Journal of Toxicological Sciences最新文献

{"title":"Clinical features and outcomes of acute paracetamol poisoning in a resource-limited setting: observations from 96 patients in Vietnam.","authors":"Nguyen Dang Duc","doi":"10.2131/jts.51.149","DOIUrl":"https://doi.org/10.2131/jts.51.149","url":null,"abstract":"","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"149"},"PeriodicalIF":1.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early biomarker prognostic signals for 30-day mortality in acute poisoning: exploratory analysis of a complete-case subgroup from a derived MIMIC-IV dataset.","authors":"Ramazan Sami Aktaş, Mehmet Şirin Büyükkaya, Fatma Okucu, İdris Tüzün, Ömer Okucu","doi":"10.2131/jts.51.517","DOIUrl":"https://doi.org/10.2131/jts.51.517","url":null,"abstract":"<p><p>Reliable early prognostic tools for acute poisoning remain limited. This study examined whether four first-measured routine biomarkers - glucose, lactate, bicarbonate, and white blood cell count (WBC) - carry prognostic signal for 30-day mortality in emergency department (ED) patients with acute poisoning, using a pre-processed, de-identified electronic health records dataset derived from MIMIC-IV (Medical Information Mart for Intensive Care, version 3.1; a publicly available critical care database from Beth Israel Deaconess Medical Center, Boston, USA, hosted on PhysioNet; n=12,039 ED visits; 59 deaths; 30-day mortality 0.49%). Due to extreme non-random missingness across all four biomarkers (lactate 95.2%; bicarbonate/glucose/WBC 88-89%), multivariable modelling was restricted to a complete-case subgroup (n=503; deaths=19). This subgroup was markedly non-representative: intensive care unit (ICU) admission rate 66.4% versus 2.1% in excluded visits (standardised mean difference [SMD]=1.844), reflecting selective laboratory ordering in clinically severe patients. In univariable analyses across available cases, all four biomarkers were significantly associated with 30-day mortality. Within the complete-case subgroup, glucose alone demonstrated good discrimination (area under the receiver operating characteristic curve [AUROC]=0.812; 95% confidence interval [CI] 0.721-0.885), and glucose and WBC were independently associated with mortality in multivariable analysis (adjusted odds ratios [aOR] 1.05 and 1.13, respectively). The calibration slope of 0.646 for the primary four-biomarker model indicated systematic overestimation of absolute risk. These findings are strictly exploratory. Critical limitations - extreme non-random missingness, ICU-enriched complete-case subgroup, absent age and vital signs, low event count (n=19), and absence of external validation - preclude clinical application. This work defines data and design requirements for a future adequately powered prospective prognostic study in acute poisoning.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 9","pages":"517-525"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypharmacological neurotoxic effects of methylisothiazolinone revealed by integrated in vitro and network-based chemoinformatics approaches.","authors":"Gül Küçükkahraman, Özge Sultan Zengin, Mohammed T Qaoud, Merve Arici, Gül Özhan","doi":"10.2131/jts.51.471","DOIUrl":"https://doi.org/10.2131/jts.51.471","url":null,"abstract":"<p><p>Methylisothiazolinone (MIT) is a widely used biocidal preservative in industrial and cosmetic products. However, evidence of its neurotoxic effects is limited, and the mechanistic pathways are poorly defined. This study investigated the neurotoxic potential of MIT and the molecular mechanisms underlying its cellular toxicity in SH-SY5Y cells. After exposing SH-SY5Y cells to MIT various concentrations (30 to 120 μM) for 24 hr, apoptosis and inflammatory responses were quantified alongside the determination of apoptotic-, oxidative stress-, cell survival-, and angiogenic-related biomarkers. To reinforce the experimental findings, a set of in silico chemoinformatics studies, including network toxicology and molecular docking were conducted to pinpoint and evaluate the potential molecular targets of MIT. The IC₅₀ value of MIT was found 115 µM. Total apoptotic cells increasing to 56.5% at 120 µM. ELISA results indicated activation of the intrinsic apoptotic pathway, evidenced by significant upregulation of p53 (9.54-fold), BAX (4.52-fold), and APAF-1 (8.85-fold), along with a disruption in the BAX/BCL-2 (4.52/4.37-fold) balance. Furthermore, an elevation in the