Journal of Toxicologic Pathology最新文献_第8页

Survey of tumorigenic sensitivity in 6-month rasH2-Tg mice studies compared with 2-year rodent assays. 6个月rasH2-Tg小鼠研究与2年啮齿动物试验的致瘤敏感性调查

IF 0.9 4区医学

Journal of Toxicologic Pathology Pub Date : 2022-01-01 Epub Date: 2021-11-01 DOI: 10.1293/tox.2021-0031

Shigeru Hisada, Kenjiro Tsubota, Kenji Inoue, Hisaharu Yamada, Takanori Ikeda, Frank D Sistare

{"title":"Survey of tumorigenic sensitivity in 6-month rasH2-Tg mice studies compared with 2-year rodent assays.","authors":"Shigeru Hisada, Kenjiro Tsubota, Kenji Inoue, Hisaharu Yamada, Takanori Ikeda, Frank D Sistare","doi":"10.1293/tox.2021-0031","DOIUrl":"10.1293/tox.2021-0031","url":null,"abstract":"<p><p>The pharmacokinetic endpoint of a 25-fold increase in human exposure is one of the specified criteria for high-dose selection for 2-year carcinogenicity studies in rodents according to ICH S1C(R2). However, this criterion is not universally accepted for 6-month carcinogenicity tests in rasH2-Tg mice. To evaluate an appropriate multiple for rasH2-Tg mice, we evaluated data for 53 compounds across five categories of rasH2-Tg mouse-positive [(1) genotoxic and (2) non-genotoxic] carcinogens and rasH2-Tg mouse-negative [(3) non-genotoxic carcinogens with clear or uncertain human relevance; (4) non-genotoxic rodent-specific carcinogens; and (5) non-carcinogens], and surveyed their tumorigenic activities and high doses in rasH2-Tg mice and 2-year rodent models. Our survey indicated that area under the curve (AUC) margins (AMs) or body surface area-adjusted dose ratios (DRs) of tumorigenesis in rasH2-Tg mice to the maximum recommended human dose (MRHD) were 0.05- to 5.2-fold in 6 category (1) compounds with small differences between models and 0.2- to 47-fold in 7 category (2) including three 2-year rat study-negative compounds. Among all 53 compounds, including 40 compounds of the rasH2-Tg mouse-negative category (3), (4), and (5), no histopathologic risk factors for rodent neoplasia were induced only at doses above 50-fold AM or DR in rasH2-Tg mice except for two compounds, which induced hyperplasia and had no relationship with the tumors observed in the rasH2-Tg mouse or 2-year rodent studies. From the results of these surveys, we confirmed that exceeding a high dose level of 50-fold AM in rasH2-Tg mouse carcinogenicity studies does not appear to be of value.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"53-73"},"PeriodicalIF":0.9,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43229605","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}

引用次数: 0

Elevated level of microRNA-210 at the initiation of muscular regeneration in acetic acid-induced non-ischemic skeletal muscular injury in mice 醋酸诱导小鼠非缺血性骨骼肌损伤后肌肉再生开始时microRNA-210水平升高

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-12-24 DOI: 10.1293/tox.2021-0061

