J Toxicol Sci [JOURNAL]
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200 papers
Paternal exposure to methylphenidate causes behavioral abnormalities in grandchildren.
Nakano R, Ikeda R, Yamazaki Y … +8 more , Munetomo-Aoki S, Morinaka H, Abe S, Isobe H, Hosonuma M, Kamijo S, Kaizaki-Mitsumoto A, Numazawa S
J Toxicol Sci · 2025 · PMID 40887248 · Publisher ↗
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is widely observed from childhood to adulthood and is treated with methylphenidate (MPH) as a first-line treatment. However, recent fi...
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is widely observed from childhood to adulthood and is treated with methylphenidate (MPH) as a first-line treatment. However, recent findings indicate that the paternal environment preceding conception may influence offspring health, potentially affecting subsequent generations. Moreover, we previously reported that MPH administration to sires reduced anxiety-related behaviors and induced memory impairments in the F1 generation. Therefore, in the present study, we investigated the effects of MPH exposure to sires on development, behavior, and brain gene expression in the F2 generation to extend our previous findings and examine the range of transgenerational effects. Although MPH exposure did not affect the number of births or survival rates, the body weight of mice in the MPH group was significantly lower than those in the control group. Additionally, motor development showed transient delays in early development but normalized by the age of weaning. Behavioral analysis further revealed a pronounced reduction in anxiety-like behaviors in the MPH group, particularly in female mice, with no effect on learning or memory. Finally, transcriptome analysis of the female cortex predicted the activation of neuroplasticity-related pathways, including the S100 family and CREB signaling. Notably, MPH was not administered to male F1 mice whose fathers had been administered MPH. Therefore, the ova of females mated with F1 males were not exposed to MPH. Nevertheless, the confirmation of behavioral abnormalities in the F2 generation strongly suggests that these abnormalities may have been induced by epigenetic changes in germ cells.
Variation and classification of chemically-induced zebrafish malformations for the ICH S5 (R3) guideline: an atlas for zebrafish teratogenesis.
Mori K, Aoki Y, Hayashi M … +10 more , Sugimoto W, Ono M, Umekita S, Niino T, Ebata T, Mikashima F, Maki K, Tanaka T, Hirata H, Kojima H
J Toxicol Sci · 2025 · PMID 40754437 · Publisher ↗
Exposure of embryos or fetuses to harmful substances, such as teratogens, can result in embryonic or fetal death and a wide range of malformations. Zebrafish models have emerged as a valuable tool for assessing developme...
Exposure of embryos or fetuses to harmful substances, such as teratogens, can result in embryonic or fetal death and a wide range of malformations. Zebrafish models have emerged as a valuable tool for assessing developmental toxicity and safety profiles of chemical compounds. Our previous research demonstrated that zebrafish larvae exhibit developmental abnormalities that mirror those observed in mammalian studies for more than 80% of the known Reference Compounds listed in the ICH S5 (R3) guideline. In this study, we presented high-resolution images depicting pharmaceutical-induced malformations across multiple anatomical regions, including the body axis, somites, notochord, fins, head, eyes, otoliths, jaw, heart, abdomen, and whole body. Frequent co-occurrence of specific defects, such as body axis and notochord malformations, was observed as described previously. Some physiological and morphological features, including heartbeat rate alterations and swim bladder inflation, were deemed dispensable for MEFL testing in zebrafish. Reproducibility was confirmed through inter-laboratory testing conducted both within our group and by other groups, supporting the reliability of zebrafish MEFL testing as an alternative approach in line with ICH S5 (R3).
Slow-releasing hydrogen sulfide donor GYY4137 induces epithelial-mesenchymal transition in A549 human lung adenocarcinoma cells.
Kajihara M, Aki T, Funakoshi T … +1 more , Unuma K
J Toxicol Sci · 2025 · PMID 40754436 · Publisher ↗
The slow-releasing hydrogen sulfide (HS) donor GYY4137 and A549 human alveolar epithelial cells were used to investigate HS toxicity in pulmonary epithelial cells. The cells were exposed to 0, 0.3, 1, or 3 mM GYY4137 for...
