J Toxicol Sci [JOURNAL]
Sun
200 papers
Linalool inhalation‒induced anxiety-like effects occur independently of olfactory input and require cytochrome P450 activity.
Sato H, Oguro A, Miyara M … +1 more , Kotake Y
J Toxicol Sci · 2026 · PMID 42386544 · Publisher ↗
Multiple chemical sensitivity (MCS) is characterized by neuropsychological symptoms including anxiety, depression, and fatigue following exposure to environmental chemicals, yet its underlying mechanisms remain poorly un...
Multiple chemical sensitivity (MCS) is characterized by neuropsychological symptoms including anxiety, depression, and fatigue following exposure to environmental chemicals, yet its underlying mechanisms remain poorly understood. Linalool, a monoterpene alcohol widely used in consumer products, has been suggested as a potential contributor to MCS. To elucidate its neural effects, we examined the behavioral effects of linalool inhalation in mice. Linalool exposure induced both anxiety- and depression-like behaviors. While the depression-like behavior required olfactory input, the anxiety-like behavior occurred independently of olfactory perception. Our previous studies demonstrated that inhaled linalool accumulates in the brain and undergoes cytochrome P450 (P450)-dependent metabolism. We therefore tested whether P450-mediated metabolism contributes to the behavioral effects of linalool. Significantly, inhibition of P450 activity abolished the anxiety-like behavior. These findings reveal an olfactory-independent mechanism by which inhaled linalool induces anxiety-like behavior in mice and suggest that P450 activity is required for this effect, providing a basis for investigating fragrance-induced MCS-like neurobehavioral responses.
Protein homeostasis disruption in cisplatin-induced skeletal muscle atrophy: toxicological insights from experimental studies.
Sakai H, Kon R, Ikarashi N … +1 more , Ogawa K
J Toxicol Sci · 2026 · PMID 42386543 · Publisher ↗
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 m...
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.
A high-fat/high-sucrose/high-cholesterol diet leads to early indications of metabolic dysfunction-associated steatohepatitis-like lesions in obese diabetic mice.
Uno K, Shirasaka K, Muro Y … +11 more , Kuroki F, Nishida M, Yamaguchi K, Mandai K, Sekiguchi K, Sasase T, Shinohara M, Sugimoto M, Maekawa T, Miyajima K, Ohta T
J Toxicol Sci · 2026 · PMID 42386542 · Publisher ↗
Chronic hyperlipidemia and/ or hyperglycemia can impair various organs, such as the liver, kidney, and pancreas, through metabolic abnormalities. Metabolic dysfunction-associated steatohepatitis (MASH), related from nona...
Chronic hyperlipidemia and/ or hyperglycemia can impair various organs, such as the liver, kidney, and pancreas, through metabolic abnormalities. Metabolic dysfunction-associated steatohepatitis (MASH), related from nonalcoholic steatohepatitis (NASH), exhibits complex pathophysiological features, and animal models of MASH are essential for elucidating its underlying mechanisms. This study aimed to induce MASH-like lesions in obese type 2 diabetic mice by feeding them a high-fat/high-sucrose/high-cholesterol (HFSC) diet. C57BL/6J, db/db, and KK-Ay mice at 6 weeks of age were fed an HFSC diet for 8 weeks. Collected samples were subjected to hematobiochemical, gene expression, and histopathological analyses. At 14 weeks of age, both diabetic mouse models showed hyperglycemia and hyperlipidemia, with hypercholesterolemia observed in HFSC-fed groups. HFSC-fed db/db and KK-Ay mice showed increased hepatic steatosis, and KK-Ay mice also showed partial hepatic fibrosis in pericentral venous and perivascular areas. mRNA analysis revealed upregulation of hepatic genes involved in lipid synthesis, inflammation, and fibrosis in diabetic mice fed the HFSC diet. Obese type 2 diabetic mice fed a high-fat/high-sucrose/high-cholesterol diet showed early indications of MASH-like lesions, supporting their utility as MASH animal models.
Sensitivity of respiratory cell lines to unsaturated carbonyl compounds in cigarette smoke is regulated by intracellular glutathione.
Higashi T, Naganuma F, Mai Y … +4 more , Handa H, Maenaka K, Tadokoro T, Yoshikawa T
J Toxicol Sci · 2026 · PMID 42219359 · Publisher ↗
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 compoun...
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.