Y. Takai, Takeshi Watanabe, T. Sano

{"title":"Elevated level of microRNA-210 at the initiation of muscular regeneration in acetic acid-induced non-ischemic skeletal muscular injury in mice","authors":"Y. Takai, Takeshi Watanabe, T. Sano","doi":"10.1293/tox.2021-0061","DOIUrl":"https://doi.org/10.1293/tox.2021-0061","url":null,"abstract":"The alteration in microRNA-210 level, a hypoxia-inducible microRNA, is not well known in non-ischemic tissue injury. In this study, we characterized the histopathological time course of acetic acid-induced skeletal muscle injury as a non-ischemic tissue injury model and investigated the expression of microRNA-210, hypoxia-inducible factor 1α, and growth factors using quantitative polymerase chain reaction analysis. After a single intramuscular dose of 3% (v/v) acetic acid to C57BL/6J mice, focal coagulative necrosis of muscle fibers was noted from 3 h after dosing and infiltration of F4/80 and Galectin-3 positive M2 macrophage was noted at 1 d after dosing. Muscular regeneration was initiated from 3 d, when M2 macrophage infiltration was most prominent, till 14 d after dosing. Hif1α and Hgf expression increased from 3 h onwards, and microRNA-210 level increased after 3 d after the treatment. However, no clear elevation in the levels of Igf1 or Vegf was observed. The infiltrative macrophages and regenerative muscle fibers were positive for hypoxia-inducible factor 1α, microRNA-210, and hepatocyte growth factor as assessed by immunohistochemistry or in situ hybridization. In this study, dominant infiltration of M2 macrophages at muscular necrosis and subsequent regeneration after a single intramuscular injection of acetic acid in mice were observed. The increase in hif1α level was observed just after the muscular injury in this non-ischemic tissue injury model, and the elevation in microRNA-210 level was noted at the initiation of tissue regeneration, indicating its effects on tissue protection and repair.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"183 - 192"},"PeriodicalIF":1.2,"publicationDate":"2021-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49264074","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}

引用次数: 0

Microarray-based gene expression analysis combined with laser capture microdissection is beneficial in investigating the modes of action of ocular toxicity 基于微阵列的基因表达分析与激光捕获显微切割相结合有助于研究眼部毒性的作用模式

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-12-18 DOI: 10.1293/tox.2021-0064

M. Shirai, Noriyo Niino, K. Mori, Kiyonori Kai

{"title":"Microarray-based gene expression analysis combined with laser capture microdissection is beneficial in investigating the modes of action of ocular toxicity","authors":"M. Shirai, Noriyo Niino, K. Mori, Kiyonori Kai","doi":"10.1293/tox.2021-0064","DOIUrl":"https://doi.org/10.1293/tox.2021-0064","url":null,"abstract":"The retina consists of several layers, and drugs can affect the retina and choroid separately. Therefore, investigating the target layers of toxicity can provide useful information pertaining to its modes of action. Herein, we compared gene expression profiles obtained via microarray analyses using samples of target layers collected via laser capture microdissection and samples of the whole globe of the eye of rats treated with N-methyl-N-nitrosourea. Pathway analyses suggested changes in the different pathways between the laser capture microdissection samples and the whole globe samples. Consistent with the histological distribution of glial cells, upregulation of several inflammation-related pathways was noted only in the whole globe samples. Individual gene expression analyses revealed several gene expression changes in the laser capture microdissection samples, such as caspase- and glycolysis-related gene expression changes, which is similar to previous reports regarding N-methyl-N-nitrosourea-treated animals; however, caspase- and glycolysis-related gene expressions did not change or changed unexpectedly in the whole globe samples. Analyses of the laser capture microdissection samples revealed new potential candidate genes involved in the modes of action of N-methyl-N-nitrosourea-induced retinal toxicity. Collectively, our results suggest that specific retinal layers, which may be targeted by specific toxins, are beneficial in identifying genes responsible for drug-induced ocular toxicity.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"171 - 182"},"PeriodicalIF":1.2,"publicationDate":"2021-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45875390","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}

引用次数: 0

CD44 expression in the bile duct epithelium is related to hepatic fibrosis in nonalcoholic steatohepatitis rats induced by a choline-deficient, methionine-lowered, L-amino acid diet 胆管上皮CD44表达与胆碱缺乏、蛋氨酸降低、l -氨基酸饮食诱导的非酒精性脂肪性肝炎大鼠肝纤维化有关

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-12-06 DOI: 10.1293/tox.2021-0069

