null,"abstract":"</p><p> Exposure of Sprague-Dawley (SD) rats to acrylamide (AA) or di-butyl-phthalate (DBP) from the 12th gestational day to the 16th postnatal week (PNW) has been shown to reduce the effectiveness of orchiopexy in recovering the testicular alterations associated with experimental cryptorchidism established at weaning. Herein, we provide information about the long-term effects of AA or DBP on the testes of cryptorchid/orchiopexic rats. Male offspring exposed <i>in utero</i> to 10 mg/kg/day AA or 500 mg/kg/day DBP underwent bilateral surgical cryptorchidism at the 3rd PNW and orchiopexy at the 6th week, with continuous exposure to the chemicals through diet until the 58th week. Regardless of the test chemical, there were severe qualitative/quantitative alterations in the seminiferous tubules and increased numbers of Leydig cells. There was an increase and decrease in the number of tubules with c-Kit- and placental alkaline phosphatase-labeled germ cells, respectively, as compared to those in the control group, suggesting an imbalance between apoptosis and cell proliferation processes. The histological scores of the testicular lesions at the end of this one-year study were higher than those in the previous 16-week study, indicating that exposure of rats to the toxicants AA or DBP enhanced the testicular alterations induced by the chemicals beginning at the intra-uterine life, and impaired the effectiveness of orchiopexy in restoring the testes to normal morphology. Although the present experimental protocol does not completely replicate the natural human undescended testes, our findings may contribute to understanding the alterations occurring in cryptorchid/orchiopexic testes potentially exposed to exogenous chemicals for extended periods.</p>\u0000<p></p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"122 1","pages":""},"PeriodicalIF":1.2,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138518850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wensheng Mou, Shi-ru Chen, Zhengqi Wu, Libin Hu, Ji-ye Zhang, Hong-Jie Chang, Hang Zhou, Y. Liu
{"title":"LPS-TLR4/MD-2–TNF-α signaling mediates alcohol-induced liver fibrosis in rats","authors":"Wensheng Mou, Shi-ru Chen, Zhengqi Wu, Libin Hu, Ji-ye Zhang, Hong-Jie Chang, Hang Zhou, Y. Liu","doi":"10.1293/tox.2021-0018","DOIUrl":"https://doi.org/10.1293/tox.2021-0018","url":null,"abstract":"Liver fibrosis results from liver inflammation and progresses to liver cirrhosis or liver cancer. It is known that nonalcoholic liver disease is mediated by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2)–tumor necrosis factor-alpha (TNF-α) signaling pathway. This study aimed to investigate whether alcoholic liver disease is also mediated by this pathway. To this end, we first established rat models of liver fibrosis by administering alcohol. Next, the rats were injected with anti-TLR4 and anti-MD-2 antibodies. Real Time Quantitative PCR (RT-qPCR) and Western blotting were used to detect the activation of the TLR4/MD-2–TNF-α signaling pathway and hepatic stellate cells (HSCs). Moreover, the expression of molecules related to liver fibrosis was estimated. The morphology of rat liver tissue was observed through hematoxylin–eosin staining and Masson staining. For in vitro studies, Kupffer cells (KCs) isolated from the liver were transfected with si-TLR4 and si-MD-2 and co-cultured with HSCs to determine the activity of HSCs. It was found that alcohol treatment activated the TLR4/MD-2–TNF-α signaling pathway and upregulated the molecules associated with liver fibrosis. However, inhibition of TLR4 and MD-2 partially reversed this trend. Notably, in vitro studies indicated that knockdown of TLR4 and MD-2 in KCs partially inhibited LPS-induced activation of KCs and HSCs. Overall, this study showed that alcohol induces liver fibrosis via the LPS-TLR4/MD-2–TNF-α signaling pathway.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"193 - 203"},"PeriodicalIF":1.2,"publicationDate":"2022-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48268443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"rasH2 mouse: reproducibility and stability of carcinogenicity due to a standardized production and monitoring system.","authors":"Hideki Tsutsumi, Ryo Inoue, Masahiko Yasuda, Riichi Takahashi, Masami Suzuki, Koji Urano","doi":"10.1293/tox.2021-0068","DOIUrl":"10.1293/tox.2021-0068","url":null,"abstract":"<p><p>The rasH2 mouse was developed as a model for carcinogenicity studies in regulatory science. Its phenotype is stable during high-volume production and over successive generations. To produce rasH2 mice, three strains of mice (C57BL/6J-TgrasH2, C57BL/6J, and BALB/cByJ) were maintained individually. Since the homozygous <i>c-HRAS</i> genotype is lethal, hemizygous transgenic mice were maintained by crossing with inbred C57BL/6J mice. After breeding, male B6-transgenic mice were mated with female BALB/cByJ mice to obtain transgenic mice. Pups that were rasH2-Tg (tg/wt) or rasH2-Wt (wt/wt) were confirmed by genotyping. Frozen embryos were preserved by the Central Institute for Experimental Animals (CIEA) and sent to two facilities, CLEA Japan and Taconic Biosciences, where the mice were produced. Production colonies are created in both facilities and supplied to customers worldwide. To prevent genetic drift, the colonies were renewed for up to 10 generations, and renewals were carried out four times every five years from 2005 to 2021. To ensure the uniformity and maintenance of the phenotype of rasH2 mice, the carcinogen susceptibilities were monitored in every renewal of colonies by CIEA based on a standard protocol of the short-term carcinogenicity study using the positive control compound N-methyl-N-nitrosourea (MNU). Furthermore, simple carcinogenicity monitoring targeting the forestomach, the organ most sensitive to MNU, was performed approximately once a year. Based on the optimally designed production and monitoring systems, the quality of rasH2 mice with reproducibility and stability of carcinogenicity is maintained and supplied globally.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"19-24"},"PeriodicalIF":0.9,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45880536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}