Virtual internal exposures of lansoprazole administered to cytochrome P450 2C19 poor metabolizers estimated by simplified physiologically based pharmacokinetic modeling.
Shimizu M, Adachi K, Shimura Y … +4 more , Ohyama K, Tanaka Y, Saito Y, Yamazaki H
J Toxicol Sci · 2026 · PMID 42219358 · Publisher ↗
Although the importance of polymorphic cytochrome P450 2C19 (CYP2C19) in the metabolism of proton pump inhibitors is well recognized, genotyping patients for CYP2C19 before prescribing proton pump inhibitors is not curre...
Although the importance of polymorphic cytochrome P450 2C19 (CYP2C19) in the metabolism of proton pump inhibitors is well recognized, genotyping patients for CYP2C19 before prescribing proton pump inhibitors is not currently recommended in some Asian countries. Adverse events in patients prescribed 30-mg lansoprazole alone have been reported in the Japanese Adverse Drug Event Report database. This study aimed to evaluate virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers using a simplified physiologically based pharmacokinetic (PBPK) model. The input parameters for the simplified PBPK model were based on reported plasma concentrations for 30-mg lansoprazole. For poor metabolizers, the in vivo hepatic intrinsic clearance value was reduced from 13.4 L/hr to 3.4 L/hr. For comparison, a population-based (full) model was used based on the incorporated parameters for lansoprazole (latest Simcyp Simulator version 25). High virtual plasma and hepatic maximum concentrations and the areas under the concentration-time curves of lansoprazole in the poor metabolizers were generated by the simplified and full PBPK models. These results suggest that virtual internal exposure to lansoprazole in CYP2C19 poor metabolizers can be evaluated using PBPK modeling systems. Despite the limited references to CYP2C19 polymorphisms in current Asian drug labeling, such in silico information could be informative.
A case study of virtual control group verification using historical control data at a single facility.
Amano Y, Hara H, Takakura I … +8 more , Tanaharu T, Motoyama K, Nishikawa S, Kurooka T, Sakai K, Sato G, Hashimoto K, Suzuki M
J Toxicol Sci · 2026 · PMID 42219357 · Publisher ↗
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...
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.
A novel ICP-MS strategy identifies arsenite as an inhibitor of selenocysteine-tRNA charging.
Takashima H, Makino R, Taguchi H … +6 more , Takenaka Y, Akiyama Y, Tomikoka Y, Sumi D, Toyama T, Saito Y
J Toxicol Sci · 2026 · PMID 42219356 · Publisher ↗
Arsenite (As(III)) is a widespread environmental contaminant that increases susceptibility to oxidative stress. We recently reported that As(III) suppresses the induction of glutathione peroxidases (GPx) by various selen...
Arsenite (As(III)) is a widespread environmental contaminant that increases susceptibility to oxidative stress. We recently reported that As(III) suppresses the induction of glutathione peroxidases (GPx) by various selenium sources in cultured cells; however, its underlying mechanism remains unclear. GPx contains a selenocysteine (Sec) residue essential for catalytic activity, and Sec biosynthesis requires multiple steps of selenium metabolism. Selenite is directly incorporated into the Sec biosynthetic pathway via selenophosphate synthetase 2 (SEPHS2) and utilized for Sec-tRNA formation. Because Sec-tRNA decodes UGA codons, impaired synthesis of Sec-tRNA leads to nonsense-mediated decay or truncated translation of selenoprotein mRNAs. Here, we developed an inductively coupled plasma (ICP)-MS based method to evaluate Sec-tRNA and found that As(III) inhibits Sec charging of tRNA. As(III) markedly suppressed GPx protein induction with minimal effects on mRNA abundance. As(III) did not affect total tRNA levels; however, As(III) significantly decreased RNA-bound selenium released by deacylation, indicating reduced Sec-tRNA formation. These results suggest that As(III) impairs selenoprotein translation by inhibiting Sec charging of tRNA.
Ordinal association between cytochrome P450 inhibition and hepatotoxicity severity in rats.
Uchida N, Shibata M, Ooka A … +3 more , Shizu R, Takeshita JI, Yoshinari K
J Toxicol Sci · 2026 · PMID 42091496 · Publisher ↗
Cytochrome P450s (P450s) are essential for xenobiotic metabolism, and their inhibition is associated with chemical-induced liver toxicity. While qualitative associations between P450 inhibition and hepatotoxicity have be...
