Journal of Toxicological Sciences最新文献_第2页

An exploratory study of sex differences in thallium-induced nephrotoxicity in rats. 大鼠铊肾毒性性别差异的探索性研究。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.151

Shuheng Wen, Toshihiko Aki, Akihiro Tojo, Kana Unuma

{"title":"An exploratory study of sex differences in thallium-induced nephrotoxicity in rats.","authors":"Shuheng Wen, Toshihiko Aki, Akihiro Tojo, Kana Unuma","doi":"10.2131/jts.51.151","DOIUrl":"10.2131/jts.51.151","url":null,"abstract":"Sexual dimorphism is recognized in nephrotoxic acute kidney injury, with females being less susceptible than males. Thallium (Tl), a highly toxic heavy metal, induces severe systemic disorders following exposure, including gastrointestinal and neurological disorders and renal failure. However, sex-related differences in Tl-induced nephrotoxicity remain poorly understood. Previous studies have shown that Tl preferentially accumulates in the outer medulla of the kidney of male rats, resulting in mitochondrial dysfunction and medullary thick ascending limb (mTAL) injury, characterized by calcium deposits and impaired renal function. This study investigated the effects of Tl on the kidneys of female rats and the underlying mechanisms. Tl2SO4 (30 mg/kg) was administered to rats. Nephrotoxicity was measured 2, 5, and 14 days after Tl-administration using biochemical assays of blood and urine samples, histopathology of the kidney, and transcriptome analysis using microarrays. As in male rats, female Tl-loaded rats developed severe renal dysfunction with calcium deposits in the outer medulla within 5 days after Tl administration. The pathological features were similar to those of male rats; however, the mitochondrial oxidative stress and calcium deposits in the medulla were less extensive in female rats than in male rats. These preliminary findings suggest sex-dependent differences, which might be derived from the differences in sex-hormones, in Tl-induced renal injury and suggest potential involvement of differential oxidative stress handling, mitochondrial responses, and transporter activity. These new insights could assist with the development of therapeutic strategies for treating Tl intoxication in humans.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 3","pages":"151-161"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326389","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

Human erythropoietin mRNA as an impurity from a mRNA-LNP vaccine induces immune-mediated anemia in rats. 人促红细胞生成素mRNA作为mRNA- lnp疫苗的杂质诱导大鼠免疫介导性贫血。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.201

Yukie Murata, Shingo Kitamura, Yoshiji Asaoka, Shun Kitahata, Keisaku Wakabayashi, Hidetoshi Kouno, Norikazu Kuroda, Kayo Ishida, Shinobu Miki, Takafumi Sato, Osamu Yoshida, Akira Kugimiya, Tomokazu Yoshinaga, Tamio Fukushima

{"title":"Human erythropoietin mRNA as an impurity from a mRNA-LNP vaccine induces immune-mediated anemia in rats.","authors":"Yukie Murata, Shingo Kitamura, Yoshiji Asaoka, Shun Kitahata, Keisaku Wakabayashi, Hidetoshi Kouno, Norikazu Kuroda, Kayo Ishida, Shinobu Miki, Takafumi Sato, Osamu Yoshida, Akira Kugimiya, Tomokazu Yoshinaga, Tamio Fukushima","doi":"10.2131/jts.51.201","DOIUrl":"10.2131/jts.51.201","url":null,"abstract":"Non-clinical safety evaluations, including those of impurities, are important for vaccine development to ensure safety in humans. However, information on the mechanisms of impurity-induced adverse effects remains limited. In a repeated-dose toxicity study of our lipid nanoparticle formulated mRNA vaccine (mRNA-LNP vaccine) candidate, severe anemia was observed in rats after multiple administrations. In this study, we conducted hematological analyses and bone marrow examinations in vivo to investigate the cause and mechanism of test article-related delayed anemia. In addition, we performed in vitro mechanistic studies including antibody titer measurements and colony-forming unit assays. We found that test article-related anemia was caused by the inhibition of erythroid differentiation in the bone marrow, mediated by antibodies against erythropoietin (EPO). Furthermore, the test article was found to contain human EPO mRNA as an impurity. Lastly, the spike study showed that a minute quantity of human EPO mRNA present in mRNA-LNP vaccines as an impurity induced anemia in rats. Taken together, our data demonstrate that immune-mediated delayed anemia can be induced by impurity-oriented anti-EPO antibodies that neutralize endogenous EPO and inhibit erythroid differentiation. Our presented approach of determining the mechanism of delayed toxicity caused by impurities may be helpful in future safety evaluations.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 3","pages":"201-213"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326424","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