The slow-releasing hydrogen sulfide (HS) donor GYY4137 and A549 human alveolar epithelial cells were used to investigate HS toxicity in pulmonary epithelial cells. The cells were exposed to 0, 0.3, 1, or 3 mM GYY4137 for 6 days. Morphological changes, including cell death and transformation into spindle-shaped mesenchymal-like cells, were observed in cells exposed to 1 or 3 mM GYY4137. Transcriptome analysis of cells exposed to 3 mM GYY4137 for 6 days indicated ER stress and epithelial-mesenchymal transition (EMT), the latter confirmed by qRT-PCR, immunoblot, and immunocytochemical analyses. These results show the possible roles of EMT in the homeostasis of pulmonary epithelial cells during exposure to HS.
Testosterone contributes sex differences of urinary biomarkers for nephrotoxicity in rats.
Tsuji S, Hasegawa-Izaki A, Ogawa B … +1 more , Yamada H
J Toxicol Sci · 2025 · PMID 40754435 · Publisher ↗
Urinary biomarkers have been used widely in non-clinical toxicity studies to detect kidney dysfunction/injury caused by drugs under development. Although their usefulness to evaluate nephrotoxicity has been well studied,...
Urinary biomarkers have been used widely in non-clinical toxicity studies to detect kidney dysfunction/injury caused by drugs under development. Although their usefulness to evaluate nephrotoxicity has been well studied, knowledge about sex differences in the urinary excretion levels of these biomarkers remains inadequate. We previously demonstrated the existence of sex differences in the excretion levels of urinary biomarkers and that these differences were associated with the endogenous testosterone levels. In this study, testosterone was repeatedly administered subcutaneously to female rats for 4 weeks along with male rats as a comparison control, to investigate how the blood levels of testosterone contribute to the sex differences in the urinary biomarker and renal cortical protein levels. The results showed that the urinary excretion of leucine aminopeptidase (LAP), gamma-glutamyltransferase (γ-GTP), cystatin C (Cys-C), liver-type fatty acid binding protein (L-FABP), and beta2-microglobulin (β2MG) were increased, and the urinary excretion of kidney injury molecule 1 (Kim-1) was decreased. The protein level of megalin, an endocytic receptor, in the renal cortex, was higher in female rats than in male rats, and testosterone treatment led to decrease in the level in the female rats. Our results suggest that the blood testosterone level might be responsible for the sex differences in the urinary excretion levels of low-molecular-weight proteins via regulating the expression level of megalin in the renal cortex.
Optimisation of Photo-KeratinoSens™ for in vitro photoallergenicity assessment.
Atobe T, Chawapun S, Hatakeyama Y … +6 more , Oeda S, Ohtake T, Ashikaga T, Kouzuki H, Hirota M, Tamura A
J Toxicol Sci · 2025 · PMID 40754434 · Publisher ↗
The aim of this work was to develop and validate a cell-based in vitro assay for predicting photoallergenicity by expanding the scope of our previously reported in vitro method, photo-KeratinoSens™, which is a luciferase...
The aim of this work was to develop and validate a cell-based in vitro assay for predicting photoallergenicity by expanding the scope of our previously reported in vitro method, photo-KeratinoSens™, which is a luciferase-based assay dependent on activation of the Keap1-Nrf2-ARE pathway. First, we increased the maximum starting test concentration from a fixed 2000 µM in the original KeratinoSens™ to either 5000 μg/mL or 4 times the concentration providing a cell viability of 75% (under UV irradiation), depending on the cytotoxicity. Then, we established that 0.5% ethanol, 0.5% acetone and 0.1% tetrahydrofuran are available as solvents in addition to 1% DMSO, which is used in the standard KeratinoSens™ method (OECD TG442D). We confirmed that a representative photoallergen, 6-methylcoumarin, gave reproducible results. To validate the developed assay, we used it to evaluate a library of 90 chemicals consisting of 60 known photoallergens and 30 non-photoallergens. The accuracy, sensitivity, specificity and balanced accuracy of photo-KeratinoSens™ were 76.7% (69/90), 66.7% (40/60), 96.7% (29/30) and 81.7%, respectively. When we excluded chemicals with no UVA absorption, the accuracy, sensitivity, specificity and balanced accuracy were improved to 81.8% (45/55), 80.0% (36/45), 90.0% (9/10) and 85%, respectively. Our results suggest that photo-KeratinoSens™, which combines the OECD TG442D in vitro skin sensitization test detecting key event 2 in the adverse outcome pathway (AOP) of skin sensitization with exposure to UV iradiation, may be useful as a contributory input in a weight-of-evidence approach for evaluating photoallergenicity potential without animal testing.