Cytochrome P450s (P450s) are essential for xenobiotic metabolism, and their inhibition is associated with chemical-induced liver toxicity. While qualitative associations between P450 inhibition and hepatotoxicity have been reported, the quantitative relationship between the degree of inhibition and the severity of hepatotoxicity remains unclear. In this study, we explored the quantitative association between P450 inhibition and hepatotoxicity using lowest observed effect levels (LOELs) from rat repeated-dose toxicity (RDT) studies on 326 chemicals. Inhibitory activities against seven rat P450 isoforms were compared between compounds positive and negative for six liver-related group endpoints (gEPs). The results revealed that inhibitory activity against CYP1A1, CYP2B1, CYP2C6, and CYP3A2 was significantly higher in compounds positive for hepatocellular hypertrophy or dyslipidemia than in negative compounds. Although regression analyses did not show clear linear relationships between P450 inhibition and LOELs, nonparametric trend tests revealed modest monotonic associations, with increased P450 inhibition corresponding to lower LOELs. To identify structural factors influencing inhibition among highly toxic compounds, we compared molecular descriptors between those exhibiting strong or weak P450 inhibition. Descriptors related to aqueous solubility, Verhaar baseline toxicity, and structural complexity were consistently higher in the weak-inhibition group across multiple P450-gEP combinations. These findings suggest that inhibition of CYP1A1, CYP2B1, CYP2C6, and CYP3A2 partly contributes to the severity of hepatocellular hypertrophy and dyslipidemia, whereas highly toxic compounds with low P450 inhibition may exert their toxicity through P450-independent mechanisms.
Synergistic toxicity of methylmercury and cadmium through NRF2 suppression and mercury retention.
Takanezawa Y, Suda N, Orimo N … +4 more , Nakamura R, Ohshiro Y, Uraguchi S, Kiyono M
J Toxicol Sci · 2026 · PMID 42091495 · Publisher ↗
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 c...
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.
Effect of zwitterionic liquids on cytochrome P450 and P-glycoprotein.
Kubota Y, Funaki R, Sana Y … +4 more , Ishizaki T, Wong RW, Hirata E, Kuroda K
J Toxicol Sci · 2026 · PMID 42091494 · Publisher ↗
OEimCC, a zwitterionic ionic liquid, has attracted considerable attention as a low-toxicity solvent. However, the effects of OEimCC on the pharmacokinetics of drugs have not yet been investigated. In this study, we exami...
OEimCC, a zwitterionic ionic liquid, has attracted considerable attention as a low-toxicity solvent. However, the effects of OEimCC on the pharmacokinetics of drugs have not yet been investigated. In this study, we examined the effects of OEimCC on p-glycoprotein (P-gp) and cytochrome P450 (CYPs), typical factors associated with pharmacokinetic interactions. No notable inhibition of P-gp by OEimCC was observed at the tested concentrations. OEimCC inhibited several CYPs (IC:0.048-0.66 vol% for 70 wt% aq OEimCC stock solution) and induced the gene expression of several CYPs. Based on these findings, practical guidance for the use of OEimCC was proposed here. A previous study suggested that OEimCC does not penetrate the cell membrane, and therefore, we had hypothesized that it does not inhibit CYPs inside cells. However, OEimCC inhibited CYPs. The related transporter was assumed to be organic cation transporter 1 (OCT1). These results suggest that OEimCC effect on CYPs should be considered in both in vitro and in vivo experiments. The CYP inhibition was alleviated through structural modification of OEimCC.
Visually evoked potentials as an early indicator of acrylamide-induced visual dysfunction in rats.
Kawamoto K, Shimotsuma Y, Okada K … +2 more , Fukunaga S, Asano H
J Toxicol Sci · 2026 · PMID 42091493 · Publisher ↗
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 visua...
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.
Air pollution and COPD: Unveiling the mechanisms through network toxicology and transcriptomics.
Song D, Xie L, Gao X … +5 more , Chen Y, Zhong C, Li H, Zhan S, Lian L
J Toxicol Sci · 2026 · PMID 41922271 · Publisher ↗
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 relati...
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.
Hydrogen sulfide donor GYY4137 attenuates RANKL-induced osteoclast differentiation and multi-nucleation.
