Journal of Toxicologic Pathology最新文献

{"title":"A case of spontaneous autoimmune skin disease in a cynomolgus monkey (Macaca fascicularis)","authors":"Shinichi Onishi, M. Nakagawa, S. Matsuo, J. Shinozuka, Mio Hiramatsu, Takehito Isobe, Toshihiko Watanabe, A. Kato","doi":"10.1293/tox.2021-0048","DOIUrl":"https://doi.org/10.1293/tox.2021-0048","url":null,"abstract":"Pemphigus is an autoimmune blistering disease characterized by lesions on the skin and mucous membranes. To date, no spontaneous cases of this disease have been reported in cynomolgus monkeys. This report describes the histopathological characteristics of spontaneous pemphigus in a cynomolgus monkey. Macroscopically, redness and scaling with pruritus were observed on the skin of the entire body. Histopathologically, the epidermis showed intercellular edema, and eosinophils and mononuclear cells infiltrated the epidermis. There was no obvious acantholysis in the epidermis. The perivascular area showed edema, and eosinophils and mononuclear cells infiltrated the vessels in the dermis. Immunohistochemically, the intercellular area in the epidermis was positive for Immunoglobulin G and Complement component 3. Serologically, anti-desmoglein 1 and desmoglein 3 antibodies in the serum were negative. From these findings, this case was diagnosed as an autoimmune skin disease, suspected to be pemphigus, and concluded as lesions being similar to those in human “pemphigus herpetiformis”.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"103 - 106"},"PeriodicalIF":1.2,"publicationDate":"2021-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45278986","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":"Confounders for kidney carcinogenesis in rodent cancer bioassays","authors":"G. Hard","doi":"10.1293/tox.2021-0000","DOIUrl":"https://doi.org/10.1293/tox.2021-0000","url":null,"abstract":"In the long-term safety testing of chemicals for carcinogenicity the toxicologist needs to be aware of a number of scenarios where renal tubule tumors, or their precursors, arise that are not due to a carcinogenic action of the test article. Situations producing false positive results in the kidney include exacerbation of chronic progressive nephropathy (CPN) in rats, confusion of atypical tubule hyperplasia (the obligate precursor of renal tubule tumor) with foci of benign CPN-related renal tubule cell proliferation, inclusion of spontaneous tumor entities, such as the amphophilic-vacuolar tumor, in the test article tumor count, the possibility of a link between spontaneous forms of tubule dilatation and renal tubule tumor formation in mice, and the supposed predictivity of chemically-induced karyomegaly for renal carcinogenicity in both rats and mice. Examples of these misleading situations are described and discussed.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"72 4","pages":"1 - 6"},"PeriodicalIF":1.2,"publicationDate":"2021-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41301593","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":"Evaluation of Caspase-3 and Ki-67 expression in squamous cell hyperplasia of the stomach induced by Platycodi radix water extract in Sprague–Dawley rats","authors":"Yinghua Li, Seung-Beom Cha, Youngil Park, Bo-Ho Gong, Inae Jeong, H. Kim, Min-Soo Kang, Young-Suk Kim, Chang Hoon Han, Hyun-Kul Lee, Si-Whan Song, C. Park, B. Kang","doi":"10.1293/tox.2021-0003","DOIUrl":"https://doi.org/10.1293/tox.2021-0003","url":null,"abstract":"Platycodi radix is widely used in traditional herbal medicine for the treatment of bronchitis, asthma, pulmonary tuberculosis, hypertension, hyperlipidemia, and diabetes. This study aimed to investigate cell proliferation (Ki-67) and apoptosis (Caspase-3) potential in squamous cell hyperplasia of the stomach induced by a Platycodi radix water extract in a subchronic toxicity study. One hundred formalin-fixed, paraffin-embedded stomach tissues of rats treated with Platycodi radix at doses of 0, 500, 1,000, and 3,000 mg/kg body weight/day were used for the analysis. They were conventionally stained using hematoxylin and eosin (H&E) and immunohistochemically (IHC) stained using caspase-3 and Ki-67 antibodies. The incidence of squamous cell hyperplasia was significantly increased in the 3,000 mg/kg b.w./day treatment group in both sexes (p<0.01). However, the hyperplastic change was completely repaired after 4 weeks of recovery period. Ki-67 expression was similar in all groups, with no statistically significant differences among the groups. Caspase-3 expression was significantly increased in both sexes in the 3,000 mg/kg b.w./day treatment group (p<0.01), compared with the vehicle control groups, and then reduced to normal levels in the recovery groups in both sexes. In conclusion, this study showed that squamous cell hyperplasia induced by the Platycodi radix water extract in the limiting ridge of the stomach is not considered to be abnormal proliferative change; as a result, squamous cell hyperplasia is considered to be a non-adverse effect when induced by the oral administration of the Platycodi radix water extract once daily for 13 weeks in rats.