Protocatechuic acid suppresses diethylnitrosamine-induced hepatic preneoplastic lesions by inhibiting phase I enzymes, reducing cell proliferation, and promoting apoptosis.
Punvittayagul C, Taya S, Luangsuphabool T … +1 more , Wongpoomchai R
J Toxicol Sci · 2025 · PMID 40754433 · Publisher ↗
Protocatechuic acid (PCA) is a phenolic compound naturally occurring in various plants. Although numerous studies have reported on its various biological activities, information on the anti-carcinogenic potential and its...
Protocatechuic acid (PCA) is a phenolic compound naturally occurring in various plants. Although numerous studies have reported on its various biological activities, information on the anti-carcinogenic potential and its molecular mechanisms in animal models has never been conclusively determined. Therefore, this study aimed to study the inhibitory effect of PCA against diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis. Rats received three intraperitoneal injections of 100 mg kg body weight of DEN to initiate hepatic preneoplastic lesions, and glutathione S-transferase placental form (GST-P)-positive foci were used as the end-point marker. Rats were treated with PCA at 40 mg kg body weight by oral gavage administration for 15 weeks to study its chemopreventive effect on the early stages of hepatocarcinogenesis. PCA treatment decreased the number and the area of hepatic GST-P-positive foci in DEN-induced rats. It inhibits the activity of cytochrome P450 reductase and reduces the expression of cytochrome P450 2E1 protein. It also suppresses cell proliferation by down-regulation of Cyclin D1 expression. Additionally, it induces apoptosis, as indicated by the up-regulation of pro-apoptotic genes, Bax and Bad, in DEN-induced rats. These findings suggest that PCA is an anti-cancer agent that inhibits hepatocarcinogenesis in DEN-treated rats.
Alteration of bile acid composition is a possible risk factor for antibiotics-induced liver injury.
Takemura A, Suminoe S, Hirai T … +4 more , Nakasone K, Hayasaki K, Song B, Ito K
J Toxicol Sci · 2025 · PMID 40754432 · Publisher ↗
Drug-induced liver injury (DILI), in rare instances, can become severe and lead to fatal outcomes; therefore, it is crucial to clarify the mechanisms underlying DILI. Antibiotics are well known to induce a high frequency...
Drug-induced liver injury (DILI), in rare instances, can become severe and lead to fatal outcomes; therefore, it is crucial to clarify the mechanisms underlying DILI. Antibiotics are well known to induce a high frequency of DILI. We hypothesized that alterations in the bile acid composition, owing to the destruction of enterobacteria, is one factor frequently associated with antibiotics-induced liver injury. To verify this hypothesis, we constructed and evaluated a mouse model of antibiotic-induced liver injury. Although no liver injury was observed upon administering three antibiotics (vancomycin, flucloxacillin, and ampicillin) alone, oral administration of antibiotics (vancomycin and flucloxacillin) with cholic acid (CA) increased levels of alanine transaminase (ALT). In the high ALT group, plasma taurocholic acid (TCA) levels were significantly increased, with a positive correlation detected between ALT and blood TCA levels (Spearman's ρ = 0.839). Overall, we constructed a mouse model of antibiotic-induced livery injury and confirmed our hypothesis that elevated blood levels of conjugated bile acids (increased TCA levels in this mouse model) can induce DILI.
Retraction: MZF1 alleviates oxidative stress and apoptosis induced by rotenone in SH-SY5Y cells by promoting RBM3 transcription.
Zhang J, Chai W, Xiang Z … +2 more , Zhou X, Zhang P
J Toxicol Sci · 2025 · PMID 40653373 · Publisher ↗
Editor's AnnouncementMZF1 alleviates oxidative stress and apoptosis induced by rotenone in SH-SY5Y cells by promoting RBM3 transcriptionJi Zhang, Wen Chai, Zhengbing Xiang, Xinhua Zhou, Ping Zhang(The Journal of Toxicolo...