Takagi T, Inoue H, Morimoto H … +2 more , Takahashi N, Uehara M
J Toxicol Sci · 2026 · PMID 41922270 · Publisher ↗
Hydrogen sulfide (HS) is a novel gasotransmitter produced in mammalian cells and is known to various regulate physiological functions. Previous study reported that an imbalance in HS metabolism is associated with defecti...
Hydrogen sulfide (HS) is a novel gasotransmitter produced in mammalian cells and is known to various regulate physiological functions. Previous study reported that an imbalance in HS metabolism is associated with defective bone homeostasis. However, the detailed mechanism of how HS affect osteoclast differentiation remains unclear. In the present study, we demonstrated that the effect of HS donor GYY4137 on osteoclast differentiation and multi-nucleation. Treatment of GYY4137 significantly decreased the number of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive cells and inhibited the expression of osteoclast-related genes, nuclear factor of activated T-cells 1 (NFATc1) and Cathepsin K(Ctsk). Additionally, the increased gene expression of dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast stimulatory transmembrane protein (OC-STAMP), and v-ATPase V0 subunit d2 (Atp6v0d2), which are cell-cell fusion-related molecules by RANKL treatment, was attenuated by GYY4137. Furthermore, GYY4137 suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK1/2, and p38MAPK, compared to RANKL-treated cells. Thus, our data suggested that HS donor GYY4137 as a novel osteoclast genesis inhibitor, significantly decreases osteoclast differentiation and multi-nucleation by inhibiting the expression of the cell-cell fusion molecules.
Toxicity of the novel mercury species α-mercuri-acetaldehyde and α-mercuri-acetic acid, in comparison with that of methylmercury, in rats.
Shinoda Y, Yoshida E, Arae S … +6 more , Irie R, Fujimoto Y, Yamashiro K, Takahashi T, Fujiwara Y, Kaji T
J Toxicol Sci · 2026 · PMID 41922269 · Publisher ↗
Methylmercury (MeHg) is a well-established environmental neurotoxicant and the primary cause of Minamata disease. Recently, α-mercuri-acetaldehyde (HgCHCHO) and α-mercuri-acetic acid (HgCHCOOH) have been proposed to be r...
Methylmercury (MeHg) is a well-established environmental neurotoxicant and the primary cause of Minamata disease. Recently, α-mercuri-acetaldehyde (HgCHCHO) and α-mercuri-acetic acid (HgCHCOOH) 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 HgCHCHO and HgCHCOOH using the dosing regimen previously established for MeHg. Male Wistar rats were orally administered MeHg, HgCHCHO, or HgCHCOOH (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 HgCHCHO or HgCHCOOH 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 HgCHCHO- and HgCHCOOH-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 HgCHCHO and HgCHCOOH groups being extremely low, suggesting distinct toxicokinetic properties. Overall, HgCHCHO and HgCHCOOH 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.
Considerations for infection risks identified in target safety review.
Amano Y, Inui Y, Yoshioka S … +1 more , Goodwin J
J Toxicol Sci · 2026 · PMID 41922268 · Publisher ↗
Target Safety Review (TSR) is a document that triggers the Target Safety Assessment and is designed to predict and identify on-target safety risks. However, with regard to the anticipated on-target risks extracted by TSR...
Target Safety Review (TSR) is a document that triggers the Target Safety Assessment and is designed to predict and identify on-target safety risks. However, with regard to the anticipated on-target risks extracted by TSR, nonclinical toxicity studies sometimes have limitations in predicting clinical safety risks. In this study, we investigated whether nonclinical toxicity studies could predict clinical infection risks expected in TSR. Using the OFF-X database, we identified 942 targets and 1323 drugs associated with infection risks. Through successive filters, i.e., applying "drug alert", "on-target", "causality with severity", "class score", and "evidence levels", biologics became the focus, resulting in six targets and 17 drugs approved by PMDA. From PMDA reports, package inserts, and interview forms, we extracted immune-related findings in nonclinical toxicity studies and infection risks in clinical settings to analyze predictivity by target. Our survey shows clear immune-related toxicity in nonclinical studies of CD20 inhibitors (obinutuzumab, ofatumumab, rituximab), TNF-alpha inhibitors (adalimumab, golimumab), and IL-6R antagonists (sarilumab, tocilizumab). Indicators included B cell depletion, thymus atrophy, and decreased neutrophils. For IL-17, IL-23, and IL-1beta inhibitors, nonclinical studies did not always predict the infection risks observed in clinical settings. Although nonclinical toxicity studies sometimes provided insights into potential infection risks which can be anticipated by its target, their predictive power for specific mechanism of actions and infections appeared limited. Understanding the MOAs and biological background of the drug through the TSR and identifying and mitigating risks early in the project are essential for the safe development of new therapeutic agents.
