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Effects of salt supplementation in uninephrectomized KK-Ay mice: Examining the potential of a diabetic kidney disease model. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ryuhei Sano,Kanjiro Ryu,Tomohiko Sasase,Yuichi Shinozaki,Soon Hui Teoh,Ayane Yamaguchi,Kinuko Uno,Tatsuya Maekawa,Takeshi Ohta,Katsuhiro Miyajima
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD). Although current therapeutic strategies for DKD, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists, have shown some degree of efficacy, they have failed to completely halt the progression of DKD to ESRD owing to the complexity of DKD pathogenesis. Elucidating the pathophysiological
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Epigenetic mutagen-like environmental chemicals alter neural differentiation of human induced pluripotent stem cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yoshikazu Arai,Koichiro Nishino
Various chemicals, including pesticides, heavy metals, and metabolites of tobacco, have been detected in fetal environment. Fetuses are exposed to these chemicals at relatively low concentrations; however, their risk of developing neurological and behavioral disorders increases after birth. We aimed to evaluate the effects of five chemicals (diethylphosphate, cotinine, octachlorodipropyl ether, mercury
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Lidocaine induces neurotoxicity in spinal cord neurons in Goto-Kakizaki rats via AMPK-mediated mitophagy. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ling Chen,ChenLu Fan,Xuekang Zhang,Shibiao Chen,Lingling Ye,Xiaolan Zheng
OBJECTIVE Lidocaine has been reported to induce neurotoxicity, which is further enhanced by high glucose levels. This study is aimed to explore the underlying mechanisms of lidocaine neurotoxicity in spinal cord neurons of diabetes. METHODS Take thirty specific pathogen-free (SPF) healthy Sprague-Dawley (SD) rats and thirty Goto-Kakizaki (GK) rats, aged 12 weeks, weighing 180-200 g. The spinal cord
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Effects of microsampling on toxicity evaluation of 1-naphthylisothiocyanate (ANIT), a hepatotoxic substance, in a mouse toxicity study. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Kazuaki Takahashi,Shun Kawaguchi,Tomohiro Ikeda,Yuki Tomonari,Takeshi Funakoshi,Keiko Nakai,Tooru Fujimoto,Dai Yamamoto,Takayuki Okamura,Hideomi Uchida,Yoshiro Saito,Seiji Otake
ICH S3A Q&A focused on microsampling (MS) was published to help accelerate the use of MS and states that MS is useful because toxicokinetic (TK) evaluation with conventional blood sampling volume requires many animals for TK satellite groups; however, there are few reports of MS application in mice. We investigated the influence of MS on toxicity evaluation in mice by comparing the toxicity parameters
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Evaluation of circulating miR-216a and miR-217 as biomarkers of pancreatic damage in the L-arginine-induced acute pancreatitis mouse model. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Seiichiro Kurashige,Naomi Matsutani,Toyohiko Aoki,Terutaka Kodama,Yasuteru Otagiri,Yuko Togashi
We investigated the usefulness of circulating miR-216a-5p and miR-217-5p that are pancreas-enriched micro RNAs (miRNAs) as biomarkers of acute pancreatic damage, and compared them with conventional pancreatic biomarkers in L-arginine-induced acute pancreatitis mouse model. As the results, amylase and lipase levels apparently increased and peaked on Day 3 when acute pancreatitis including acinar cell
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Ephedrine alleviates bleomycin-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition and restraining NF-κB signaling. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Hui Tian,Limei Wang,Taoli Fu
Pulmonary fibrosis is a lethal and progressive pulmonary disorder in human beings. Ephedrine is a compound isolated from Ephedra and plays a regulatory role in inflammatory response. This study focused on the anti-pulmonary fibrosis effect of ephedrine and its potential molecular mechanism. After a mouse model of pulmonary fibrosis was established through bleomycin (BLM) induction, the survival percentage
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N-acetyl cysteine inhibits IL-1α release from murine keratinocytes induced by 2-hydroxyethyl methacrylate. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takahiro Kaji,Toshinobu Kuroishi,Kanan Bando,Masatoshi Takahashi,Shunji Sugawara
The hydrophilic compound 2-hydroxyethyl methacrylate (HEMA) is a major component of dental bonding materials, and it enhances the binding of resin-composites to biomolecules. However, HEMA is a well-known contact sensitizer. We reported previously that intradermal injection of HEMA induces the production of IL-1 locally in the skin. Keratinocytes are the first barrier against chemical insults and constitutively
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Small noncoding RNA dysregulation is implicated in manganism in a rat model of methylcyclopentadienyl manganese tricarbonyl-induced unrepaired striatum damage. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Qifeng Zhu,Fan Jiang,Yuanbo Song,Lili Lu,Fajian He,Shuqi Huang,Zhaoying Huang,Jing Yao,Ningning Lei,Jianmin Huang,Shijin Lu