Editor's AnnouncementMZF1 alleviates oxidative stress and apoptosis induced by rotenone in SH-SY5Y cells by promoting RBM3 transcriptionJi Zhang, Wen Chai, Zhengbing Xiang, Xinhua Zhou, Ping Zhang(The Journal of Toxicological Sciences, 46, 477-486, 2021)This paper has been withdrawn at the request of the authors.This article was accepted for publication by the Editorial Committee of The Journal of Toxicological Sciences after a regular peer review process. However, the Editorial Committee received an email from the corresponding author, Dr. Ping Zhang, requesting that the paper be withdrawn. The Editorial Board asked him to submit a letter of consent from all co-authors, and he subsequently provided one with the signatures of all co-authors. As that letter attested to the authors' intention, we approved the withdrawal of this paper.The authors have not disclosed the reasons for the withdrawal. However, the Editorial Committee has decided to respect their decision. Therefore, this action was taken at the authors' own responsibility.Toshiyuki Kaji, Ph.D. Editor-in-ChiefThe Journal of Toxicological Sciences.
Differential response of SNU-1826 colon cells on the autophagy, ER stress, and inflammation during the regulation of microplastic internalization.
Seol A, Kim JE, Song HJ … +10 more , Kim TR, Park ES, Park KH, Lim SJ, Wang SH, Park SC, Choi Y, Kim H, Seo S, Hwang DY
J Toxicol Sci · 2025 · PMID 40603046 · Publisher ↗
The internalization mechanism of microplastics (MPs) into human cells has attracted considerable attention because these mechanisms are closely related to the physical and chemical properties of MPs. This study examined...
The internalization mechanism of microplastics (MPs) into human cells has attracted considerable attention because these mechanisms are closely related to the physical and chemical properties of MPs. This study examined the response of human colon cells to autophagy, ER stress, and inflammation during the regulation on the internalization of polystyrene (PS)-MPs (0.4-0.6 μm size). To achieve this, changes in their key markers were analyzed in MPs-treated SNU-1826 cells after a cotreatment with uptake inhibitors or stimulators. The internalization of MPs was significantly higher in SNU-1826 cells than in other cells originated from differential tissues, such as the small intestine, kidneys, and nerves. On the other hand, the internalization of MPs into SNU-1826 cells was suppressed by cytochalasin D (CD) but not by pitstop (Pt). During this inhibition, the levels of the key parameters for autophagy (Light Chain 3-I/II (LC3-I/II) and Beclin1), ER stress (eukaryotic translation initiation factor 2 subunit alpha (EIF2α) and inositol-requiring kinase 1 alpha (IRE1α)), and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6) were suppressed in MPs+CD-treated SNU-1826 cells. In addition, the internalization of MPs into SNU-1826 cells was stimulated by a ZnSO treatment, not by CaCl. These stimulation effects were reflected in the alteration of the critical parameters for autophagy, ER stress, and inflammation. Furthermore, the positive correlation was detected between MPs internalization and most parameters for cellular responses although their inhibition is stronger than stimulation. These results suggest that the internalization of MPs into SNU-1826 cells may be strongly associated with the changes in autophagy, ER stress, and inflammation during the regulation of CD and ZnSO.
The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.
Yamada Y, Ito R, Noguchi T … +5 more , Hamano S, Otani K, Komatsu T, Hirata Y, Matsuzawa A
J Toxicol Sci · 2025 · PMID 40603045 · Publisher ↗
It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by th...
It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.
Pathophysiological interaction of dextran sodium sulfate-induced colitis and diet-induced hepatic lesions in mice.
Uno K, Sekiguchi K, Suzuki-Kemuriyama N … +2 more , Ohta T, Miyajima K
J Toxicol Sci · 2025 · PMID 40603044 · Publisher ↗
Nonalcoholic fatty liver disease (NAFLD) is a lifestyle-related disease. A gut-liver axis is involved in the progression of NAFLD. Disruption of the intestinal barrier function is an exacerbating factor of NAFLD. In this...