COX/COX-2 (8.04/6.93-fold), SRC (7.08-fold), and VEGFR2 (20.96-fold) levels which indicated the concurrent oxidative stress and stress-induced pro-survival signaling at 120 µM. MIT selectively amplified some inflammatory mediators, suggesting inflammasome-driven neuroinflammation. In silico analysis further support MIT as a polypharmacological toxicant with the potential to modulate key molecular targets, including PARP-1, GSK-3β, and iNOS. MIT induced multifaceted neurotoxicity in SH-SY5Y cells through the simultaneous activation of intrinsic apoptotic signaling, oxidative stress, and selective neuroinflammatory pathways. The findings emphasize the potential neurotoxic risks associated with MIT exposure and underscore the necessity for strengthened regulatory evaluation and in vivo validation.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 9","pages":"471-487"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental studies.","authors":"Hiroyasu Sakai, Risako Kon, Nobutomo Ikarashi, Kumiko Ogawa","doi":"10.2131/jts.51.379","DOIUrl":"https://doi.org/10.2131/jts.51.379","url":null,"abstract":"<p><p>Cisplatin is a widely used platinum-based chemotherapeutic agent whose dose-limiting toxicities, including nephrotoxicity, neurotoxicity, and myelosuppression, have been extensively characterized. In contrast, skeletal muscle has not traditionally been regarded as a primary target of cisplatin toxicity. However, accumulating experimental evidence indicates that cisplatin administration leads to a significant reduction in skeletal muscle mass and fiber size, even in the absence of tumor burden or overt cachexia. These findings suggest that cisplatin itself can directly induce skeletal muscle atrophy as a form of drug-induced toxicity. Animal and cell-based studies have demonstrated that cisplatin activates catabolic signaling in skeletal muscle, most notably through enhanced protein degradation via the ubiquitin-proteasome system. This response is accompanied by increased expression of muscle-specific E3 ubiquitin ligases, including muscle RING finger 1 (MuRF1) and muscle atrophy F-box protein (MAFbx/atrogin-1), which are established mediators of skeletal muscle atrophy. In parallel, suppression of anabolic signaling, particularly impairment of the insulin-like growth factor-1/Akt/mechanistic target of rapamycin complex 1 (mTORC1) pathway, has been reported, indicating a shift in muscle protein turnover toward a catabolic state. Recent studies suggest that cellular stress responses, such as endoplasmic reticulum stress, may be involved in regulating these processes. This review summarizes experimental evidence supporting cisplatin-induced skeletal muscle atrophy and discusses the underlying toxicological processes from a muscle-centered perspective. By distinguishing drug-induced muscle toxicity from cancer cachexia and other wasting conditions, we propose that skeletal muscle should be recognized as a clinically relevant but underestimated target organ of cisplatin toxicity. Improved understanding of these processes may support the development of strategies to preserve muscle mass and function during cancer chemotherapy.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 7","pages":"379-391"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148368861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a decision flow-based read-across approach for assessing skin sensitization using publicly available tools.","authors":"Yuri Hatakeyama, Kosuke Imai, Hayato Nishida, Shiho Oeda, Tomomi Atobe, Morihiko Hirota","doi":"10.2131/jts.51.501","DOIUrl":"https://doi.org/10.2131/jts.51.501","url":null,"abstract":"<p><p>Animal tests like the guinea pig maximization test (GPMT) and murine local lymph node assay (LLNA) were historically used to assess skin sensitization in cosmetics. The EU banned animal testing for cosmetics in 2013, prompting the development of alternative in vitro methods and new approach methodologies (NAMs) based on adverse outcome pathways (AOPs). These NAMs are integrated into Defined Approaches (DAs) to evaluate skin sensitization hazards and potency, which challenge is incorporating them into next-generation risk assessment (NGRA) frameworks. To address this challenge, we aim to achieve quantitative risk assessment in humans. The NGRA framework proposed by Cosmetics Europe emphasizes read-across methods, which predict toxicity using data from similar substances. This approach, which