J Toxicol Sci [JOURNAL]
Sun
200 papers
Rodent-specific induction of cholestasis and cholangioma through the reduction of bile salt export pump by bardoxolone methyl.
Otsuki H, Araki T, Takami A … +4 more , Inomata K, Hiura M, Nan-Ya KI, Yoshinari K
J Toxicol Sci · 2025 · PMID 41320260 · Publisher ↗
Bardoxolone methyl, also known as CDDO-Me or RTA 402, was a new investigational drug that improves the estimated glomerular filtration rate by activating the Keap1-Nrf2 pathway. Bardoxolone methyl is a synthetic triterpe...
Bardoxolone methyl, also known as CDDO-Me or RTA 402, was a new investigational drug that improves the estimated glomerular filtration rate by activating the Keap1-Nrf2 pathway. Bardoxolone methyl is a synthetic triterpenoid compound derived from oleanolic acid (OA). OA-mediated cholestasis has not been reported in the clinical treatment of treat liver disorders but has been reported in mice. Cholestasis can be transient (e.g., during pregnancy) but can also be chronic and is a risk factor for hepatobiliary carcinoma. Therefore, it is important to evaluate and understand the risk of drug-induced cholestasis and its mechanisms, including species differences. We evaluated the effects of bardoxolone methyl on the in vivo hepatobiliary systems in rats and monkeys, as well as sandwich-cultured hepatocytes. Bardoxolone methyl was administered daily to rats and monkeys for 26 or 52 weeks, respectively. As a result, bardoxolone methyl was associated with the development of cholestasis and cholangioma in rats but not in monkeys. In an in vitro evaluation using sandwich-cultured hepatocytes treated with bardoxolone methyl, cholestasis was observed in rat hepatocytes, but not in monkey or human hepatocytes. A gene expression analysis showed that rat-specific cholestasis was caused by the reduction of the bile salt export pump gene expression after treatment with bardoxolone methyl. These results strongly suggest that the effects of bardoxolone methyl on the hepatobiliary system differ among animal species, especially between rodents and non-rodents. In conclusion, the risk of cholestasis and cholestasis-derived carcinogenicity associated with bardoxolone methyl are expected to be quite low in humans.
Lenvatinib induces diarrhea in rats by promoting intestinal barrier injury via targeting AQP4.
Long G, Li X, Xiao C … +2 more , Tan L, Cai C
J Toxicol Sci · 2025 · PMID 41320259 · Publisher ↗
Our study evaluated whether lenvatinib induces the disease process of diarrhea by facilitating intestinal epithelial barrier damage. Sprague-Dawley rats were orally administrated with 0.2 or 2 mg/kg lenvatinib for six co...
Our study evaluated whether lenvatinib induces the disease process of diarrhea by facilitating intestinal epithelial barrier damage. Sprague-Dawley rats were orally administrated with 0.2 or 2 mg/kg lenvatinib for six consecutive days to induce diarrhea models. The diarrhea rate was monitored every day, and rats were sacrificed on day 6. We found that rats began to develop diarrhea on day 3 after lenvatinib treatment. Almost all rats treated with lenvatinib (2 mg/kg) developed grade 3 diarrhea. Intestinal villi structure damage and obvious inflammatory cell infiltration were observed in the colon tissues of lenvatinib-administrated rats. Lenvatinib significantly upregulated serum contents of intestinal injury biomarkers (D-lactate and DAO) but downregulated colon levels of tight junction proteins (ZO-1, Occludin, and Claudin-1) in rats. In vitro results showed that lenvatinib higher than 5 μM significantly attenuated the viability of human intestinal epithelial cell line Caco-2. Lenvatinib suppressed ZO-1, Occludin, and Claudin-1 levels, decreased the transepithelial electrical resistance value, and elevated paracellular permeability in Caco-2 cells. Mechanically, lenvatinib targeted AQP4 and inhibited its expression. Overexpressing AQP4 reversed lenvatinib-induced intestinal epithelial barrier injury in Caco-2 cells by inhibiting the MLCK/p-MLC2 signaling pathway. Collectively, lenvatinib triggers diarrhea by disrupting the intestinal barrier through downregulating AQP4 and activating the MLCK/p-MLC2 signaling pathway.
Effects of food restriction and sex hormonal intervention on alkaline phosphatase isoenzymes in serum, liver, bone and small intestine of rats.