Nonalcoholic fatty liver disease (NAFLD) is a lifestyle-related disease. A gut-liver axis is involved in the progression of NAFLD. Disruption of the intestinal barrier function is an exacerbating factor of NAFLD. In this study, we have investigated the interaction between colitis and NAFLD in mouse models of dextran sodium sulfate (DSS)-induced colitis and diet-induced NAFLD-like lesions. Male C57BL/6J mice were provided with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and 1.25% DSS water for 3 weeks. The DSS water was administered intermittently. In the large intestine, the DSS-treated groups clearly demonstrated inflammation. Dilation of crypt and goblet cells was observed in the DSS + CDAHFD group. The expression of minor inflammation-related genes was increased in the CDAHFD group. In the liver, the CDAHFD group demonstrated non-alcoholic steatohepatitis (NASH)-like lesions. The number of C-X-C motif chemokine ligand 16 (CXCL16)-positive cells increased in the CDAHFD group and tended to increase in the DSS + CDAHFD group. Toll-like receptor 4 (TLR4)-positive cells were observed mainly in gallbladder epithelial cells in all groups and were more pronounced in the DSS-administered groups. Inflammation-related genes were upregulated in the DSS group. The expression of fibrosis-related genes increased in the DSS + CDAHFD group. DSS-induced colitis and CDAHFD-induced NASH interacted with each other. NAFLD lesions were induced by CDAHFD and exacerbated by TLR4 and CXCL16 in DSS-induced colitis. Colitis is induced by DSS and exacerbated by changes in the intestinal environment due to liver injury. This combined model was useful in analyzing early lesions of liver-gut axis for NAFLD.
Anticancer agent doxorubicin toxicity to in vitro X. laevis tadpole organ heart and mature frog heart and liver mitochondria.
Hanada H, Sanoh S, Kashiwagi K … +1 more , Kashiwagi A
J Toxicol Sci · 2025 · PMID 40603043 · Publisher ↗
One of the cancer drugs discharged into hospital wastewater, doxorubicin (DOX), is suspected of toxic effects on aquatic organisms. Cardiac and mitochondrial toxicity of DOX was investigated using cultured Xenopus (X.) l...
One of the cancer drugs discharged into hospital wastewater, doxorubicin (DOX), is suspected of toxic effects on aquatic organisms. Cardiac and mitochondrial toxicity of DOX was investigated using cultured Xenopus (X.) laevis tadpole heart and mature frog liver mitochondria as materials. While 10 DOX was not found to suppress heart rate, 10 M DOX caused short-term heartbeat suppression in a preliminary experiment. Compared to the heart rate of untreated organ hearts kept in heart-organ medium without hydrogen-peroxide oxidoreductase enzyme catalase (CAT) for 9 days, that of 10 M DOX-treated hearts decreased over time. The heartbeat suppression was improved by adding CAT to the heart culture medium, suggesting that DOX induces reactive oxygen species (ROS) in cultured tadpole hearts. Mitochondrial swelling assay was conducted. DOX was found to suppress slight swelling of heart and liver mitochondria with adenosine triphosphate (ATP) treatment. DOX also suppressed Ca-induced swelling of heart and liver mitochondria with ATP treatment. These findings suggest that the side effects of DOX on X. laevis heart and liver mitochondria are likely similar to those of cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPT) and also a ROS generator, leading to cardiac and mitochondrial dysfunction.
Identification of postmortem product of amlodipine decomposition by hemoglobin with LC-Q-Orbitrap-MS.
Yamagishi Y, Inoue H, Nagasawa S … +2 more , Iwase H, Ogra Y
J Toxicol Sci · 2025 · PMID 40603042 · Publisher ↗
Amlodipine (AM), a dihydropyridine calcium channel blocker, is frequently prescribed for hypertension in the clinical setting. Because AM has been detected in various lethal poisoning and suicide cases, it is important t...