A zwitterionic solvent for in vitro toxicity tests of insoluble compounds. 一种用于不溶性化合物体外毒性试验的两性离子溶剂。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.227

Yusuke Kubota, Ayako Hohsaka, Eishu Hirata, Kosuke Kuroda

{"title":"A zwitterionic solvent for in vitro toxicity tests of insoluble compounds.","authors":"Yusuke Kubota, Ayako Hohsaka, Eishu Hirata, Kosuke Kuroda","doi":"10.2131/jts.51.227","DOIUrl":"10.2131/jts.51.227","url":null,"abstract":"OE2imC3C, a zwitterionic liquid, has attracted considerable attention as an emerging solvent with low toxicity. However, the safety data in research reports are limited, and its applicability to toxicity tests remains unclear. Therefore, we investigated the detailed safety profile of OE2imC3C and found that it was negative in both the bacterial reverse mutation and chromosome aberration tests, indicating no concern for genotoxicity. The hepatocellular toxicity of OE2imC3C stock solution (OS) was lower than that of dimethyl sulfoxide (DMSO). OS was widely applied and gave correct hepatocellular toxicity of ellagic acid (a functional food molecule with anticancer, antioxidant, and other properties), based on the high solubility. In contrast, DMSO revealed false toxicity in the test because the undissolved ellagic acid crystals damaged the cells. The general applicability of OS to food-related compounds was confirmed using Hansen solubility parameters. OS is a unique solvent capable to prevent artifacts in toxicity assays involving poorly soluble compounds such as food and drug molecules.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 3","pages":"227-237"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326463","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

Predicting nucleic acid drug-induced nephrotoxicity using a 3D human renal proximal tubule spheroid model. 利用三维人肾近端小管球体模型预测核酸药物引起的肾毒性。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.75

Kaoru Morimura, Etsushi Takahashi, Hayata Maeda, Yukiko Nishioka, Ayano Araki, Hiroshi Mizumoto, Yoichi Jimbo

{"title":"Predicting nucleic acid drug-induced nephrotoxicity using a 3D human renal proximal tubule spheroid model.","authors":"Kaoru Morimura, Etsushi Takahashi, Hayata Maeda, Yukiko Nishioka, Ayano Araki, Hiroshi Mizumoto, Yoichi Jimbo","doi":"10.2131/jts.51.75","DOIUrl":"10.2131/jts.51.75","url":null,"abstract":"Nucleic acid drugs hold considerable promise; however, their toxicological profiles are often difficult to assess in animal models. Clinical studies have reported adverse effects, including thrombocytopenia, complement activation, hepatotoxicity, and nephrotoxicity. While human cell-based models for hepatotoxicity are advancing, nephrotoxicity assessment remains limited by the scarcity of physiologically relevant kidney cells. In this study, a three-dimensional spheroid model of human primary renal proximal tubule epithelial cells (3D-RPTEC, Nikkiso) was employed to evaluate the nephrotoxicity of nucleic acid drugs. Proteomic profiling revealed enhanced expression of drug transporters and endocytic machinery in 3D-RPTEC compared with two-dimensional cultures. Lipofection enabled efficient intracellular delivery of nucleic acids. Toxicity was assessed using ATP quantification, biomarker analysis (LDH, KIM-1, NGAL), and high-content analysis (HCA). Significant ATP depletion was observed only after prolonged exposure to SPC5001, a nephrotoxic antisense oligonucleotide. In contrast, biomarker expression and HCA facilitated early detection of compound-specific toxicity and implicated endoplasmic reticulum and mitochondrial stress as underlying mechanisms. These findings establish 3D-RPTEC as a sensitive and physiologically relevant platform for predicting the nephrotoxic potential of nucleic acid drugs.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"75-87"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917906","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

Perillyl alcohol-induced hematological modulations: insights into human blood cells damage, eryptosis, and systemic perturbations. 紫苏醇诱导的血液学调节：对人类血细胞损伤、红细胞衰竭和全身紊乱的见解。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.45