Hasegawa-Izaki A, Morita J, Kirihata Y … +7 more , Tanaka N, Noguchi C, Matsue K, Kurihara Y, Tsuji S, Ishii A, Wakamatsu M
J Toxicol Sci · 2025 · PMID 41320258 · Publisher ↗
To investigate the effects of reduced food intake on the serum and tissue levels of alkaline phosphatase (ALP) isoenzymes in rats, ALP1, ALP2, ALP3, and ALP5 were analyzed in serum, liver, bone, and small intestine of ma...
To investigate the effects of reduced food intake on the serum and tissue levels of alkaline phosphatase (ALP) isoenzymes in rats, ALP1, ALP2, ALP3, and ALP5 were analyzed in serum, liver, bone, and small intestine of male and female Sprague-Dawley rats reared under a diet-restricted condition (fed 65% or 45% of the amount of the free-feeding group) for 4 weeks from six-week-old. In addition, to examine the effect of sex hormonal, each ALP isoenzyme level was also analyzed in free-feeding female rats with ovariectomy or testosterone administration. Food restriction was associated with the following changes: an increase of the serum ALP5 level in the females, mainly caused by an increase derived from the small intestine; increases in the liver ALP1 and small intestinal ALP5 levels in both sexes, which represented a compensatory increase of these ALP isoenzyme levels to enhance lipid absorption under the low nutritional condition; a decrease of the bone ALP3 level in females, which was considered reflective of suppressed bone formation. Regarding the sex differences, serum ALP2 and liver ALP1 levels were higher in the males than in the females; the levels in ovariectomized or testosterone-treated females shifted closer to those in the males. These results indicate that food restriction and sex hormonal intervention influenced the serum and tissue ALP isoenzyme levels in rats. These findings provide helpful information for understanding the effects of reduced food intake, often observed in toxicity studies, and sex differences in rats on ALP and help to properly evaluate the effects of test compounds.
Coptisine improves sepsis-induced acute kidney injury by inhibiting ferroptosis.
Zhang Y, Huang J, Ji X … +1 more , Ren K
J Toxicol Sci · 2025 · PMID 41320257 · Publisher ↗
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening complication characterized by high morbidity and mortality. However, effective pharmacological therapies are currently unavailable. Ferroptosis, an iro...
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening complication characterized by high morbidity and mortality. However, effective pharmacological therapies are currently unavailable. Ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in the pathogenesis of SA-AKI. Coptisine, a natural isoquinoline alkaloid derived from Coptis chinensis, has demonstrated anti-inflammatory and antioxidant effects, but its specific role in SA-AKI remains to be elucidated. In this study, we investigated the protective effects of Coptisine against SA-AKI and the underlying mechanisms involved. Using a cecal ligation and puncture (CLP) mouse model, our study revealed that administering Coptisine significantly alleviated renal injury and inflammation, decreased oxidative stress, and inhibited ferroptosis in kidney tissues. In vitro studies showed that Coptisine suppressed LPS-induced ferroptotic injury in HK2 cells. Nevertheless, this protective effect was reversed by Nrf2 knockdown or iron supplementation. Mechanistically, Coptisine upregulated the levels of Nrf2 and GPX4, resulting in reduced ROS, MDA, and Fe levels, while enhancing GSH content. Collectively, our findings indicate that Coptisine alleviates sepsis-induced AKI by inhibiting ferroptosis through the activation of the Nrf2 signaling pathway, highlighting its potential as a therapeutic agent for SA-AKI.
Development of an AI algorithm for the automatic detection and classification of rat bone marrow cells.
Yamada N, Suzuki Y, Shimazaki T … +3 more , Muta K, Takahashi T, Shoda T
J Toxicol Sci · 2025 · PMID 41183900 · Publisher ↗
Morphological observation and classification of bone marrow cells in smear specimens is an important examination in toxicity studies for pharmaceuticals. However, acquiring the expertise for classifying bone marrow cells...
Morphological observation and classification of bone marrow cells in smear specimens is an important examination in toxicity studies for pharmaceuticals. However, acquiring the expertise for classifying bone marrow cells using light microscopy requires years of training, resulting in significant labor and time. To efficiently acquire accurate and objective data without oversight, a system for the automated detection and morphological classification of rat bone marrow cells was developed through machine learning using whole slide images (WSIs) obtained from smear specimens. Our system integrates SSD300 for object detection, VDSR for image super-resolution, and EfficientNetV2B0 for classification. WSIs of rat bone marrow smear specimens were obtained at 40× magnification using a WSI scanner. The fine-tuning of the bone marrow cell detection model using SSD300 was performed with 720 images obtained from WSIs of rat bone marrow smear specimens. The morphological classification model for 13 types of bone marrow cells using VDSR-EfficientNetV2B0 was optimized with a total of 144,000 cell images. The system for detection of bone mallow cells achieved an average precision of 79%. Additionally, the morphological classification achieved an accuracy of 98% when compared to expert classification. Our algorithm enabled the automated classification of cells on rat bone marrow smear specimens with extremely high accuracy and in a short time, approximately 80 sec, to classify 5,000 cells per image, without oversight. This capability suggests that the algorithm could potentially be utilized as a supportive tool for the toxicity evaluation of bone marrow smear specimens.