Amlodipine (AM), a dihydropyridine calcium channel blocker, is frequently prescribed for hypertension in the clinical setting. Because AM has been detected in various lethal poisoning and suicide cases, it is important to determine its precise concentration in postmortem blood to serve as definitive evidence of death by intoxication. However, blood AM concentration at autopsy frequently differs from that at the time of death. In this study, we found that AM undergoes dehydrogenation by HO at temperatures ranging from 4 to 45ºC. Mass spectra measured by quadrupole-Orbitrap mass spectrometry hyphenated with liquid chromatography showed the generation of 3-ethyl 5-methyl 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate (AM-PDP-1) in HO and Hb/HO reaction solutions incubated with AM and in postmortem blood of persons who died of drowning, fire, disease, drug poisoning, CO poisoning, traumatic shock, falling, or choking, after intentional ingestion of AM. AM-PDP-1 is the novel postmortem degradation compound of AM in blood. This compound in the Hb/HO reaction solution was more stable than AM at 4-45ºC. These results show that AM-PDP-1, formed by HO-mediated postmortem AM decomposition, is a potential biomarker to correct for AM concentration in postmortem blood.
Comprehensive molecular docking on the AlphaFold-predicted protein structure proteome: identifying target protein candidates for puberulic acid.
Hayama T, Sugawara R, Kamata R … +2 more , Sekijima M, Takeda K
J Toxicol Sci · 2025 · PMID 40603041 · Publisher ↗
Identifying the molecular targets of toxic compounds remains a major challenge in toxicology, particularly when adverse effects occur in off-target organs and the mechanism of action is unknown. To address this issue, a...
Identifying the molecular targets of toxic compounds remains a major challenge in toxicology, particularly when adverse effects occur in off-target organs and the mechanism of action is unknown. To address this issue, a comprehensive computational pipeline was developed to perform high-throughput molecular docking across the entire AlphaFold2-predicted structural proteome of representative organisms such as human and mouse, followed by enrichment analysis to estimate biological processes potentially affected by ligand binding. The pipeline was first evaluated using six known drug-target pairs. In several cases, the known targets were ranked between the top 2 and 250 proteins (top 0.009-1.15%) among more than 21,000 proteins, and displayed docking poses consistent with experimentally observed binding conformations. However, performance was limited for certain targets, such as carbonic anhydrase II with acetazolamide, where the binding pocket was broad, leading to inaccurate docking results. The pipeline was subsequently applied to puberulic acid, a compound suspected of causing severe nephrotoxicity. Screening identified sodium/myo-inositol cotransporter 2 (SLC5A11) as a high-affinity target in both human and mouse, suggesting a mechanism involving disruption of renal osmoregulation. Although docking scores represent only theoretical binding estimates and do not directly imply physiological effects, their distribution was independent of protein length and AlphaFold2 confidence scores (pLDDT), supporting the methodological robustness. This in silico framework enables hypothesis-driven identification of potential target proteins for toxicants or therapeutics and offers a useful tool for predictive toxicology, particularly when experimental data are limited. The pipeline is available at: https://github.com/toxtoxcat/reAlldock.
Diphenylarsinic acid induced astrocyte-preferential cell-type-specific aberrant activation of signal transduction related to oxidative stress, MAP kinase activation, transcription factor regulation, and glutathione metabolism.
Negishi T, Yoshioka D, Kajiura A … +5 more , Suzuki D, Tasaki R, Sasaki S, Tsuzuki T, Yukawa K
J Toxicol Sci · 2025 · PMID 40451858 · Publisher ↗
Diphenylarsinic acid (DPAA) was responsible for the 2003 arsenic poisoning incident in Japan, in which DPAA-exposed individuals experienced cerebellum-related neurological symptoms. We previously reported that DPAA targe...
Diphenylarsinic acid (DPAA) was responsible for the 2003 arsenic poisoning incident in Japan, in which DPAA-exposed individuals experienced cerebellum-related neurological symptoms. We previously reported that DPAA targets cerebellar astrocytes rather than neurons in rats in vivo and induced the aberrant activation of particular signal transduction pathways, such as the MAP kinase and transcription factor pathway, as well as the oxidative stress response in cultured normal rat cerebellar astrocytes (NRA). Here, we examined the effects of 10 µM DPAA exposure for 96 hr in a panel of nine cell lines (HepG2, U251MG, T98G, 1321N1, SK-N-SH, SH-SY5Y, MCF7, A549, and C6) as well as NRA, and examined the DPAA-susceptible signal transduction pathways: oxidative-stress responsive factors [heme oxygenase-1 (HO-1), Hsp70, superoxide dismutase-1, and catalase), MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK), transcription factors (CREB, c-Jun, and c-Fos), glutathione (GSH), and GSH-related enzymes (glutamate-cysteine ligase and glutathione synthetase). In NRA, DPAA significantly activated these signal transduction pathways. Although there were cell-type specificities in susceptibility to DPAA, multivariate clustering analyses classified NRA, rat glioma-derived C6, and two human glioma-derived cell lines, U251MG and 1321N1, into an identical group. These results suggest that DPAA might affect cellular signal transduction preferentially in astrocytes among the diverse types of cells.