Ahmed M Basudan, Jawaher Alsughayyir, Yazeed A Al-Sheikh, Mohammad A Alfhili

{"title":"Perillyl alcohol-induced hematological modulations: insights into human blood cells damage, eryptosis, and systemic perturbations.","authors":"Ahmed M Basudan, Jawaher Alsughayyir, Yazeed A Al-Sheikh, Mohammad A Alfhili","doi":"10.2131/jts.51.45","DOIUrl":"10.2131/jts.51.45","url":null,"abstract":"Perillyl alcohol (POH) is a natural monoterpene with established antitumor activity. Although its anticancer efficacy is well-documented, its impact on normal blood cells, particularly red blood cells (RBCs), remains underexplored. Given the importance of RBC integrity in maintaining homeostasis, this study aims to investigate the hematological effects of POH, focusing on hemolysis, eryptosis, and systemic blood parameters. Erythrocytes collected from June-August 2023 were treated with POH (0.5-2.5 mM) for 24 hr at 37°C. Hemolysis was assessed using photometric assays. Eryptosis was detected by flow cytometry using annexin V, Fluo4/AM, and H2DCFDA to quantify phosphatidylserine (PS) translocation, intracellular Ca2+, and oxidative stress, respectively. Complete blood count (CBC) parameters were also analyzed. POH induced dose-dependent hemolysis, elevated intracellular Ca2+, and significant PS externalization, indicating increased eryptosis. The hemolytic activity of POH was supported by marked increases in LDH, CK, and AST. Notably, polyethylene glycol (PEG) significantly attenuated hemolysis, suggesting a protective effect. In whole blood, POH reduced RBC count, hemoglobin, and hematocrit, while increasing RDW-CV. Reticulocyte profiling showed elevated immature reticulocyte fraction (IRF) and a medium fluorescence ratio (MFR). Moreover, POH induced leukopenia with immature granulocytes and platelet aggregation. POH disrupts RBC integrity, triggering hemolysis and eryptosis independently of oxidative stress. The observed hematological alterations underscore potential systemic toxicity and highlight the need for further preclinical evaluation to guide its therapeutic use in oncology.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"45-55"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917930","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

Evaluation of cytotoxicity of vesnarinone causing drug-induced agranulocytosis by a myeloperoxidase-like nonenzymatic metabolic approach using hypochlorous acid and application of the constructed assay method. 利用次氯酸髓过氧化物酶样非酶代谢方法评价维甾酮引起药物性粒细胞缺乏症的细胞毒性及构建的测定方法的应用。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.239

Toshihisa Koga, Yuko Sahara, Tadaaki Ohtani

{"title":"Evaluation of cytotoxicity of vesnarinone causing drug-induced agranulocytosis by a myeloperoxidase-like nonenzymatic metabolic approach using hypochlorous acid and application of the constructed assay method.","authors":"Toshihisa Koga, Yuko Sahara, Tadaaki Ohtani","doi":"10.2131/jts.51.239","DOIUrl":"10.2131/jts.51.239","url":null,"abstract":"The involvement of metabolism by myeloperoxidase (MPO) has been reported in drug-induced agranulocytosis (AG). In this study, we investigated whether MPO metabolic reactions could be nonenzymatically mimicked using hypochlorous acid (HClO) and HL-60 cells to generate the reactive metabolite of vesnarinone, a drug known to cause AG, and to detect its cytotoxicity. First, HClO is a strong radical agent and has a direct cytotoxic effect on cells. We tried to reduce its cytotoxicity by using dimethyl sulfoxide (DMSO), which is a solvent but also has the characteristics of a radical scavenger. Thus, the cytotoxicity disappeared when ≥ 20% DMSO was added against HClO. When vesnarinone was reacted under this condition, we observed its concentration-dependent cytotoxicity and converting vesnarinone into two metabolites (metabolite 1 and 2). Next, the presence of reduced glutathione protected its cytotoxicity and converted metabolite 2 into metabolite 1, which were consistent with the MPO reaction. Furthermore, we performed the assessment using this assay system utilizing 12 drugs with different AG incidences. The correlation diagram created between the clinical maximum plasma/serum concentration (Cmax) and the reciprocal concentration of 50% cell viability (1/CV50) was suggested that drugs with high Cmax (≥ 0.062 μg/mL) and strong cytotoxicity (CV50 ≤ 40.9 µM) were related to a clear probability incidence of AG. In conclusion, it was suggested that the constructed HClO test system can be applied to drugs with a clear probability incidence of AG.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 4","pages":"239-249"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592943","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

Toxicity of the novel mercury species α-mercuri-acetaldehyde and α-mercuri-acetic acid, in comparison with that of methylmercury, in rats. 新汞种α-汞-乙醛和α-汞-乙酸与甲基汞对大鼠的毒性比较

