{"title":"Canine generalized ceroid lipofuscinosis characterized by predominant deposition in pancreatic acinar cells and intestinal smooth muscle cells.","authors":"Ryoko Fujikawa, Kyohei Yasuno, Masako Imaoka, Shinobu Hakamata, Kumi Honda, Keiko Okado, Hitomi Shimoda, Yoshimi Tsuchiya","doi":"10.1293/tox.2025-0049","DOIUrl":"10.1293/tox.2025-0049","url":null,"abstract":"<p><p>Canine generalized ceroid lipofuscinosis (GCL) is a rare disease characterized by the deposition of lipofuscin in systemic organs and tissues. In this case report, we encountered a dog with GCL and performed a detailed histopathological examination. A 7-year-old male beagle was euthanized due to progressive weight loss and loose or bloody stools, without any neurological symptoms. Histopathologically, deposition of lipofuscin was observed in the parenchymal cells of systemic organs, particularly in the pancreatic acini and intestinal smooth muscle, accompanied by interstitial infiltration of macrophages. No neuronal loss was observed in the central nervous system, despite such findings and neurological symptoms being commonly associated with GCL. However, some lipofuscin deposition was evident in systemic organs, so the present case was diagnosed as GCL characterized by predominant deposition in the pancreatic acini and intestinal smooth muscle. This detailed description of the morphological features may contribute to a deeper understanding of lipofuscinosis.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"263-271"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280628","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":"Ectopic intestinal cyst in the liver of a Sprague-Dawley rat.","authors":"Momoka Shobudani, Yuzo Yasui, Akiko Anagawa-Nakamura, Taishi Shimazaki, Ryo Yamazaki, Kaoru Toyoda, Yusuke Kemmochi, Akemi Takahashi, Toshiyuki Shoda","doi":"10.1293/tox.2025-0027","DOIUrl":"10.1293/tox.2025-0027","url":null,"abstract":"<p><p>Ectopic intestinal cysts are extremely rare in the rat liver. Here, we report a case of a spontaneous ectopic intestinal cyst in the liver of an 8-week-old male Crl:CD (SD) rat. Necropsy revealed a solitary white, firm nodule, approximately 3 mm in diameter on the diaphragmatic surface near the porta hepatis of the medial lobe of the liver. Histologically, the lesion exhibited a cystic structure lined with tissue resembling intestinal mucosa, located on the liver capsule. Periodic acid-Schiff and Alcian blue (pH 1.0) staining-positive mucous cells, similar to goblet cells, and Paneth cell-like cells containing eosinophilic granules were observed in the mucosal epithelium. Immunohistochemically, the mucosal epithelium demonstrated low proliferative activity, as confirmed by Ki-67 staining. The thin outer layer of the mucosa was positive for alpha-smooth muscle actin, suggesting the presence of the lamina muscularis or a poorly developed muscular layer. Based on the lesion's location and histological features, this case was diagnosed as an ectopic intestinal cyst, likely resulting from persistence of the vitelline duct. To the best of our knowledge, there are no previous reports of ectopic intestinal cysts in the rat liver that include such detailed histochemical and immunohistochemical findings. This report provides valuable insights into congenital lesions of the rat hepatobiliary system.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"257-262"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280635","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":"Inactivation of major hepcidin pathways leads to systemic and hepatic iron overload during development of chemically-induced liver cirrhosis in rats.","authors":"Takashi Horiuchi, Takeshi Izawa, Mitsuru Kuwamura","doi":"10.1293/tox.2025-0069","DOIUrl":"10.1293/tox.2025-0069","url":null,"abstract":"<p><p>Hepatic iron overload is a common complication of human chronic liver diseases, including liver cirrhosis; however, the underlying mechanisms remain unclear. In the present study, we investigated the temporal changes in iron metabolism and the expression of iron-regulatory molecules during thioacetamide-induced liver cirrhosis in rats. Histopathological and biochemical analyses revealed that iron overload develops concurrently with the suppression of hepcidin expression in advanced cirrhosis. Hepatic expression of genes involved in cellular iron intake, storage, and export increased persistently in cirrhotic livers. The IL6-STAT3 and BMP6-SMAD pathways, which are the major intracellular mechanisms that induce hepcidin transcription, were inactivated in advanced cirrhosis. Furthermore, microRNA-135b-5p (miR-135b-5p), which targets JAK2 and SMAD5, key molecules of the IL6-STAT3 and BMP6-SMAD pathways, respectively, was highly upregulated in parallel with the progression of cirrhosis. These results indicate that inactivation of multiple hepcidin pathways, possibly mediated by miR-135b-5p upregulation, is responsible for hepatic iron overload in advanced cirrhosis. Our findings provide new insights into the mechanisms underlying iron dysregulation in liver cirrhosis.