Ginkgetin ameliorates IL-1β-stimulated inflammation via modulating PI3K/AKT/NF-κB cascade in human osteoarthritis chondrocytes.
Yang G, Zhang X, Wang Z … +1 more , Bi S
J Toxicol Sci · 2025 · PMID 41183899 · Publisher ↗
Osteoarthritis (OA) is a degenerative joint condition characterized by an increased density of the subchondral osseous tissue, cartilage degradation, and synovial membrane inflammation. Ginkgetin, a bioactive compound de...
Osteoarthritis (OA) is a degenerative joint condition characterized by an increased density of the subchondral osseous tissue, cartilage degradation, and synovial membrane inflammation. Ginkgetin, a bioactive compound derived from Ginkgo biloba, exhibits notable anti-inflammatory properties in various disease models. In the current study, we aimed to determine the therapeutic potential of ginkgetin in mitigating IL-1β-induced inflammatory responses in human osteoarthritis chondrocytes. Our findings demonstrated that ginkgetin significantly inhibited the IL-1β-induced production of prostaglandin E2 (PGE2) and nitric oxide (NO). Additionally, ginkgetin downregulated the expression of IL-1β-induced proinflammatory mediators and cartilage-degrading enzymes. Furthermore, ginkgetin attenuated the degradation of key extracellular matrix components, including aggrecan and type II collagen. Mechanistically, ginkgetin exerted its protective effects by markedly suppressing the activation of the PI3K/AKT/NF-κB signaling pathway. Taken together, our findings demonstrated that ginkgetin ameliorates IL-1β-stimulated inflammation via modulation of the PI3K/AKT/NF-κB cascade, underscoring its viability as a promising therapeutic strategy for managing OA.
Exogenous carbon monoxide prevents a decrease of mitochondrial membrane potential in lipopolysaccharide-stimulated platelets.
Yakura T, Nanizawa E, Natsuyama Y … +6 more , Kawata S, Kuramasu M, Li ZL, Miyaso H, Naito M, Itoh M
J Toxicol Sci · 2025 · PMID 41183898 · Publisher ↗
BACKGROUND: Acute inflammation is induced by lipopolysaccharide (LPS), accompanied by activation of platelets. Carbon monoxide (CO), an endogenous bioactive gas, has been shown to bind to mitochondria and exert anti-infl...
BACKGROUND: Acute inflammation is induced by lipopolysaccharide (LPS), accompanied by activation of platelets. Carbon monoxide (CO), an endogenous bioactive gas, has been shown to bind to mitochondria and exert anti-inflammatory effects. In this study, we investigated the effect of CO on the mitochondrial membrane potential of platelets activated by LPS. METHODS: To elucidate the mechanism of the LPS-induced platelet response, human platelets were stimulated with LPS (10 μg/mL). Human platelet concentrates were divided into four groups: Untreated (Control), LPS-treated (LPS), LPS and CO-dissolved solution-treated (LPS + CO), and LPS and exogenous carbon monoxide releasing molecule-2-treated (LPS + CORM-2) groups. After 30 minutes, lactate levels and mitochondrial membrane potential (ΔΨm) in the platelets were measured. Morphological changes of the platelets were also observed using transmission electron microscopy. RESULTS: In the LPS group, the proportion of platelets with depolarized ΔΨm increased, accompanied by elevated lactate levels compared with the control group. On the other hand, in the LPS+CO and LPS+CORM-2 groups, the proportion of depolarized platelets did not significantly increase, and lactate levels were not significantly elevated. Morphologically, elongating pseudopods and cell condensation were observed in the LPS group, however, these changes were not induced in the LPS+CO and LPS+CORM-2 groups. CONCLUSION: These results suggest that CO prevents a decrease in the platelet ΔΨm and thereby inhibits platelet activation by LPS treatment.