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.
Koga T, Sahara Y, Ohtani T
J Toxicol Sci · 2026 · PMID 41922267 · Publisher ↗
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 hypoc...
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 (C) and the reciprocal concentration of 50% cell viability (1/CV) was suggested that drugs with high C (≥ 0.062 μg/mL) and strong cytotoxicity (CV ≤ 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.
A zwitterionic solvent for in vitro toxicity tests of insoluble compounds.
Kubota Y, Hohsaka A, Hirata E … +1 more , Kuroda K
J Toxicol Sci · 2026 · PMID 41765461 · Publisher ↗
OEimCC, 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 uncl...
OEimCC, 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 OEimCC 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 OEimCC 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.
Triphenyl phosphate-induced cell injury through endoplasmic reticulum stress in human kidney cells.
Duan H, Huang L, Feng Y
J Toxicol Sci · 2026 · PMID 41765460 · Publisher ↗
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 retic...
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 (LC) 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.
Human erythropoietin mRNA as an impurity from a mRNA-LNP vaccine induces immune-mediated anemia in rats.
Murata Y, Kitamura S, Asaoka Y … +11 more , Kitahata S, Wakabayashi K, Kouno H, Kuroda N, Ishida K, Miki S, Sato T, Yoshida O, Kugimiya A, Yoshinaga T, Fukushima T
J Toxicol Sci · 2026 · PMID 41765459 · Publisher ↗
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...
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.
Neurotoxicity of acrylamide in wild-type and TNF-α depletion mice: possible alternative role of IL-6 and dipolar effects of TNF-α depletion on oxidative stress pathway.
Zong C, Sato H, Ichihara S … +3 more , Iwakura Y, Ohsako S, Ichihara G
J Toxicol Sci · 2026 · PMID 41765458 · Publisher ↗
Neurotoxicity of acrylamide has been demonstrated both in humans and animals, while the mechanisms remain largely unknown. We recently reported TNF-α deletion suppressed acrylamide-induced neurotoxicity in mice at low do...
Neurotoxicity of acrylamide has been demonstrated both in humans and animals, while the mechanisms remain largely unknown. We recently reported TNF-α deletion suppressed acrylamide-induced neurotoxicity in mice at low dose. Here we further investigated expression of antioxidant and proinflammatory cytokines to explore roles of TNF-α. Wild type and TNF-α KO mice were exposed to acrylamide at 0/12.5/25 mg/kg bw for 28 days. The results showed that acrylamide significantly decreased body weight at 12.5 and 25 mg/kg bw, but decreased brain weight only at 25 mg/kg bw. TNF-α deletion didn't alleviate the above effects. Also, TNF-α deletion didn't alleviate decrease of grip strength at 25 mg/kg bw. Immunohistochemical results showed that TNF-α deletion alleviated noradrenergic axon degeneration in cortex S1FL and S1HL regions at 12.5 mg/kg bw, but not 25 mg/kg bw. Moreover, TNF-α deletion suppressed acrylamide-induced upregulation of TGF-β and NF-κB, but didn't suppress upregulation of IL-6, suggesting possible roles of IL-6 in acrylamide-induced neurotoxicity, particularly at high concentration. Moreover, this study showed a dipolar effect of TNF-α deletion on oxidative stress pathways, i.e., at 25 mg/kg bw, TNF-α deletion suppressed upregulation of oxidative stress (Keap1/HO-1/Gclc/Gclm/Sod/Cat/Gstm/MT-1); however, at 12.5 mg/kg bw, TNF-α deletion accelerated upregulation of Nqo1/Gclm/Sod1/Cat/Gsr. Taken together, genetic TNF-α ablation, at least partially, alleviated acrylamide neurotoxicity at low concentration. Limited alleviation effects at high concentration generated a hypothesis that this may be due to IL-6 signaling and dipolar regulating effects of TNF-α deletion on oxidative stress pathway. This study provided new insights into acrylamide neurotoxicity and TNF-α-targeting strategy.
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