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.259

Yo Shinoda, Eiko Yoshida, Sachie Arae, Ryo Irie, Yuuki Fujimoto, Kaito Yamashiro, Tsutomu Takahashi, Yasuyuki Fujiwara, Toshiyuki Kaji

{"title":"Toxicity of the novel mercury species α-mercuri-acetaldehyde and α-mercuri-acetic acid, in comparison with that of methylmercury, in rats.","authors":"Yo Shinoda, Eiko Yoshida, Sachie Arae, Ryo Irie, Yuuki Fujimoto, Kaito Yamashiro, Tsutomu Takahashi, Yasuyuki Fujiwara, Toshiyuki Kaji","doi":"10.2131/jts.51.259","DOIUrl":"10.2131/jts.51.259","url":null,"abstract":"Methylmercury (MeHg) is a well-established environmental neurotoxicant and the primary cause of Minamata disease. Recently, α-mercuri-acetaldehyde (HgCH2CHO) and α-mercuri-acetic acid (HgCH2COOH) have been proposed to be relevant to the Minamata tragedy. However, their in vivo toxicity has not been compared with that of MeHg under identical conditions. We conducted a comparative in vivo toxicity study of HgCH2CHO and HgCH2COOH using the dosing regimen previously established for MeHg. Male Wistar rats were orally administered MeHg, HgCH2CHO, or HgCH2COOH (26.6 µmol/kg/day) for 5 days, which was followed by a 2-day drug-free period and a single repeat of this cycle. Systemic toxicity was evaluated using the change in body mass, neurobehavioral effects were assessed using the hindlimb crossing test, and the total mercury accumulation in blood and organs was quantified. MeHg exposure resulted in marked weight loss and significant neurobehavioral impairment. In contrast, rats exposed to HgCH2CHO or HgCH2COOH exhibited only mild weight loss and substantially attenuated hindlimb crossing responses. The total mercury levels in the blood, liver, brain, muscle, and spleen were considerably lower in the HgCH2CHO- and HgCH2COOH-treated groups than in the MeHg group. The renal accumulation of mercury did not differ among the groups, despite the blood mercury levels in the HgCH2CHO and HgCH2COOH groups being extremely low, suggesting distinct toxicokinetic properties. Overall, HgCH2CHO and HgCH2COOH demonstrated much lower in vivo toxicity and systemic mercury burden than MeHg under equivalent dosing conditions. These findings do not challenge the established role of MeHg as the primary causative agent of Minamata disease.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 4","pages":"259-266"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592981","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

Visually evoked potentials as an early indicator of acrylamide-induced visual dysfunction in rats. 视觉诱发电位作为丙烯酰胺诱导的大鼠视觉功能障碍的早期指标。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.295

Kensuke Kawamoto, Yukako Shimotsuma, Kazunari Okada, Satoki Fukunaga, Hiroyuki Asano

{"title":"Visually evoked potentials as an early indicator of acrylamide-induced visual dysfunction in rats.","authors":"Kensuke Kawamoto, Yukako Shimotsuma, Kazunari Okada, Satoki Fukunaga, Hiroyuki Asano","doi":"10.2131/jts.51.295","DOIUrl":"10.2131/jts.51.295","url":null,"abstract":"Humans rely heavily on visual function to gather information, and loss of vision has a significant impact on quality of life. However, it is difficult to quantitatively evaluate the effects of chemical compounds on visual function in toxicity studies using animals (such as OECD guideline studies). Consequently, evaluation including ophthalmological and histopathological examinations has played a major role to date. Visually evoked potential (VEP) is a type of brain wave that reflects the activity of the entire visual pathway, including the retina, optic nerve, and visual cortex. We investigated whether VEP could detect the effects of acrylamide, a toxicant known to affect peripheral nerves, on visual function. Acrylamide was administered to rats via drinking water at concentrations of 0 (control) and 200 ppm for 4 weeks, and electroretinograms (ERGs) and VEPs were recorded at weeks 0, 2, and 4. After the 4-week treatment period, the eyes and optic nerves were examined by light microscope. Acrylamide exposure significantly delayed VEP latency, while no effects were observed on the retina and optic nerve by ERG or histopathology. A significant decrease in grip strength in the hindlimbs and degeneration of sciatic nerve fibers were observed in the acrylamide-treated group, indicating that acrylamide damaged peripheral nerves. In conclusion, our study demonstrated that VEP can detect the effects of acrylamide on visual function earlier than histopathological examination, suggesting that VEP could be useful for detecting early-phase effects of chemical compounds on visual function and for evaluating whether morphological changes observed in toxicity studies are toxicologically significant.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 5","pages":"295-302"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839784","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