Prevention of prolactin reduction: a novel strategy countering multi-generational growth retardation caused by maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Zou X, Yuan M, Takeda T … +3 more , Koga T, Tanaka Y, Ishii Y
J Toxicol Sci · 2025 · PMID 41183897 · Publisher ↗
Neonatal growth and development are significantly influenced by maternal care and breastfeeding. Our previous research showed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in dams reduced prolactin...
Neonatal growth and development are significantly influenced by maternal care and breastfeeding. Our previous research showed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in dams reduced prolactin (PRL) levels, nursing behavior, and milk production during lactation. Intracerebroventricular infusion of PRL in TCDD-exposed dams partially reversed these defects in mothers and offspring. However, the mechanism by which maternal TCCD exposure causes reduced PRL levels and multigenerational effects remains unclear. This study aimed to investigate the multigenerational effects of maternal TCDD exposure and sought solutions to the developmental issues arising from low PRL levels due to TCDD exposure during gestation. Oral administration of TCDD (1 µg/kg) to pregnant rats on gestational day 15 (F dams) led to decreased PRL concentrations in female offspring (F/F) and impaired maternal licking behavior when F females had given birth, resulting in adverse effects on body weight and short-term memory in F/F offspring. Aripiprazole (ARI), a partial dopamine D2 receptor (D2R) agonist, increases PRL levels by inhibiting the effect of dopamine during PRL synthesis and secretion. Importantly, administration of ARI to F dams not only restored PRL levels, nursing behavior, and milk volume in the treated mothers but also mitigated the developmental deficits observed in F/F offspring. These findings highlight the critical role of PRL in maternal care and offspring development and suggest that ARI could be a potential therapeutic intervention to mitigate the effects of TCDD-induced multi-generational developmental disruptions.
Incorporation of target safety review in drug discovery.
Amano Y, Jeffy B, Anayama H … +1 more , Goodwin J
J Toxicol Sci · 2025 · PMID 41183896 · Publisher ↗
Ensuring the safety of new pharmaceuticals and therapies is paramount in drug discovery. Takeda's Discovery Toxicology plays a crucial role in reducing safety-related risks by focusing on the quality of drug discovery ta...
Ensuring the safety of new pharmaceuticals and therapies is paramount in drug discovery. Takeda's Discovery Toxicology plays a crucial role in reducing safety-related risks by focusing on the quality of drug discovery targets. This involves identifying potential toxicities early in the development phase, enabling the mitigation of risks before they impact later stages of drug development. The Target Safety Review (TSR) initiates the Target Safety Assessment (TSA) process, providing a strategic assessment of safety concerns arising from target modulation. The TSR types range from comprehensive evaluations to simplified versions, assessing on-target and off-target effects, project background, biological information, and chemistry. Importantly, the TSR includes risk ranking and de-risking plans. Risks are ranked based on their probability and impact, enabling informed decision-making throughout the drug development process. This minireview discusses several case studies at Takeda, illustrating the importance of early risk identification. Of course, challenges remain, such as the appropriate timing of TSR creation, limited human on-target information, the need for effective risk assessment methods, incorporation of safety indicators into pharmacological studies, and addressing specific background risks in patient populations. Nonetheless, utilizing the TSR and TSA processes ensures a streamlined and safer drug development journey and provides a comprehensive approach to effectively address potential safety risks.
Expression profiles of purinergic P1 and P2 receptors in cultured bovine aortic endothelial cells, bovine aortic smooth muscle cells, and human vascular endothelial EA.hy926 cells.
Ikeuchi L, Hara T, Kitabatake K … +5 more , Uchiumi F, Yamamoto C, Tsukimoto M, Fujie T, Kaji T
J Toxicol Sci · 2025 · PMID 41034045 · Publisher ↗
Purinergic signaling plays an important role in vascular biology by vascular tone, inflammation, and remodeling through extracellular nucleotides that activate the P1 and P2 receptors. However, the expression patterns of...
Purinergic signaling plays an important role in vascular biology by vascular tone, inflammation, and remodeling through extracellular nucleotides that activate the P1 and P2 receptors. However, the expression patterns of these receptors in commonly used vascular cell models are not well characterized. In this study, we examined purinergic receptor expression in bovine aortic endothelial cells (BAECs), bovine aortic smooth muscle cells (BASMCs), and human vascular endothelial EA.hy926 cells. In BAECs, ADORA2A, ADORA2B, P2X4R, P2X7R, P2Y1R, P2Y2R, P2Y4R, P2Y6R, and P2Y11R were expressed, whereas the other purinergic receptors were not. BASMCs expressed ADORA2A, ADORA2B, P2X4R, P2X5R, P2Y1R, P2Y2R, P2Y6R, and P2Y11R. EA.hy926 cells expressed ADORA2A, ADORA2B, P2X4R, P2Y2R, P2Y6R, and P2Y11R. These results showed distinct expression profiles of purinergic receptors across different cell types. BAECs exhibited a purinergic receptor expression pattern similar to that of primary human vascular endothelial cells, suggesting that BAECs are a suitable model for studying purinergic signaling in vascular endothelial cells.