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"45 - 52"},"PeriodicalIF":1.2,"publicationDate":"2021-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46245948","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":"Spontaneous well-differentiated pancreatic islet cell carcinoma with vascular invasion in a male F344 rat","authors":"Shiori Fujiwara, Y. Yamaguchi, Tsubasa Saito, T. Nakazawa, K. Tamura","doi":"10.1293/tox.2021-0037","DOIUrl":"https://doi.org/10.1293/tox.2021-0037","url":null,"abstract":"This case report describes a case of spontaneous pancreatic islet cell carcinoma with vascular invasion in a 110-week-old male F344 rat. Histologically, a pancreatic nodule consisting of tumor cells and many blood-rich vessels, and covered with a fibrous capsule showed local invasion in the capsule and adjacent acinar tissues, encircling a large duct-like structure (DS). The tumor was composed of well-differentiated tumor cells resembling normal pancreatic islet cells, which had small round nuclei and eosinophilic cytoplasm. Mitotic figures were rare. Immunohistochemistry revealed that the tumor cells were positive for insulin. Although endothelial cells were not detected, the DS wall showed cells positive for α-smooth muscle actin and elastic fibers, suggesting that the DS is the pancreatic artery. This is a rare case of islet cell carcinoma consisting of well-differentiated tumor cells with invasion of the pancreatic artery in a rat.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"99 - 102"},"PeriodicalIF":1.2,"publicationDate":"2021-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42770030","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":"A 13-week subchronic toxicity study of 2-(<i>l</i>-menthoxy)ethanol in F344 rats.","authors":"Takeshi Toyoda,&nbsp;Kohei Matsushita,&nbsp;Hirotoshi Akane,&nbsp;Tomomi Morikawa,&nbsp;Kumiko Ogawa","doi":"10.1293/tox.2020-0091","DOIUrl":"https://doi.org/10.1293/tox.2020-0091","url":null,"abstract":"<p><p>2-(<i>l</i>-Menthoxy)ethanol has been frequently employed as a flavoring agent; however, data regarding 2-(<i>l</i>-menthoxy)ethanol toxicity remain limited. We performed a 13-week subchronic toxicity study of 2-(<i>l</i>-menthoxy)ethanol in male and female F344 rats, with doses of 0, 15, 60, or 250 mg/kg body weight (BW)/day orally administered by gavage using corn oil as the vehicle. No significant toxicological changes in general condition, body weight, or food intake were observed in any groups. The hematological assessment showed decreased hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin and increased platelet count in the male 250 mg/kg group. Serum biochemistry revealed elevated total cholesterol in the 250 mg/kg group of male and female rats, reduced triglyceride in the female 250 mg/kg group, and increased total protein in the male 250 mg/kg group, indicating effects on lipid metabolism and protein synthesis. For organ weights, absolute and relative weights of the liver and adrenal glands were increased in the 250 mg/kg group of both sexes and the male 250 mg/kg group, respectively. Histopathological analysis showed chronic nephropathy in the male 15 mg/kg or higher groups, with increased absolute and relative kidney weights, as well as elevated serum creatinine, in the male 60 and 250 mg/kg groups. However, eosinophilic granules containing α_2u-globulin were identified in proximal tubules, suggesting α_2u-globulin nephropathy specific to male rats and without toxicological significance. These results indicated that the no-observed-adverse-effect level of 2-(<i>l</i>-menthoxy)ethanol was 60 mg/kg BW/day for both sexes.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"309-317"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c4/f2/tox-34-309.PMC8484932.