utilizes data from analogues, is described as an effective way to reduce uncertainty in risk assessment. This paper proposes a transparent read-across method using the OECD QSAR Toolbox, ranked by reliability based on structural similarity, protein binding, sensitization alerts, and percutaneous absorption. The sensitization data of the extracted analogues prioritize the LLNA EC3 values, followed by predicted EC3 values from Derek nexus or GPMT data. A case study using p-isobutyl-α-methyl hydrocinnamaldehyde confirmed the target's classification as a moderate sensitizer. The proposed method ensures transparency by relying on publicly available tools, reducing uncertainty in NGRA.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 9","pages":"501-515"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aged black garlic-derived S-allyl-L-cysteine serves as a dietary precursor for supersulfide production by cystathionine γ-lyase.","authors":"Shoma Araki, Takahisa Nakane, Yasuo Watanabe, Yukihiro Tsuchiya","doi":"10.2131/jts.51.557","DOIUrl":"https://doi.org/10.2131/jts.51.557","url":null,"abstract":"<p><p>S-allyl-L-cysteine (SAC) is a major bioactive compound in aged black garlic with multiple pharmacological benefits, including antioxidant and neuroprotective effects; however, the underlying molecular mechanisms of these benefits remain unclear. In our previous study, we demonstrated that cystathionine γ-lyase (CSE), a sulfur-containing amino acid-metabolizing enzyme involved in the transsulfuration pathway, metabolizes S-nitroso-L-cysteine via a C-S lyase reaction. In this study, we investigated whether CSE-mediated metabolism is involved in the physiological effects of various cysteine derivatives, including SAC. We evaluated the potential of a series of S-alkylcysteine derivatives with varying alkyl chain lengths and degrees of unsaturation as CSE substrates. Recombinant CSE experiments revealed that thiol compounds were produced from propyl derivatives, whereas supersulfides were generated from ethyl, propyl, and allyl derivatives. Kinetic analysis demonstrated that the allyl derivative exhibited a stronger substrate affinity than the propyl derivative, similar to that of the endogenous substrate cystathionine. This study suggests a novel molecular basis for CSE-mediated metabolism and subsequent supersulfide production, which contributes to the diverse health-promoting effects of SAC in mammalian tissues.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 10","pages":"557-563"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149111515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Air pollution and COPD: Unveiling the mechanisms through network toxicology and transcriptomics.","authors":"Dong Song, Lin Xie, Xuege Gao, Yushan Chen, Chunjun Zhong, Huicong Li, Shaofeng Zhan, Leshen Lian","doi":"10.2131/jts.51.275","DOIUrl":"10.2131/jts.51.275","url":null,"abstract":"<p><p>Over the past five decades, air pollution has posed a growing threat to human health, particularly affecting the respiratory system. This study aims to investigate the potential molecular mechanisms underlying the relationship between exposure to air pollutants and the development of COPD and to identify potential gene targets that may play a key role in this process. In this study, researchers used several publicly available databases to obtain target genes related to air pollutants and COPD, determine the overlapping genes between them and performed GO and KEGG enrichment analyses to elucidate the underlying mechanisms. Cross-validation was performed using multiple datasets from the Gene Expression Omnibus (GEO) database to screen out candidate targets, and molecular docking techniques were utilized to investigated molecular interactions between candidate targets and air pollutants. Candidate targets were subsequently validated and analyzed using immune cell infiltration analysis, single-cell transcriptome data, risk prediction model construction and clinical data to further elucidate their relationship with COPD. Findings suggest that HDAC9, DPP9 and KCNN4 are candidate targets of air pollutants that are potentially involved in COPD development. These results offer new insights into the potential molecular mechanisms linking air pollution exposure to COPD and underscore the need for further in-depth research on air pollution issues.