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"247-256"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280685","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":"Protective effects of roselle (<i>Hibiscus sabdariffa</i>) aqueous extract against aristolochic acid-induced developmental nephrotoxicity in zebrafish.","authors":"Ping-Hsun Lu, Yun-Hsin Wang, Chi-Chung Wen, Yau-Hung Chen","doi":"10.1293/tox.2025-0014","DOIUrl":"10.1293/tox.2025-0014","url":null,"abstract":"<p><p>This study investigates the protective effects of roselle aqueous extract (RAE) against aristolochic acid (AA)-induced developmental nephrotoxicity in zebrafish embryos. Fluorescence imaging, immunohistochemistry, and real-time polymerase chain reaction (PCR) experiments were conducted. The results showed that pre-treatment with RAE significantly improved survival rates and reduced kidney malformations in AA-exposed zebrafish. Specifically, survival rates in the AA-treated group decreased to 81.11% by 72 hours post-fertilisation, whereas those in the AA+RAE (30 and 60 ppm) groups increased to 86.67-90%. Additionally, RAE pre-treatment reduced kidney malformation rates from 98.89% in the AA group to 75.56% and 63.33% in the AA+RAE (30 and 60 ppm) groups, respectively. Histological analysis revealed that RAE mitigated structural damage in the pronephric tubes, restoring their compact architecture. Molecular analysis using real-time reverse transcription (RT)-PCR further indicated that RAE reduced the expression of inflammatory markers, suggesting that its protective effects are mediated through the attenuation of AA-induced inflammation. These findings demonstrate that RAE exerts a protective role against AA-induced developmental kidney malformations in zebrafish, likely through its antioxidant and anti-inflammatory properties.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"213-221"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280707","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}
Dai Yamamoto, Junko Sato, Takuya Doi, Jun Sasaki, Takeshi Kanno, Toshiaki Kokubo
{"title":"Effects of timing differences in γ-ray irradiation on ovarian development in rats.","authors":"Dai Yamamoto, Junko Sato, Takuya Doi, Jun Sasaki, Takeshi Kanno, Toshiaki Kokubo","doi":"10.1293/tox.2025-0032","DOIUrl":"10.1293/tox.2025-0032","url":null,"abstract":"<p><p>This study investigated the effects on ovarian development in adult rats irradiated with γ-rays at fetal, neonatal, weaning, and early sexual maturation. Female Fischer-344 (F344) rats mated with male rats and their F1 offspring were irradiated with a single dose of 0.5 or 2 Gy of γ-rays on gestation day 15 or 19 (GD15 or 19), or postnatal day 5, 20, or 49 (PND5, 20, or 49). F1 females were reared until 27 weeks of age and necropsied. HE-stained specimens of the reproductive organs were prepared for histological examination (n=10-22 per group). The corpus luteum and follicle numbers were also counted in all ovaries. In addition, PCNA-stained specimens were used to count the primordial follicles. At 2 Gy, corpora lutea and follicle depletion was observed in the GD15, PND5, and PND20 irradiation groups. Instead of lost follicles consisting of granulosa cells, numerous tubular structures composed of Sertoli-like cells similar to those found in the testes were noted. In the GD19 group, the ovaries showed less sensitivity to γ-rays. In the PND49 irradiation group, the number of corpora lutea was normal; however, the number of follicles, including primordial follicles, decreased. At 0.5 Gy, the ovaries appeared histologically normal in all the groups; however, the number of follicles decreased in the GD15 and PND5 irradiation groups. In conclusion, we found that the timing of γ-ray irradiation significantly affected subsequent ovarian development, and the degree of change depended on the γ-ray dose.