Toxicological effects of Sb(III), Sb(V), and NMG-Sb(V) in human lung, kidney, and liver cells: cytotoxicity and fibrotic factor induction.
Roldán N, Verdugo M, Suzuki N … +5 more , Zamora N, Quiroz W, Gonzalez A, Tognarelli J, Ogra Y
J Toxicol Sci · 2025 · PMID 40451857 · Publisher ↗
Antimony ecotoxicity studies are often hindered by the incorrect selection of Sb(III) standards and the application of concentrations that do not reflect real environmental exposure. In this study, we used environmentall...
Antimony ecotoxicity studies are often hindered by the incorrect selection of Sb(III) standards and the application of concentrations that do not reflect real environmental exposure. In this study, we used environmentally relevant concentrations of inorganic Sb in its pentavalent [Sb(V)] and trivalent [Sb(III)] oxidation states, as well as the organic species NMG-Sb(V), which is present in Meglumine Antimoniate, to evaluate the effects of Sb on cell viability in human lung (A549), kidney (HEK293), and liver (HepG2) cell lines. Cell viability was assessed in these cells following treatment with 0.001 to 1 µg/L of Sb(V), 1 to 500 µg/L of Sb(III), and 0 to 1000 mg/L of MA. We also measured ROS production and the expression of the profibrotic markers CTGF, α-SMA, and PAI-1, which are associated with fibrosis activation. No significant changes in cell viability were observed in HepG2 and A549 cells. However, in HEK293 cells, viability decreased by 20-40% at Sb(III) concentrations between 1 µg/L and 1 mg/L. CTGF expression was significantly increased at 17 µg/L of Sb(III), while α-SMA and PAI-1 expression increased at 21 µg/L of Sb(V). These findings suggest that different species of Sb can induce increased expression of mRNA for fibrotic genes in human liver and kidney cell lines at concentrations found in the environment.
Dabrafenib stimulates autophagy in thyroid carcinoma cells via HMGB-1.
Wang X, Wu D, Wang Y … +2 more , Han F, Feng X
J Toxicol Sci · 2025 · PMID 40451856 · Publisher ↗
Autophagy has been implicated in the pathophysiology of thyroid cancer and in determining the response of cancer cells to anticancer therapy. Dabrafenib, a BRAF inhibitor, has demonstrated efficacy and safety in several...
Autophagy has been implicated in the pathophysiology of thyroid cancer and in determining the response of cancer cells to anticancer therapy. Dabrafenib, a BRAF inhibitor, has demonstrated efficacy and safety in several types of cancers. However, it is unknown whether Dabrafenib exerts a protective effect on autophagy in thyroid carcinoma cells. In the current study, our findings demonstrate that treatment with Dabrafenib reduced cell viability and promoted LDH release in SW579 thyroid carcinoma cells. Dabrafenib was then shown to promote autophagy by increasing the level of Beclin1 and the LC3-II/LC3-I ratio while reducing the level of p62. Additionally, exposure to Dabrafenib upregulated the expression of HMGB-1 at both mRNA and protein levels. Interestingly, silencing of HMGB-1 abrogated Dabrafenib-induced autophagy, suggesting that the effects of Dabrafenib are mediated by HMGB-1. Further study revealed that Dabrafenib activated the JAK1/STAT1 signaling pathway and that blockage of the JAK1/STAT1 signaling pathway with its inhibitor Pyridone 6 ameliorated Dabrafenib-induced HMGB-1 upregulation and autophagy, implicating the involvement of the JAK1/STAT1 signaling pathway in this process. Collectively, these findings demonstrate that Dabrafenib induces autophagy in thyroid carcinoma cells via the JAK1/STAT1/HMGB-1 axis. Notably, this effect occurs independently of BRAF V600E mutation status, suggesting a novel therapeutic mechanism.
