Shanshan Wu, Sang Hu, Wenjuan Fan, Xiao-ju Zhang, Haili Wang, Chaojie Li, J. Deng
{"title":"Nitrite exposure may induce infertility in mice","authors":"Shanshan Wu, Sang Hu, Wenjuan Fan, Xiao-ju Zhang, Haili Wang, Chaojie Li, J. Deng","doi":"10.1293/tox.2021-0002","DOIUrl":"https://doi.org/10.1293/tox.2021-0002","url":null,"abstract":"In the present study, we investigated the potential of nitrite exposure to induce infertility in mice. Adult female C57BL/6J mice were randomly divided into control and nitrite exposure groups. Subsequently, the rate of mouse infertility was calculated, and pathological changes in ovarian tissues were examined using hematoxylin and eosin staining. In addition, TUNEL staining, immunofluorescent labeling, and western blotting were performed to assess cell apoptosis and oxidative stress response in ovarian tissues from various groups. We observed that nitrite exposure could induce infertility (p<0.05) in mice. High-dose nitrite exposure caused infertility in a time-dependent manner, and two-round exposure induced higher infertility than that one-round exposure (p<0.01). In addition, a higher number of atretic follicles were detected in the ovaries of nitrite-exposed groups than in the control group. Furthermore, TUNEL-positive cells were observed in granulosa cells of atretic follicles, and overexpression of caspase 8, c-Fos, and inducible nitric oxide synthase (iNOS) was detected in ovaries after nitrite exposure (p<0.01), suggesting that cell apoptosis and oxidative stress response were induced following nitrite exposure. Collectively, these findings suggest that nitrite exposure can induce mouse infertility in a time-dependent manner. Oxidative stress response and cell apoptosis are involved in mediating nitrite-induced infertility.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"75 - 82"},"PeriodicalIF":1.2,"publicationDate":"2021-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43055208","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}
Taishi Shimazaki, Ameya Deshpande, Anindya Hajra, Tijo Thomas, Kyotaka Muta, Naohito Yamada, Y. Yasui, T. Shoda
{"title":"Deep learning-based image-analysis algorithm for classification and quantification of multiple histopathological lesions in rat liver","authors":"Taishi Shimazaki, Ameya Deshpande, Anindya Hajra, Tijo Thomas, Kyotaka Muta, Naohito Yamada, Y. Yasui, T. Shoda","doi":"10.1293/tox.2021-0053","DOIUrl":"https://doi.org/10.1293/tox.2021-0053","url":null,"abstract":"Artificial intelligence (AI)-based image analysis is increasingly being used for preclinical safety-assessment studies in the pharmaceutical industry. In this paper, we present an AI-based solution for preclinical toxicology studies. We trained a set of algorithms to learn and quantify multiple typical histopathological findings in whole slide images (WSIs) of the livers of young Sprague Dawley rats by using a U-Net-based deep learning network. The trained algorithms were validated using 255 liver WSIs to detect, classify, and quantify seven types of histopathological findings (including vacuolation, bile duct hyperplasia, and single-cell necrosis) in the liver. The algorithms showed consistently good performance in detecting abnormal areas. Approximately 75% of all specimens could be classified as true positive or true negative. In general, findings with clear boundaries with the surrounding normal structures, such as vacuolation and single-cell necrosis, were accurately detected with high statistical scores. The results of quantitative analyses and classification of the diagnosis based on the threshold values between “no findings” and “abnormal findings” correlated well with diagnoses made by professional pathologists. However, the scores for findings ambiguous boundaries, such as hepatocellular hypertrophy, were poor. These results suggest that deep learning-based algorithms can detect, classify, and quantify multiple findings simultaneously on rat liver WSIs. Thus, it can be a useful supportive tool for a histopathological evaluation, especially for primary screening in rat toxicity studies.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"135 - 147"},"PeriodicalIF":1.2,"publicationDate":"2021-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49046046","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}
Mizuho Takagi, Y. Yamaguchi, S. Yamakawa, K. Tamura
{"title":"Malignant pinealoma observed in the deep cerebral parenchyma of a male Wistar rat","authors":"Mizuho Takagi, Y. Yamaguchi, S. Yamakawa, K. Tamura","doi":"10.1293/tox.2021-0047","DOIUrl":"https://doi.org/10.1293/tox.2021-0047","url":null,"abstract":"This report describes a case of spontaneous malignant pinealoma in a 90-week-old male Wistar rat. The tumor mass occurred in the deep cerebral parenchyma and no intact pineal gland was observed in the area between the posterior-dorsal median line of the cerebrum and the cerebellum. The tumor was characterized by a large nodular proliferation occupying the central area of the brain, extending from the dorsal surface to the base of the brain, corresponding to the thalamus. The tumor cells had round to irregular oblong nuclei approximately 5–17 μm in diameter and showed faintly or moderately eosinophilic cytoplasm and indistinct cell boundaries. Immunohistochemically, the tumor cells were positive for synaptophysin and partially positive for neuron-specific enolase (NSE). The tumor showed malignant features including cellular pleomorphism, high mitotic index, necrotic foci, and invasive and extensive growth and was, therefore, diagnosed as an extremely rare malignant pinealoma in the deep cerebral parenchyma.