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"237-245"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280690","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 28-day subacute toxicity study of puberulic acid in Crl:CD(SD) rats.","authors":"Kohei Matsushita, Genichiro Tsuji, Hirotoshi Akane, Yuji Ishii, Shinji Takasu, Kumiko Ogawa, Takahito Ito, Hidetomo Yokoo, Goh Sennari, Masato Iwatsuki, Tomoyasu Hirose, Hideaki Hanaki, Yosuke Demizu, Yoko Hirabayashi, Yoshiro Saito, Masamitsu Honma, Takeshi Toyoda","doi":"10.1293/tox.2025-0057","DOIUrl":"10.1293/tox.2025-0057","url":null,"abstract":"<p><p>In March 2024, a health hazard associated with the consumption of food products containing red yeast rice (beni-koji), which could lead to renal dysfunction, was reported in Japan. Puberulic acid (PA) was identified as an unintentional contaminant in these products; however, information on PA toxicity remains limited. The toxicological profile of PA was evaluated in a 28-day subacute toxicity study in rats. Synthesized PA was administrated by gavage to 6-week-old Crl:CD(SD) rats at 0, 1, 3, or 10 mg/kg/day (male) or 0, 0.3, 1, or 3 mg/kg/day (female) over 28 days, and satellite groups were used to evaluate the reversibility over a 14-day period. Male rats in the 10 mg/kg group exhibited increased urinary glucose and serum creatinine levels compared to controls. Histopathological examination revealed vacuolation, necrosis, and regeneration of proximal tubules in kidneys of all rats in the male 10 mg/kg and female 3 mg/kg groups. After the 14-day recovery period, focal interstitial fibrosis was observed in one male rats from the high-dose group, whereas no renal lesions were detected in the remaining rats of either sex. These results suggest that PA-induced nephrotoxicity is largely reversible under the conditions studied, although residual chronic lesions may occur in severe cases. Apoptosis/necrosis and diffuse hyperplasia of the glandular stomach mucosa were observed in male 3 and 10 mg/kg and female 3 mg/kg groups but were absent after the recovery period. These results indicate that, under the study conditions, the no-observed-adverse-effect level for PA was 1 mg/kg/day for both sexes.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 4","pages":"223-236"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280715","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":"Report of the AI Pathology Task Force, Non-clinical Evaluation Expert Committee, Japan Pharmaceutical Manufacturers Association: questionnaire survey on AI pathology and utilization of whole slide image database.","authors":"Masaki Yamazaki, Emi Tomikawa, Miyoko Okada, Satoru Kajikawa, Yui Terayama, Shino Kumabe, Tetsuya Sakairi, Akira Inomata, Izumi Matsumoto, Gen Sato, Mutsumi Suzuki","doi":"10.1293/tox.2024-0099","DOIUrl":"10.1293/tox.2024-0099","url":null,"abstract":"<p><p>In recent years, the development of Artificial Intelligence (AI) technology has led to the introduction and use of AI-based histopathological evaluation (AI pathology) by various companies and organizations. The AI Pathology Task Force of the Non-clinical Evaluation Expert Committee within the Drug Evaluation Committee of the Japan Pharmaceutical Manufacturers Association (JPMA) recognizes the importance of understanding the current use and needs surrounding AI pathology in Japan. This includes its role in non-clinical research fields, such as toxicity evaluation, drug efficacy evaluation, and basic research. In addition, assessing needs and challenges related to pathology image databases is essential. Between October and November 2023, with the cooperation of the Japanese Society of Toxicologic Pathology (JSTP), we conducted a questionnaire survey on non-clinical pathology image databases to explore these issues among JPMA-affiliated and JSTP-affiliated organizations. The questionnaire survey consisted of three items: (1) implementation and utilization of whole slide images, (2) use of AI pathology in non-clinical research fields, and (3) needs and feasibility of establishing a precompetitive pathology image database (repository) and AI pathology in the non-clinical pathology field. This report summarizes the survey results and serves as a foundation for guiding future directions in the use of AI pathology in non-clinical studies in Japan.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 3","pages":"205-211"},"PeriodicalIF":0.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553877","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}
Minkyoung Sung, Joo-Hee Choi, Soo-Eun Sung, Kyung-Ku Kang, Sun Hee Park, Duyeol Kim, Sijoon Lee