Circ_0008272 facilitates cadmium-induced malignant transformation of bronchial epithelial cells through histone modification.
Hao H, Yang Y, Cui J … +1 more , Huang L
J Toxicol Sci · 2025 · PMID 40451855 · Publisher ↗
Cadmium (Cd) exposure through the respiratory system is associated with various respiratory disorders, including lung cancer. Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis....
Cadmium (Cd) exposure through the respiratory system is associated with various respiratory disorders, including lung cancer. Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis. This study employed high-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) to identify differentially expressed circRNAs in 16HBE cells (Cd-T) after 30 weeks of cadmium chloride (CdCl, 5 μmol/L) exposure. Circ_0008272 knockdown inhibited migration, invasion, proliferation, and colony formation in Cd-T cells, whereas its overexpression enhanced these malignant phenotypes. Bioinformatics analyses and RNA-Protein Interaction Prediction (RPISeq) suggested that circ_0008272 promotes tumor-like behavior in Cd-T cells by modulating histone modification pathways. In conclusion, circ_0008272 acts as a tumor-promoting factor in the Cd-induced malignant transformation of 16HBE cells.
An update on ototoxicity: from a genetic perspective.
Akbari N, Lamooki FM, Amin MR … +3 more , Disnad SE, Yousefinejad V, Goharnia N
J Toxicol Sci · 2025 · PMID 40451854 · Publisher ↗
Ototoxicity, or hearing loss and damage to the auditory system caused by certain medications, is a significant clinical challenge. Many commonly used drugs, including antimicrobials, cancer therapies, and loop diuretics,...
Ototoxicity, or hearing loss and damage to the auditory system caused by certain medications, is a significant clinical challenge. Many commonly used drugs, including antimicrobials, cancer therapies, and loop diuretics, have the potential to induce temporary or permanent ototoxicity. The underlying mechanisms are complex, involving both genetic and environmental factors. Pharmacogenomics, the study of how an individual's genetic makeup influences their response to drugs, has emerged as a promising field for understanding and mitigating ototoxicity. Developing personalized approaches to prevent and manage ototoxicity is crucial, and this is where the pharmacogenomic basis of ototoxicity becomes crucial. This review aims to provide healthcare professionals with an updated perspective on the genetics of ototoxicity by summarizing the latest research and insights in this rapidly evolving field. It presents a comprehensive overview of the mechanisms and genetic factors associated with drug-induced ototoxicity, with a particular focus on cisplatin and aminoglycoside antibiotics.
The Journal of Toxicological Sciences and Fundamental Toxicological Sciences to become open access journals.
Kaji T, Naganuma A
J Toxicol Sci · 2025 · PMID 40307015 · Publisher ↗
We would like to express our gratitude for your contributions to our official scientific journals, The Journal of Toxicological Sciences and Fundamental Toxicological Sciences.We have decided to make both journals open a...
We would like to express our gratitude for your contributions to our official scientific journals, The Journal of Toxicological Sciences and Fundamental Toxicological Sciences.We have decided to make both journals open access in order to internationalize them and expand their reach to a broader audience. Articles will be published under the Creative Commons license with the highest degree of freedom, CC BY (4.0). As a result of this change, article copyright will belong to the authors, and secondary use, including copying, distribution, display, storage, modification, and commercial use, can be carried out without the relevant society's permission.The new Instructions for Authors will be published on the journal websites in advance. These new submission guidelines
will apply to papers submitted on or after June 1, 2025 (Japan time). Please note that the previous Instructions for Authors will apply to papers submitted until May 31, 2025 (Japan time).We hope that this change will encourage you to submit more of your excellent papers to The Journal of Toxicological Sciences and Fundamental Toxicological Sciences.Toshiyuki Kaji, Ph.D.Editor-in-ChiefThe Journal of Toxicological SciencesAkira Naganuma, Ph.D.Editor-in-ChiefFundamental Toxicological Sciences.
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