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 1.5 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":1.5,"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 1.5 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":1.5,"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

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 1.5 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":"https://doi.org/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":1.5,"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 1.5 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":"https://doi.org/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":1.5,"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 1.5 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":"https://doi.org/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":1.5,"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 preliminary evaluation of the applicability of the in vitro to in vivo extrapolation approach to quantitative risk assessment. 初步评价体外到体内外推法在定量风险评估中的适用性。

IF 1.5 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.7

Kikuo Yoshida, Takaaki Umano, Takashi Yamada, Mariko Matsumoto

{"title":"A preliminary evaluation of the applicability of the in vitro to in vivo extrapolation approach to quantitative risk assessment.","authors":"Kikuo Yoshida, Takaaki Umano, Takashi Yamada, Mariko Matsumoto","doi":"10.2131/jts.51.7","DOIUrl":"https://doi.org/10.2131/jts.51.7","url":null,"abstract":"The applicability of the in vitro to in vivo extrapolation (IVIVE) approach for the quantitative risk assessment of chemicals was evaluated using the results of mouse uterotrophic bioassays conducted by the Japanese Ministry of Health, Labour and Welfare. Five chemicals were selected. In the uterotrophic bioassay, three chemicals exhibited positive estrogenic activity, whereas two exhibited negative activity. These chemicals were active in 16 in vitro assays that investigated the key events from estrogen receptor (ER) binding (initiating event) to ER-induced proliferation, enabling us to derive IVIVE conversion factors using a physiologically based kinetic model. The oral equivalent doses (OEDs) that were extrapolated from the activity concentrations at the half-maximal response (AC50) and the cutoff point (ACC) were compared with those of other key events to determine the critical key event that plays the most important role in the occurrence of uterotrophic responses. For the three chemicals that exhibited positive estrogenic activity, the OEDs from the in vitro AC50 values for the determined critical events were within a factor of 2 of the lowest observed effect levels in the uterotrophic bioassay. In addition, the OEDs from the ACC values for the critical key events of the two chemicals that exhibited negative activity were higher than the highest dose tested in the bioassay. Based on these findings, the IVIVE approach was largely valid. However, the critical key events that significantly affect in vivo responses need to be appropriately determined to apply the IVIVE approach for the quantitative risk assessment of chemicals.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"7-18"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917887","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

Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells. 甲基汞通过抑制C17.2小鼠神经干细胞GPX4蛋白水平诱导铁下垂。

IF 1.5 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.101

Naoya Yamashita, Haruka Nozuki, Tomoshi Yamashita, Kyotaro Tsubaki, Ryoko Fukushima, Ryota Yamagata, Gi-Wook Hwang

{"title":"Methylmercury induces ferroptosis by suppressing GPX4 protein levels in C17.2 mouse neural stem cells.","authors":"Naoya Yamashita, Haruka Nozuki, Tomoshi Yamashita, Kyotaro Tsubaki, Ryoko Fukushima, Ryota Yamagata, Gi-Wook Hwang","doi":"10.2131/jts.51.101","DOIUrl":"https://doi.org/10.2131/jts.51.101","url":null,"abstract":"The causative agent of Minamata disease, which is characterized primarily by severe central nervous system dysfunction, is methylmercury; however, the mechanisms underlying methylmercury toxicity remain unclear. Ferroptosis is a type of programmed cell death that is mediated by iron-dependent lipid peroxidation and methylmercury has long been suggested to cause neuronal damage via lipid peroxidation, although the detailed mechanism of this action remains unknown. In this study we therefore investigated the involvement of ferroptosis in methylmercury-induced neuronal cell death using C17.2 mouse neural stem cells. First, we examined the effects of various ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, and deferoxamine) on methylmercury-induced cell death. All the inhibitors tested attenuated methylmercury-induced cell death. We then examined the levels of intracellular reactive oxygen species and lipid peroxides, and found that these levels were increased prior to methylmercury-induced cell death. We also examined the levels of a cystine transporter (xCT/SLC7A11) and glutathione peroxidase 4 (GPX4), major factors involved in the suppression of ferroptosis. We found that both mRNA and protein levels of xCT were increased prior to methylmercury-induced cell death, whereas GPX4 mRNA levels were largely unaffected by methylmercury and its protein levels were decreased. C17.2 cells overexpressing FLAG-GPX4 exhibited greater resistance to methylmercury than control cells. These results indicate that methylmercury induces ferroptosis in C17.2 cells by suppressing GPX4 protein levels.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"101-109"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100354","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

Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention. 甲基汞和镉通过NRF2抑制和汞滞留的协同毒性。

IF 1.5 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.315

Yasukazu Takanezawa, Narumi Suda, Nayu Orimo, Ryosuke Nakamura, Yuka Ohshiro, Shimpei Uraguchi, Masako Kiyono