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39526548","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":"Safety and efficacy of sFilm-FS, a novel biodegradable fibrin sealant, in Göttingen minipigs.","authors":"Yuval Ramot,&nbsp;Michal Steiner,&nbsp;Yossi Lavie,&nbsp;Nati Ezov,&nbsp;Orgad Laub,&nbsp;Eran Cohen,&nbsp;Yotam Schwartz,&nbsp;Abraham Nyska","doi":"10.1293/tox.2021-0030","DOIUrl":"https://doi.org/10.1293/tox.2021-0030","url":null,"abstract":"<p><p>Bleeding during surgical procedures is a common complication. Therefore, hemostatic agents have been developed to control bleeding, and fibrin sealants have several benefits. sFilm-FS is a novel fibrin sealant that comprises a biodegradable co-polymeric film embedded with human fibrinogen and thrombin. Herein, the safety and efficacy of sFilm-FS were compared using a liver and spleen puncture model of Göttingen minipigs with those of the standard hemostatic techniques (control animals) and EVARREST^®, a reference fibrin sealant. Hemostasis and reduced blood loss were more effectively achieved with sFilm-FS than with the standard techniques in the control animals and comparable to those achieved with EVARREST^®. No treatment-related adverse effects were observed in any of the groups. Histopathological evaluation indicated that sFilm-FS was slightly and moderately reactive at the liver puncture site and spleen, respectively, compared with the standard techniques in the control animals. These changes are expected degradation reactions of the co-polymeric film and are not considered as adverse events. No treatment-related abnormalities were noted in the other evaluated organs. Additionally, no evidence of local or systemic thromboses was noted. These results support the use of sFilm-FS for hemostasis in humans.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"319-330"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6c/f4/tox-34-319.PMC8484930.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39526999","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":"Time-course changes in 5-fluorouracil-induced neural progenitor cell damages in the developing rat brain.","authors":"Yuko Yamaguchi,&nbsp;Yachiyo Fukunaga,&nbsp;Mizuho Takagi,&nbsp;Tsubasa Saito,&nbsp;Kazutoshi Tamura,&nbsp;Toru Hoshiya","doi":"10.1293/tox.2020-0070","DOIUrl":"https://doi.org/10.1293/tox.2020-0070","url":null,"abstract":"<p><p>5-Fluorouracil (5-Fu) is a DNA-damaging agent and teratogenic in rodents. This study aimed to investigate its influence on neural progenitor cells (NPCs) in the developing fetal rat brain. Dams were intraperitoneally injected with 5-Fu (50 mg/kg b.w.) on gestation day 13 and its effects on fetal NPCs were observed from 3 to 72 hours after treatment (HAT), via periodic examination at six intervals. In NPCs of the fetal brain, the p53-labeling index (LI%) was markedly elevated at 3 HAT. Pyknosis and cleaved caspase-3-LI% also increased at 3 HAT, reaching peak values at 9 and 12 HAT. These parallel changes suggested the induction of apoptosis through a p53-mediated pathway. Pyknotic NPCs were distributed across the ventricular zone (VZ) of the telencephalic wall until 12 HAT, and became localized in the medial and dorsal layers at 12 and 48 HAT. Significant decreases in the numbers of mitotic NPCs and BrdU-LI% were noted from 3 HAT and 24 HAT, respectively. BrdU-positive NPCs were located in the ventral and middle layer at 24 and 48 HAT. p21-positive cells were detected at 12 and 24 HAT. The present results demonstrated that p53-mediated apoptosis was induced in all phases of the cell cycle of the NPCs in the early stage after 5-FU treatment. Furthermore, apoptosis of NPCs and suppression of cell proliferative activity are the events that take place in parallel leading to prominent reduction in the width of the telencephalic wall.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"299-308"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/83/64/tox-34-299.PMC8484929.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39519979","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":"Karnovsky's fixative prevents artifacts appearing as vacuolation derived from tissue processing in kidneys treated with antisense oligonucleotide.","authors":"Hironobu Nishina,&nbsp;Tetsuya Sakairi,&nbsp;Akane Kashimura,&nbsp;Hiroko Sato,&nbsp;Mao Mizukawa,&nbsp;Yuhei Ozawa,&nbsp;Satomi Nishikawa","doi":"10.1293/tox.2021-0007","DOIUrl":"https://doi.org/10.1293/tox.2021-0007","url":null,"abstract":"<p><p>Antisense oligonucleotide (ASO) therapies have been identified as a new treatment modality for intractable diseases. In kidneys treated with ASOs, vacuoles, in addition to basophilic granules, are often observed in the proximal tubules. Some reports have described that these vacuoles are likely to be a secondary phenomenon resulting from the extraction of ASOs during tissue processing. In this study, we compared renal morphology after fixation with Karnovsky's fixative or 4% paraformaldehyde phosphate buffer (PFA) with that of 10% neutral-buffered formaldehyde solution (NBF). Female Sprague-Dawley rats, intravenously treated