K. Uno, K. Miyajima, M. Toma, Noriko Suzuki-Kemuriyama, D. Nakae

{"title":"CD44 expression in the bile duct epithelium is related to hepatic fibrosis in nonalcoholic steatohepatitis rats induced by a choline-deficient, methionine-lowered, L-amino acid diet","authors":"K. Uno, K. Miyajima, M. Toma, Noriko Suzuki-Kemuriyama, D. Nakae","doi":"10.1293/tox.2021-0069","DOIUrl":"https://doi.org/10.1293/tox.2021-0069","url":null,"abstract":"Nonalcoholic steatohepatitis is a lifestyle-related disease and an increasing threat worldwide. Hepatic fibrosis, which results from chronic hepatic diseases including nonalcoholic steatohepatitis, is closely correlated with mortality among hepatic lesions, such as steatosis and inflammation. Thus, it is important to identify factors that can serve as diagnostic and therapeutic targets for hepatic fibrosis. In this study, we examined the function of CD44 in the development of hepatic fibrosis in choline-deficient, methionine-lowered, L-amino-acid diet-fed rats, especially with respect to the proliferation of bile duct epithelium. Male Fischer 344 rats were fed a choline-deficient, methionine-lowered, L-amino-acid diet for 2, 4, 13, or 26 weeks. This diet decreased the body weight; increased the levels of serum parameters indicating liver injury, such as aspartate and alanine aminotransferase; upregulated inflammation- and fibrosis-related gene expression in the liver; and resulted in the development of hepatic lesions, including fatty changes in hepatocytes, inflammatory cell infiltration, and fibrosis. Hepatic hyaluronan was synthesized and deposited in the liver tissue. The expression of both CD44 mRNA and protein was significantly increased throughout the experimental period. CD44 protein was observed in some of the bile duct epithelium, around which hyaluronic acid was deposited, and these bile duct lesions were concordant with the area of hepatic fibrosis. Thus, CD44 expressed in the bile duct epithelium may be a target for controlling nonalcoholic steatohepatitis-related hepatic fibrosis.","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"35 1","pages":"149 - 157"},"PeriodicalIF":1.2,"publicationDate":"2021-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42334954","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}

引用次数: 3

Nitrite exposure may induce infertility in mice 亚硝酸盐暴露可能导致小鼠不孕

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-12-04 DOI: 10.1293/tox.2021-0002

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}

引用次数: 1

Deep learning-based image-analysis algorithm for classification and quantification of multiple histopathological lesions in rat liver 基于深度学习的大鼠肝脏多组织病理病变分类与定量图像分析算法

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-11-27 DOI: 10.1293/tox.2021-0053

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}

引用次数: 0

Malignant pinealoma observed in the deep cerebral parenchyma of a male Wistar rat 雄性Wistar大鼠脑深部实质中恶性松果体瘤的观察

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-11-25 DOI: 10.1293/tox.2021-0047

Mizuho Takagi, Y. Yamaguchi, S. Yamakawa, K. Tamura

引用次数: 0

Luteal toxicity evaluation in rats 大鼠黄体毒性评价

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-11-18 DOI: 10.1293/tox.2021-0058

Yoshikazu Taketa

{"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}

引用次数: 4

Lipomatosis of axillary lymph nodes in a cynomolgus monkey (Macaca fascicularis) 食蟹猴腋窝淋巴结脂肪瘤病的研究

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-11-15 DOI: 10.1293/tox.2021-0054

M. Nakagawa, S. Hayashi, S. Matsuo, Masaki Yamazaki, A. Kato

引用次数: 1

Porencephaly with an optic organ abnormality in a beagle dog 比格犬伴有视觉器官异常的脑孔畸形

IF 1.2 4区医学

Journal of Toxicologic Pathology Pub Date : 2021-10-25 DOI: 10.1293/tox.2021-0039

Osamu Hashiguchi, Yuko Yamaguchi, S. Ikezaki, Tsubasa Saito, Saori Igura, Ryo Hirai, N. Horiuchi, K. Tamura

引用次数: 1