{"title":"Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention.","authors":"Yasukazu Takanezawa, Narumi Suda, Nayu Orimo, Ryosuke Nakamura, Yuka Ohshiro, Shimpei Uraguchi, Masako Kiyono","doi":"10.2131/jts.51.315","DOIUrl":"https://doi.org/10.2131/jts.51.315","url":null,"abstract":"Methylmercury (MeHg) is a potent environmental toxicant that frequently coexists with other heavy metals, raising concerns about combined toxic effects. Increasing evidence indicates that co-exposure to multiple metals can lead to synergistic or greater-than-additive effects; however, the molecular mechanisms underlying such interactions remain poorly understood. Among the tested metals, only co-exposure with Cd markedly enhanced MeHg cytotoxicity. Here, our objective was to evaluate the impact of MeHg co-exposure on cytotoxicity of various heavy metals in HeLa cells. We used cell viability assays, western blot analysis, and reverse-transcription-quantitative polymerase chain reactions to determine toxicity. Co-treatment with MeHg significantly reduced cell viability compared with that of Cd alone. Mechanistically, MeHg suppressed nuclear factor erythroid 2-related factor 2 (NRF2) expression more strongly at earlier time points than Cd alone, thereby impairing antioxidant and detoxification responses. This suppression was accompanied by increased intracellular mercury (Hg) retention, leading to enhanced cytotoxicity. Our results provide a mechanistic basis for metal-metal interactions and highlight the importance of considering co-exposure scenarios in environmental risk assessment.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 5","pages":"315-320"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839807","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

Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy. 内质网应激反应在顺铂诱导的肌萎缩发展中的潜在参与。

IF 1.5 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.123

Shinki Soga, Hayato Nanri, Hiroyasu Sakai, Ryunosuke Ichikawa, Yuya Chigusa, Yui Urase, Shiori Yonamine, Takayuki Ogiwara, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Kumiko Ogawa

{"title":"Potential involvement of the endoplasmic reticulum stress response in the development of cisplatin-induced muscle atrophy.","authors":"Shinki Soga, Hayato Nanri, Hiroyasu Sakai, Ryunosuke Ichikawa, Yuya Chigusa, Yui Urase, Shiori Yonamine, Takayuki Ogiwara, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Tomoo Hosoe, Kumiko Ogawa","doi":"10.2131/jts.51.123","DOIUrl":"https://doi.org/10.2131/jts.51.123","url":null,"abstract":"Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents-cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide-on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"123-130"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100395","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

Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex. 犬肾上腺皮质类固醇生成中断引起的药物性空泡损伤恢复期的病理特征。

IF 1.5 4区医学

Journal of Toxicological Sciences Pub Date : 2026-01-01 DOI: 10.2131/jts.51.57

Ryo Daniel Obara, Yuki Kato, Yoshiji Asaoka, Hiroyuki Oka, Yukie Murata, Takeshi Izawa, Mitsuru Kuwamura

{"title":"Pathological features of the recovery phase in drug-induced vacuolar lesions caused by steroidogenesis disruption in the canine adrenal cortex.","authors":"Ryo Daniel Obara, Yuki Kato, Yoshiji Asaoka, Hiroyuki Oka, Yukie Murata, Takeshi Izawa, Mitsuru Kuwamura","doi":"10.2131/jts.51.57","DOIUrl":"https://doi.org/10.2131/jts.51.57","url":null,"abstract":"Steroidogenesis disruption caused by compounds causes vacuolar lesions in the adrenal cortex. However, research on the reversibility of compound-induced adrenal lesions remains limited. In a 4-week oral repeated-dose toxicity study with a 4-week recovery period in dogs, administration of S-637880-a compound that off-target inhibits steroid hormone synthesis in vitro-resulted in diffuse microvesicular vacuolation, which was considered to reflect excess lipid accumulation in adrenocortical cells. After the 4-week recovery period, these diffuse vacuolar lesions developed into characteristic multifocal macrovesicular vacuolation in the adrenal cortex, making it difficult to evaluate lesion reversibility. Immunohistochemical evaluation suggested that the histopathological changes observed after the recovery period reflected slow degeneration of lipid-laden adrenocortical cells, culminating in cell death accompanied by macrophage activation and aggregation to process apoptotic or necrotic cells and the liberated lipids. These findings are considered to represent a transitional phase in the recovery process. The reversibility of S-637880-induced vacuolar lesions was confirmed in a subsequent 13-week oral repeated-dose toxicity study with a 13-week recovery period. This case study may be helpful in evaluating the reversibility of vacuolar lesions in the adrenal cortex during nonclinical safety assessments and in determining an appropriate recovery periods for assessing adrenal toxicity.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 1","pages":"57-73"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917899","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