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 4","pages":"275-294"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitivity of respiratory cell lines to unsaturated carbonyl compounds in cigarette smoke is regulated by intracellular glutathione.","authors":"Tsunehito Higashi, Fumito Naganuma, Yosuke Mai, Haruka Handa, Katsumi Maenaka, Takashi Tadokoro, Takeo Yoshikawa","doi":"10.2131/jts.51.357","DOIUrl":"10.2131/jts.51.357","url":null,"abstract":"<p><p>Cigarette smoking is a risk factor for various diseases, including chronic obstructive pulmonary disease (COPD). Cell death induced by cigarette smoke is one of the underlying causes of COPD. Unsaturated carbonyl compounds, such as acrolein and methyl vinyl ketone, are major cytotoxic factors in the gas phase of cigarette smoke. To elucidate the molecular mechanisms for induction of cell death by the unsaturated carbonyl compounds in respiratory cells, two lung cancer cell lines, A549 cells and SBC-3 cells, were exposed to the unsaturated carbonyl compounds. A549 cells were resistant to the unsaturated carbonyl compounds, while SBC-3 cells were sensitive to these compounds. Pharmacological analyses revealed that these compounds induce protein kinase C-dependent ferroptosis in SBC-3 cells. Inhibition of glutathione (GSH) synthesis increased the sensitivity of A549 cells to unsaturated carbonyl compounds. GSH level in A549 cells was approximately four times higher than that in SBC-3 cells. Inhibition of SLC7A11, a cystine transporter, in A549 cells increased their sensitivity to unsaturated carbonyl compounds, while overexpression of SLC7A11 in SBC-3 cells decreased their sensitivity to these compounds. These results indicate that the GSH synthetic capacity determines cell sensitivity to unsaturated carbonyl compounds. Accordingly, GSH may be a key factor for the pathogenesis of cigarette smoke-induced COPD.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 6","pages":"357-366"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triphenyl phosphate-induced cell injury through endoplasmic reticulum stress in human kidney cells.","authors":"Hejun Duan, Liyu Huang, Yixing Feng","doi":"10.2131/jts.51.215","DOIUrl":"10.2131/jts.51.215","url":null,"abstract":"<p><p>Triphenyl phosphate (TPhP) is a typical organophosphorus flame retardant (OPFR). Due to its high production and widespread use, exposure to TPhP has been shown to induce nephrotoxicity in animal models. Endoplasmic reticulum (ER) stress is found to be correlated with kidney disease caused by exogenous environmental pollutants. Nevertheless, the connection between ER stress and the nephrotoxic effects caused by TPhP is limited. In this study, human renal tubular epithelial cells (HKC) were chosen to explore the effects of TPhP on cell viability, cell apoptosis, and ER stress. Our study indicated that cell viability was dramatically inhibited in a dose-dependent manner. The half lethal concentration (LC₅₀) value of TPhP after 48 hr exposure is 126.4 µM. A concentration-related Caspase-3 activation and apoptosis occurrence were observed in HKC cells following TPhP treatment. Additionally, the induction of ER stress was demonstrated by the up-regulated expression of ER stress-related genes. To elucidate the role of ER stress in cell damage, sodium 4-phenylbutyrate (4-PBA), an ER stress inhibitor, was used in the co-treatment with TPhP. Results revealed that 4-PBA treatment effectively alleviated TPhP-induced ER stress and cytotoxicity in HKC cells. Taken together, these results indicated that ER stress plays a primary role in TPhP-induced nephrocyte damage and 4-PBA could attenuate these effects.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 3","pages":"215-225"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal low-dose MeHg exposure leads to proteomic and transcriptomic alterations consistent with neurodegenerative disease in the cerebellum of C57BL/6 mice.","authors":"Allison Loan, Rochelle D'Mello, Yingxi Li, Tuana Nurkan, Zoran Minic, Jing Wang, Hing Man Chan","doi":"10.2131/jts.51.89","DOIUrl":"10.2131/jts.51.89","url":null,"abstract":"<p><p>Methylmercury (MeHg) is a global pollutant that readily crosses the blood-brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90-120 (P90-120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.</p>","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"51 2","pages":"89-100"},"PeriodicalIF":1.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100316","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}