Dihydropyrazine activates the CAMKK2-AMPK-ULK1 signaling pathway in human hepatoma HepG2 cells.
Sawai M, Miyauchi Y, Kansui H … +1 more , Takechi S
J Toxicol Sci · 2025 · PMID 41034044 · Publisher ↗
Dihydropyrazines (DHPs) are glycation intermediates produced by nonenzymatic glycation reactions in vivo and in foods. We previously reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) activates endoplasmic reticul...
Dihydropyrazines (DHPs) are glycation intermediates produced by nonenzymatic glycation reactions in vivo and in foods. We previously reported that 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3) activates endoplasmic reticulum (ER) stress and inhibits autophagy, although its effect on autophagy initiation remained unclear. In this study, we examined the effect of DHP-3 on the autophagy initiation pathway in HepG2 cells. DHP-3 exposure resulted in activation of UNC-51-like kinase 1 (ULK1), the catalytic subunit of the ULK complex essential for autophagy initiation. Notably, phosphorylation of AMP-activated protein kinase (AMPK), an upstream activator of ULK1, was enhanced without a corresponding increase in the ADP/ATP ratio. Among the upstream kinases regulating AMPK, phosphorylation of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was increased, whereas that of liver kinase B1 (LKB1) remained unchanged. These findings suggest that DHP-3 activates the CAMKK2-AMPK-ULK1 signaling pathway, thereby inducing autophagy initiation.
Activator protein-1 mediates blue light-induced phototoxicity in retinal pigment epithelial cells.
Lee JR, Kim MR, Jeong KW
J Toxicol Sci · 2025 · PMID 41034043 · Publisher ↗
Age-related macular degeneration is a leading cause of vision loss and is characterized by the accumulation of drusen in the retinal pigment epithelium. N-retinylidene-N-retinylethanolamine (A2E), a major component of dr...
Age-related macular degeneration is a leading cause of vision loss and is characterized by the accumulation of drusen in the retinal pigment epithelium. N-retinylidene-N-retinylethanolamine (A2E), a major component of drusen, induces phototoxicity upon exposure to blue light. Given that blue light activates the MAPK pathway and triggers apoptosis, the present study aimed to determine the role of signaling via the activator protein-1 (AP-1) transcription factor in A2E-laden ARPE-19 cells. RNA-sequencing identified significant upregulation of the UV response and p53 pathways. In silico analysis predicted that JUN was a key upstream transcriptional regulator, and experimental validation confirmed increased JUN phosphorylation and AP-1 target gene expression upon blue light exposure. Furthermore, blue light treatment decreased BCL2 and increased BAX protein levels, thereby promoting apoptosis via caspase activation and PARP cleavage, as also confirmed by flow cytometry. These findings suggest that blue light induces apoptosis via JUN, which activates AP-1 in A2E-laden ARPE-19 cells. The present study provides new insights into the molecular mechanisms underlying blue light-induced retinal damage and its potential contribution to the progression of age-related macular degeneration.
Spermidine alleviates sepsis-induced acute kidney injury by suppressing apoptosis and inflammation through modulation of TLR4-mediated signaling.
Shen Y, Shi Q, Dai T … +6 more , Cai Y, Sheng M, Qiu Y, Yang M, Hu S, Cheng B
J Toxicol Sci · 2025 · PMID 41034042 · Publisher ↗
Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In...
Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In vitro, HK-2 cells were challenged with lipopolysaccharide (LPS) to establish an inflammatory injury model, followed by spermidine treatment (25-100 μM). In vivo, a cecal ligation and puncture (CLP)-induced septic AKI mouse model was employed. Key methodologies included CCK-8 viability assay, flow cytometry apoptosis analysis, western blotting (apoptotic proteins: Bcl-2/Bax/cleaved caspase-9; TLR4/MyD88/TRAF6/p-p65), ELISA (TNF-α/IL-6/IL-1β), TUNEL staining, and histopathological assessment, with spermidine doses of 25-100 μM (cells) and 50 mg/kg (mice). We found that spermidine treatment significantly mitigated renal histopathological damage and improved functional markers, including blood urea nitrogen, serum creatinine, and neutrophil gelatinase-associated lipocalin. Spermidine administration attenuated oxidative stress by restoring antioxidant enzyme activities while reducing lipid peroxidation in renal tissues. Spermidine suppressed apoptosis in both LPS-challenged HK-2 and CLP-injured kidneys, evidenced by reduced apoptotic markers and caspase activation. Furthermore, spermidine inhibited systemic and intrarenal inflammatory cytokine production through modulation of the TLR4/MyD88/NF-κB signaling axis. These findings collectively establish that spermidine alleviates sepsis-induced AKI through coordinated suppression of apoptosis and inflammation mediated by TLR4/MyD88/NF-κB pathway inhibition.
Successful multimodal treatment of venlafaxine overdose-induced catecholamine-refractory shock: a case report.
Hayakawa T, Sanagawa A, Ohashi K … +6 more , Kotoge K, Matsui R, Tamura T, Monma-Otaki J, Furukawa-Hibi Y, Hattori T
J Toxicol Sci · 2025 · PMID 41034041 · Publisher ↗
Venlafaxine was the first serotonin/noradrenaline reuptake inhibitor used to treat major depressive disorders. Its overdose can cause cardiovascular toxicity and life-threatening cardiogenic shock. We present the case of...
Venlafaxine was the first serotonin/noradrenaline reuptake inhibitor used to treat major depressive disorders. Its overdose can cause cardiovascular toxicity and life-threatening cardiogenic shock. We present the case of a 48-year-old woman who experienced venlafaxine overdose-induced cardiogenic shock. Initial treatment included gastric lavage, blood purification therapy, and ventricular assist device use. The serum venlafaxine concentration was 21.4 μg/mL at 12-24 hr after ingestion, which subsequently decreased to 11.0 and 8.4 μg/mL after 1 and 2 days, respectively. This trend in blood concentration exhibited a biphasic elimination pattern. In addition to venlafaxine-induced cardiotoxicity, the patient exhibited peripheral vascular unresponsiveness to catecholamines. Notably, this vascular dysfunction resolved more rapidly than the cardiotoxic effects. Ultimately, the patient was transferred to a psychiatric ward without sequelae. Although venlafaxine overdose-induced cardiotoxicity has been reported, reports on the unresponsiveness of peripheral blood vessels to catecholamines remain lacking. In cases of venlafaxine overdose-induced cardiogenic shock, both left ventricular function may be impaired and peripheral blood vessels may also be unresponsive to catecholamines. Therefore, rapid initiation of extracorporeal life support and multimodal removal of venlafaxine tailored to the clinical situation may contribute to patient survival.
Characterization of the toxicological findings from 90-day and 2-year repeated-dose toxicity studies of pesticides in rats.
Harakawa Y, Shibata M, Suzuki H … +7 more , Takahashi N, Shiga A, Mizuno K, Hosaka T, Shizu R, Takeshita JI, Yoshinari K
J Toxicol Sci · 2025 · PMID 41034040 · Publisher ↗
Repeated-dose toxicity (RDT) studies in rats are crucial for assessing the risks of chemicals, including pesticides, by elucidating their toxicological properties. In this study, we collected and comprehensively analyzed...
Repeated-dose toxicity (RDT) studies in rats are crucial for assessing the risks of chemicals, including pesticides, by elucidating their toxicological properties. In this study, we collected and comprehensively analyzed the results of rat RDT studies on pesticides. For over 350 pesticides across more than 400 studies, all toxicological findings observed in 90-day and 2-year RDT/carcinogenicity studies in rats were organized into 1,092 endpoints using our previously established three-level categorization system. The liver, kidney, thyroid gland, and spleen were identified as the primary non-tumor targets in both the 90-day and 2-year studies. In the 2-year study, the liver, thyroid gland, testis, and uterus were found to be the primary tumor targets, with significant sex differences in liver and thyroid tumors. We also identified findings observed at the lowest observed adverse effect level (LOAEL) for each study. Finally, analyses by pesticide class, based on their mode of action classification, demonstrated class effects on the toxicological findings observed and the LOAEL values. Taken together, these results provide valuable insights into toxicological endpoints that should be evaluated in further mechanistic studies and considered for the safety assessment of each class of pesticides.
Oral exposure to polystyrene nanoplastics induces anxiety-like behavior and cognitive deficit accompanied with alteration of neuroimmune markers in rats.