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"117 - 121"},"PeriodicalIF":1.2,"publicationDate":"2021-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43741520","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":"Luteal toxicity evaluation in rats","authors":"Yoshikazu Taketa","doi":"10.1293/tox.2021-0058","DOIUrl":"https://doi.org/10.1293/tox.2021-0058","url":null,"abstract":"The corpora lutea (CL) are endocrine glands that form in the ovary after ovulation and secrete the steroid hormone, progesterone (P4). P4 plays a critical role in estrous and menstrual cycles, implantation, and pregnancy. The incomplete rodent estrous cycle stably lasts 4–5 days and its morphological features can be distinguished during each estrous cycle stage. In rat ovaries, there are two main types of CL: newly formed ones due to the current ovulation (new CL), and CL remaining from prior estrous cycles (old CL). In the luteal regression process, CL were almost fully regressed after four estrous cycles in Sprague-Dawley rats. P4 secretion from CL in rodents is regulated by the balance between synthesis and catabolism. In general, luteal toxicity should be evaluated by considering antemortem and postmortem data. Daily vaginal smear observations provided useful information on luteal toxicity. In histopathological examinations, not only the ovaries and CL but also other related tissues and organs including the uterus, vagina, mammary gland, and adrenal glands, must be carefully examined for exploring luteal changes. In this review, histological and functional characteristics of CL in rats are summarized, and representative luteal toxicity changes are presented for improved luteal toxicity evaluation in preclinical toxicity research.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"7 - 17"},"PeriodicalIF":1.2,"publicationDate":"2021-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43907471","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}
M. Nakagawa, S. Hayashi, S. Matsuo, Masaki Yamazaki, A. Kato
{"title":"Lipomatosis of axillary lymph nodes in a cynomolgus monkey (Macaca fascicularis)","authors":"M. Nakagawa, S. Hayashi, S. Matsuo, Masaki Yamazaki, A. Kato","doi":"10.1293/tox.2021-0054","DOIUrl":"https://doi.org/10.1293/tox.2021-0054","url":null,"abstract":"Lipomatosis of lymph nodes is defined as the replacement of the lymphatic parenchyma by adipose tissue which grows in the node from the hilus toward the cortical zone. In humans, it is considered as part of the normal aging process and is common in obese patients, but there are no reports in non-human primates. In this report, we describe the first case of lymph node lipomatosis in the bilateral axillary lymph nodes of a young adult cynomolgus monkey. Macroscopically, there were no apparent abnormalities in the axillary lymph nodes on either side, and their volumes were unchanged. At the cut surface, pale yellow fat-like tissue was observed in the medullary area. Histopathologically, well differentiated adipocytes replaced a large part of the lymphatic parenchyma in the area from the hilus to the medulla without any malignant findings. Based on these findings, the patient was diagnosed with lipomatosis of the lymph nodes.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"113 - 116"},"PeriodicalIF":1.2,"publicationDate":"2021-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43488140","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}
Osamu Hashiguchi, Yuko Yamaguchi, S. Ikezaki, Tsubasa Saito, Saori Igura, Ryo Hirai, N. Horiuchi, K. Tamura
{"title":"Porencephaly with an optic organ abnormality in a beagle dog","authors":"Osamu Hashiguchi, Yuko Yamaguchi, S. Ikezaki, Tsubasa Saito, Saori Igura, Ryo Hirai, N. Horiuchi, K. Tamura","doi":"10.1293/tox.2021-0039","DOIUrl":"https://doi.org/10.1293/tox.2021-0039","url":null,"abstract":"A female TOYO beagle dog showed porencephaly and visual organ abnormalities. At necropsy, there was a cavity filled with cerebrospinal fluid in the right cerebral hemisphere and an adhesion area between the cerebral cortex and the skull, which was partially thickened. Additionally, the right optic nerve showed a slight decrease in diameter. Histopathological examination revealed increased glial fibers and collagen fibers, hemosiderin deposition, and an increased number of microglia in the adhesion area, along with a marked reduction of the cerebral parenchyma. In the right eyeball, the retina and optic nerve showed focal atrophy in the nerve fiber layer and inner granular layer to full retinal atrophy and hypoplasia of the myelinated nerve fibers, respectively. Electron microscopic examination revealed hypoplasia of the myelin sheath of nerve fibers in the right optic nerve. This is an extremely rare case of porencephaly and congenital optic nerve hypoplasia, along with independent retinal thinning.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"107 - 111"},"PeriodicalIF":1.2,"publicationDate":"2021-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48640206","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}
Shinichi Onishi, M. Nakagawa, S. Matsuo, J. Shinozuka, Mio Hiramatsu, Takehito Isobe, Toshihiko Watanabe, A. Kato
{"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}
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
{"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}
Shiori Fujiwara, Y. Yamaguchi, Tsubasa Saito, T. Nakazawa, K. Tamura
{"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}