A case study of virtual control group verification using historical control data at a single facility. 使用单个设施的历史控制数据进行虚拟控制组验证的案例研究。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.339

Yuichiro Amano, Hideto Hara, Ikuro Takakura, Takashi Tanaharu, Keiko Motoyama, Satomi Nishikawa, Takao Kurooka, Kuniyoshi Sakai, Gen Sato, Kiyohiro Hashimoto, Mutsumi Suzuki

{"title":"A case study of virtual control group verification using historical control data at a single facility.","authors":"Yuichiro Amano, Hideto Hara, Ikuro Takakura, Takashi Tanaharu, Keiko Motoyama, Satomi Nishikawa, Takao Kurooka, Kuniyoshi Sakai, Gen Sato, Kiyohiro Hashimoto, Mutsumi Suzuki","doi":"10.2131/jts.51.339","DOIUrl":"10.2131/jts.51.339","url":null,"abstract":"In general toxicity studies in rodents, groups are initially assigned based on body weight, highlighting the importance of matching the body weights of test article groups when creating Virtual Control Groups (VCGs). In this study, we aimed to generate VCGs by linking toxicity parameters to initial body weights and to verify the significance of body-weight matching. The Concurrent Control Groups (CCGs) from nine 4-week rat studies at a single facility served as Historical Control Data (HCD). VCGs were generated by random sampling of initial body weights in HCD, and a ± 5 g range from the mean initial body weight of the test article group was used as the body-weight-matching criteria. VCGs were used to assess statistical differences in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and liver weight at the end of one specific study. Of the 10 VCGs generated, two had deviations of more than 5 g from the mean initial body weight value. Statistically significant differences in AST and ALT levels observed in CCGs tended to become non-significant in VCGs, regardless of the mean initial body weight of VCGs. Meanwhile, VCGs outside the ± 5 g range revealed new statistically significant differences in liver weight. Liver weight was weakly correlated with initial body weight, suggesting that deviations in initial body weight influenced the statistical significance of liver-weight differences at the end of the study. The importance of matching body weight in VCGs was confirmed, particularly for toxicity parameters that correlate with initial body weight values.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 6","pages":"339-348"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138420","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

Lysosomal membrane permeabilization and lysosomal damage induced by silica micro/nanoparticles in murine RAW-Blue macrophages. 二氧化硅微/纳米颗粒诱导小鼠RAW-Blue巨噬细胞溶酶体膜通透性和溶酶体损伤。

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.403

Dipankar Chandra Roy, Kenji Ono, Katsumi Fukamachi, Masumi Suzui

{"title":"Lysosomal membrane permeabilization and lysosomal damage induced by silica micro/nanoparticles in murine RAW-Blue macrophages.","authors":"Dipankar Chandra Roy, Kenji Ono, Katsumi Fukamachi, Masumi Suzui","doi":"10.2131/jts.51.403","DOIUrl":"https://doi.org/10.2131/jts.51.403","url":null,"abstract":"The objective of this study was to examine the mechanisms underlying endocytic uptake, cytotoxicity, oxidative stress, and lysosomal damage caused by silica micro/nanoparticles (SiPs) in murine RAW-Blue macrophages. In parallel studies, we also assessed the effects of NF-κB on lysosomal membrane permeabilization (LMP). Three types of SiPs, 3 μm-plain (3 μm diameter particles without surface modification), 50 nm-plain (50 nm diameter particles without surface modification), and 50 nm-NH2 (50 nm diameter particles with an amine functional group as surface modification) were tested. A significant decrease in cell proliferation and a significant increase in cell death were evident, when cells were treated with 50 nm-plain. All types of SiPs plus a lysosomal inhibitor caused a significant increase and a significant decrease in cell proliferation and cell death, respectively. When cells were treated with 50 nm-plain, puncta formation was seen. Treatment with 50 nm-plain significantly increased the expression level of inflammatory cytokine/chemokine genes, whereas inhibitors of clathrin-mediated endocytosis, lysosomal function, and cathepsin activity significantly attenuated these responses. Taken together, the present findings suggest that lysosomal dysfunction is closely associated with 50 nm-plain-induced cytotoxic and inflammatory responses. Our findings also provide relevant findings for safe and effective design of SiPs and a framework to maximize their biomedical potential while mitigating lysosomal damage.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 8","pages":"403-411"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664203","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