four times with 50 mg/kg locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) for 1 or 2 weeks, were examined. Microscopically, vacuoles and basophilic granules in the proximal tubules were observed in the kidneys fixed with NBF. Basophilic granules are indicative of the accumulation of ASOs. Moreover, some of the vacuoles also contained faint basophilic granules, suggesting that the vacuoles were relevant to the accumulation of ASOs. Although moderate vacuolation was observed in the proximal tubules, the majority of the vacuolated epithelia were negative for kidney injury molecule-1 on immunohistochemical staining. Vacuoles in the proximal tubules were not observed in samples subjected to Karnovsky's fixation, although basophilic granules were observed. In samples subjected to PFA fixation, vacuoles and basophilic granules were observed in the proximal tubules, similar to those in samples subjected to NBF fixation. Overall, our findings demonstrated the possibility of overestimation of vacuolation due to artifacts during tissue processing when using conventional NBF fixation. Karnovsky's fixative is considered a useful alternative for distinguishing artificial vacuoles from true nephrotoxicity.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"367-371"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/28/ec/tox-34-367.PMC8484925.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39504622","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":"Seminiferous epithelium cycle staging based on the development of the acrosome in ram testis.","authors":"Sabina Šturm,&nbsp;Tanja Švara,&nbsp;Ellinor Spörndly-Nees,&nbsp;Vesna Cerkvenik-Flajs,&nbsp;Mitja Gombač,&nbsp;Anna-Luisa Weber,&nbsp;Klaus Weber","doi":"10.1293/tox.2021-0025","DOIUrl":"https://doi.org/10.1293/tox.2021-0025","url":null,"abstract":"<p><p>Testicular histopathology is considered the most sensitive and reliable method to detect the effects of chemicals on sperm production. To carry out a sensitive examination of testicular histopathology and interpret the changes require knowledge of spermatogenic stages. Spermatogenic staging based on acrosome development during spermiogenesis is conventionally performed in animal species routinely used for research and toxicity testing. In contrast, small ruminants, such as sheep and goats, are rarely used as animal models to evaluate toxicity in male reproductive organs. To the best of our knowledge, a comparable spermatogenic staging system in rams has not yet been fully characterised. Hence, this study aimed to adapt the existing spermatogenic staging based on acrosome development in bull testes to fit the seminiferous epithelium cycle of ram testes. The results show that spermatogenic staging based on acrosome development in bull testes can, with slight modifications, be efficiently used for the staging of ram testes.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"331-338"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0f/13/tox-34-331.PMC8484928.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39519980","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":"Spontaneous cholangiofibrosis adjacent to a dilated common bile duct with intestinal metaplasia in a Royal College of Surgeons rat.","authors":"Kiyokazu Ozaki,&nbsp;Yui Terayama,&nbsp;Tetsuro Matsuura","doi":"10.1293/tox.2021-0032","DOIUrl":"https://doi.org/10.1293/tox.2021-0032","url":null,"abstract":"<p><p>A 130-week-old male Royal College of Surgeons rat kept as a non-treated animal in a long-term animal study presented with a mass in the hepatic portal region that adhered to a dilated common bile duct and the duodenum. Histopathologically, the solitary mass showed expansive growth with no apparent compression and continued to dilate the common bile duct, which had a hyperplastic epithelium with intestinal metaplasia. The mass mainly consisted of small to large dilated and/or tortuous ducts with abundant dense connective tissue and many inflammatory cells. The single-layer lining epithelium of the duct changed from cuboidal to columnar. Immunohistochemically, the lining cells were positive for cytokeratin 7, cytokeratin 19, and OV-6, which are bile duct markers. Based on the pathological characteristics, the rat was diagnosed as spontaneous cholangiofibrosis adjacent to a dilated common bile duct with intestinal metaplasia.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"34 4","pages":"339-343"},"PeriodicalIF":1.2,"publicationDate":"2021-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/8e/tox-34-339.PMC8484927.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39519981","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}