Win-Shwe TT, Kyi-Tha-Thu C
J Toxicol Sci · 2025 · PMID 40887253 · Publisher ↗
Microplastic (MP) pollution has become a global environmental issue, but its potential health effect remains unknown. We aimed to investigate the effect of oral administration of polystyrene nanoplastics (PSNPs) on brain...
Microplastic (MP) pollution has become a global environmental issue, but its potential health effect remains unknown. We aimed to investigate the effect of oral administration of polystyrene nanoplastics (PSNPs) on brain functions and behaviors. Five-week-old Sprague Dawley male rats were given 50 nm PSNPs orally at doses of 10 or 50 mg/kg thrice per week for four weeks. At 9-week-old after completion of oral exposure, novel object recognition test and open field test were performed. The hippocampus from each rat was collected to detect neurological, immunological, and antioxidative stress markers using ELISA, real-time RT-PCR and immunohistochemical analyses. High-dose PSNP-treated rats showed decreased exploration time with a novel object, and reduced entry time and time spent in the center. Increased glutamate concentration, decreased glutamate receptor NMDA subunits (NR1, NR2B) and transcription factors CREB1 and CaMKIV mRNAs and increased cFos and early growth response 1, reduced postsynaptic density protein-95, synaptophysin mRNAs, were observed in high-dose PSNP-treated rats. Moreover, antioxidative stress markers such as superoxide dismutase and catalase were significantly decreased whereas inflammatory cytokines (interleukin 1β, tumor necrosis factor-α) and microglial marker (ionized calcium-binding adapter molecule 1) were significantly higher in high-dose PSNP-treated rats. Our results indicate oral exposure to PSNPs induced anxiety-like behavior and learning, memory impairment by altering neuron-glia-immune cells interaction at synaptic regions in the rat hippocampus. This study would be helpful to understand the association between MP pollution and increasing neurological disorders like dementia, anxiety, and Alzheimer's disease in humans.
A probabilistic approach for estimating human exposure to polychlorinated biphenyls via tuna consumption.
Jamil MZ, Zhao J, Nishi Y … +1 more , Noon OS
J Toxicol Sci · 2025 · PMID 40887252 · Publisher ↗
Previous studies on estimating human exposure to PCBs often employed daily or hourly fixed intakes, failing to consider the irregularity of PCBs accumulation under a real consumption scenario. Therefore, this study aimed...
Previous studies on estimating human exposure to PCBs often employed daily or hourly fixed intakes, failing to consider the irregularity of PCBs accumulation under a real consumption scenario. Therefore, this study aimed at simulating actual consumer behavior, estimating the specific dates and quantities of PCB-153 intake, and combining this approach with a pharmacokinetic model to estimate the human exposure to PCB-153 through Tuna consumption. A physiologically based pharmacokinetic (PBPK) model was used to predict the accumulation of PCB-153 in six tissue compartments of a hypothetical woman for a period of 10 years. The simulated intake amount was 16313 ± 3797 ng/year, resulting in accumulated PCB-153 concentration in whole blood of 460 ± 12.6 ng/L after 10 years, which aligns closely with the human biomonitoring measurement results. This study provides a promising approach to understand and evaluate the exposure and accumulation of food-source pollutants in the human body, as well as to inform public health policy.
Ionic liquid cytotoxicity in mouse macrophage J774.1 cells: Effects of alkyl chain length, cation core, and anion type.
Nishiyama T, Suda R, Hirokawa T … +3 more , Fujita K, Ichida K, Yamaori S
J Toxicol Sci · 2025 · PMID 40887251 · Publisher ↗
Ionic liquids (ILs) are salts with melting points below 100°C. These materials are promising novel solvents in organic reactions, as new electrolytes, and in protein stabilization, able to refold enzymes and aid in drug...
Ionic liquids (ILs) are salts with melting points below 100°C. These materials are promising novel solvents in organic reactions, as new electrolytes, and in protein stabilization, able to refold enzymes and aid in drug discovery. IL properties are strongly influenced by the types of their constituent cations and anions. To date, many ILs with unique solvent properties not found in water or organic solvents are reported. However, IL toxicity evaluations often focus on trends associated with widely used imidazolium cations. Consequently, knowledge regarding the toxicity of individual ionic structures and their combinations is limited. This study investigated alkylphosphonium and alkylammonium cation derivatives, evaluating their cytotoxicity against mouse macrophage J774.1 cells using dihydrogen phosphate ([dhp]) or bromide (Br) ions as anions. Experiments were conducted using alkylphosphonium cation derivatives ((CH)RP, [P444R]) with varying alkyl chain lengths (R: 4; CH, 8; CH, and 12; CH) and on tetrabutylammonium cation derivatives [N4444]. This study revealed that [P44412][dhp] yielded the highest toxicity, which decreased with shorter alkyl chains. A similar trend was observed with Br as the anion. For [P444R], anion variation did not significantly affect toxicity. Comparing [P4444][dhp] and [N4444][dhp], the phosphonium cation showed lower ED values, indicating higher toxicity. This tendency persisted when Br was used as the anionic species. In summary, for the ILs evaluated, the quaternary cationic species of the IL effects the greatest influence on IL toxicity.