{"title":"Spontaneous T-cell lymphoblastic lymphoma in a young ICR mouse: a case report.","authors":"Minkyoung Sung, Joo-Hee Choi, Soo-Eun Sung, Kyung-Ku Kang, Sun Hee Park, Duyeol Kim, Sijoon Lee","doi":"10.1293/tox.2024-0086","DOIUrl":"10.1293/tox.2024-0086","url":null,"abstract":"<p><p>Lymphoblastic lymphoma (LBL) is an aggressive neoplasm characterized by the proliferation of undifferentiated lymphocytes. It primarily spreads to immune organs such as the thymus, spleen, lymph nodes, bone marrow, and liver. Although well-documented in humans, spontaneous LBL cases in laboratory animals are exceedingly rare. This study reports a case of T cell-derived LBL in a young adult ICR mouse, notably without bone marrow metastasis. This case provides valuable insights into the spontaneous occurrence of LBL in laboratory rodents by contributing to comparative oncology and preclinical research.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 3","pages":"199-203"},"PeriodicalIF":0.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553878","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":"Report of the AI Pathology Task Force, Non-clinical Evaluation Expert Committee, Japan Pharmaceutical Manufacturers Association: an overview of recent publications about AI pathology.","authors":"Emi Tomikawa, Satoshi Sakai, Yoshinori Yamagiwa, Yumi Kangawa, Yusuke Kagawa, Yuki Kato, Kensuke Kojima, Akira Inomata, Izumi Matsumoto, Gen Sato, Mutsumi Suzuki","doi":"10.1293/tox.2024-0100","DOIUrl":"10.1293/tox.2024-0100","url":null,"abstract":"<p><p>The use of artificial intelligence (AI) in non-clinical pathology is rapidly expanding. In this study, we conducted a literature survey of articles published after 2017 that used AI to analyze the histopathological images of experimental animals. We identified 44 articles that used AI for various purposes, including the detection of abnormal sites, determination and quantification of normal tissues, and classification of normal/abnormal images. AI systems or applications were either custom-built, commercially available, or a combination of both. Rats and mice were mainly used, and the liver was the most frequently analyzed organ. Our findings suggest that AI can be useful in non-clinical pathology and that collaboration between pharmaceutical companies or cooperation with IT experts can be a potential approach to further advance the utilization of AI in this field.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 3","pages":"191-198"},"PeriodicalIF":0.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553876","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":"Novel three-dimensional analysis method for accurate evaluation of cutaneous small sensory nerve fibers in mice.","authors":"Minori Inanaga- Kojima, Tetsuro Matsuura, Kiyokazu Ozaki","doi":"10.1293/tox.2024-0085","DOIUrl":"10.1293/tox.2024-0085","url":null,"abstract":"<p><p>Intraepidermal nerve fiber (IENF) density is commonly evaluated to diagnose peripheral neuropathy. However, conventional two-dimensional (2D) analysis using rodent models shows high interstudy variability. Three-dimensional (3D) IENF analysis has been proposed for human skin biopsies because the spatial location of each nerve can be easily determined. However, no studies have compared 2D and 3D analyses of mouse cutaneous nerve fibers under the same conditions. We aimed to establish a more accurate analysis method for mouse cutaneous nerve fibers. We used the glabrous plantar metatarsal skin of male C57BL/6J mice. The middle area of the plantar skin was used for 2D and 3D analyses, and the marginal area was also investigated in the 3D analysis. Tissue transparency, nerve fiber-specific antibodies, confocal microscopy, and IMARIS software were used for the 3D analysis. The 3D analysis clearly defined branching points and continuity, allowing accurate IENF density measurement. Conversely, the 2D analysis could not accurately determine IENF density because it could not detect the continuity of the nerve from the dermis to epidermis. Thus, the actual IENF density from the 3D analysis was significantly less than that from the 2D analysis. In addition, the density and length of IENFs in the middle area were significantly higher than those in the marginal area. This 3D approach enables the precise capture of IENF trajectories with various parameters, establishing a standard method for evaluating peripheral neuropathy models. Furthermore, our findings indicate that comparative studies aiming to analyze mouse IENF need to consider the site of skin sampling.</p>","PeriodicalId":17437,"journal":{"name":"Journal of Toxicologic Pathology","volume":"38 2","pages":"167-175"},"PeriodicalIF":0.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796014","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}