Estimation of intravenous TTC (TTCiv) for Extractables and Leachables (E&Ls) by applying a modifying factor based on blood concentration predicted using an open-source PBPK model.
Hayashi T, Kotaki A, Fukushima A … +4 more , Kawamura T, Katsutani N, Yamada T, Hirose A
J Toxicol Sci · 2025 · PMID 40887250 · Publisher ↗
Pharmaceutical manufacturing and storage processes pose the potential risk of chemicals migrating from the packaging materials into pharmaceuticals. These migrants, known as extractables and leachables (E&Ls), consist of...
Pharmaceutical manufacturing and storage processes pose the potential risk of chemicals migrating from the packaging materials into pharmaceuticals. These migrants, known as extractables and leachables (E&Ls), consist of various chemicals that may pose a risk to patients during therapeutic use. Although exposure to E&Ls via the intravenous route is of greater concern, there is almost no toxicity information for these chemicals to determine the Permitted Daily Exposure (PDE). The purpose of this study was to establish the Threshold of Toxicological Concern for intravenous route exposure (TTCiv) for risk management of E&Ls contained in pharmaceuticals. First, we derived the oral PDEs of 287 chemicals from a list of 923 known E&Ls. Then, the modifying factor (α) for estimating the intravenous PDE from each oral PDE was calculated based on the ratio of the predicted blood concentrations (area under the curve (AUC) and maximum blood concentration (C)) after oral and intravenous administration using the Integrated Chemical Environment (ICE) PBPK model. Additionally, due to uncertainty of the predictions without bioavailability information, the intravenous PDE was calculated using modifying factor 3 based on the maximum value of the root mean square error (RMSE) reported in varification of the High-Throughput Toxicokinetics (HTTK) model. In conclusion, by analyzing the distribution of the intravenous PDE for 287 chemicals, we propose a TTCiv of 27 µg/day/human, based on the ratio of C. Our route extrapolation approach could contribute to the establishment of scientifically valid TTCs for not only E&Ls, but also for other impurities without toxicity information.
1,2-Naphthoquinone promotes cell migration through EGFR-ERK signaling pathway in human A549 cells.
Pan Y, Kubota S, Zhang Y … +4 more , Fang S, Takasugi N, Kumagai Y, Uehara T
J Toxicol Sci · 2025 · PMID 40887249 · Publisher ↗
Hazardous environmental factors contribute to various irreversible threats to human health worldwide. Accumulating evidence suggests that exposure to particulate matter with an aerodynamic diameter of <2.5 µm (PM) plays...
Hazardous environmental factors contribute to various irreversible threats to human health worldwide. Accumulating evidence suggests that exposure to particulate matter with an aerodynamic diameter of <2.5 µm (PM) plays a critical role in lung carcinogenesis. Previously, we reported that 1,2-naphthoquinone (1,2-NQ), a component of atmospheric PM and diesel exhaust particles, forms a covalent bond with the epidermal growth factor receptor (EGFR) via protein N-arylation, thereby activating the downstream protein kinase B (Akt) signaling pathway. Here, we elucidate a regulatory mechanism by which 1,2-NQ modulates the migratory activity of human lung adenocarcinoma A549 cells. Specifically, exposure of A549 cells to 1,2-NQ induces phosphorylation of EGFR, leading to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This activation is significantly suppressed by anti-EGFR antibodies (cetuximab and panitumumab) and inhibitors targeting rapidly accelerated fibrosarcoma (Raf; LY3009120) and mitogen-activated protein kinase kinase (MEK; U0126). These findings suggest that 1,2-NQ induces ERK1/2 phosphorylation by activating the Raf-MEK pathway. Notably, suppression of EGFR-ERK1/2 signaling resulted in a decrease in migratory activity. Our findings provide new insights into lung cancer carcinogenesis and may contribute to the development of novel therapeutic strategies.
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