The accumulation of excessively high manganese levels within the brain can contribute to a series of Parkinsonian symptoms referred to as manganism. The gasoline antiknock additive Methylcyclopentadienyl Manganese Tricarbonyl (MMT) is an environmental source of manganese exposure and can induce manganism in rats. While some prior reports have demonstrated the differential expression of small noncoding
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Effects of perfluorooctane sulfonate (PFOS) on cognitive behavior and autophagy of male mice. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Aojia Zhou,Li Wang,Xuejiao Pi,Cheng Fan,Wenwen Chen,Ziping Wang,Shuang Rong,Ting Wang
Perfluorooctane sulfonate (PFOS), an emerging environmental pollutant, is reported to cause neurotoxicity in animals and humans, but its underlying mechanisms are still unclear. We used in vivo models to investigate the effects of PFOS on cognition-related behaviors and related mechanisms. After 45 days of intragastric administration of PFOS (2 mg/kg or 8 mg/kg) in 7-week-old C57BL/6 mice, muscle strength
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Comparison of the acceptable surface limits derived from the skin sensitization potency for workers and swab residue limits determined from the permitted daily exposure derived from the systemic effects. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Asako Fukushima,Tae Hayashi,Masahiro Takeyoshi
Allergic contact dermatitis is a common occupational and environmental health problem and setting of health-based exposure limits (HBELs) to prevent induction of skin sensitization is strongly desired. When manufacturing pharmaceuticals in a shared facility, cleaning validation using surface residue levels (SRLs) derived from permitted daily exposures (PDEs) is conducted to avoid cross-contamination
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CHAC1 exacerbates arsenite cytotoxicity by lowering intracellular glutathione levels. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Daigo Sumi,Hiroki Taguchi,Kumiko Takeuchi,Hitomi Fujishiro
We here examined whether CHAC1 is implicated in arsenite (As(III))-induced cytotoxicity in HaCaT cells. We found that HaCaT cells in which the intracellular GSH levels were elevated by transfection with CHAC1 siRNA showed decreased sensitivity to As(III) compared to the control cells. Treatment with BSO (an inhibitor of GSH biosynthesis) abolished the decrease in sensitivity to As(III), suggesting
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Neuro-protective effects of n-butylphthalide on carbon monoxide poisoning rats by modulating IL-2, AKT and BCL-2. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Shengtao Tang,Kunyu Wang,Xiaokun Qi
Acute carbon monoxide poisoning (CO-poisoning) causes neurotoxicity by inducing necrosis, apoptosis, lipid peroxidation, and oxidative stress. DL-3-n-butylphthalide (NBP) is a synthetic compound originally extracted from the seeds of Chinese celery and based on pure l-3-n-butylphthalide. In ischemia/reperfusion, it exerts neuroprotective effects through its anti-apoptotic, anti-necrotic and antioxidant
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The protective effect of thiolutin on doxorubicin-induced H9c2 cardiomyocyte injury. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Wenyuan Cai,Tingting Teng,Xiaoyan Wang,Baihong Li,Xin Gu,Yafeng Zhou
The use of doxorubicin (DOX) may contribute to cardiotoxicity, limiting its clinical application. Thiolutin (THL) has been found to exert protective roles in various biological activities, while its effects on DOX-induced cardiotoxicity are still uncovered. Cell counting kit 8 assay was utilized to detect cell viability and half maximal inhibitory concentration of THL in H9c2 cardiomyocytes. The level
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Cadmium induces chondroitin sulfate synthase 1 via protein kinase Cα and elongates chondroitin/dermatan sulfate chains in cultured vascular endothelial cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takato Hara,Shogo Matsuura,Keita Aikawa,Misaki Shirai,Mai Yoshida,Toshiyuki Kaji,Chika Yamamoto
Cadmium is an environmental pollutant and a risk factor for atherosclerosis. In the atherosclerotic intima, dermatan sulfate chains accelerate accumulation and oxidation of LDL cholesterol. The major type of dermatan sulfate proteoglycan that is synthesized by vascular endothelial cells is biglycan. In the present study, we analyzed the effect of cadmium on the biglycan synthesis using cultured bovine
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Toxicological applications of human induced pluripotent stem cell-derived hepatocyte-like cells: an updated review. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Xiugong Gao,Jeffrey J Yourick,Robert L Sprando
Variability in supply, paucity of donors and cellular instability under in vitro conditions have limited the application of primary human hepatocytes (PHHs) to hepatotoxicity testing. Therefore, alternative sources have been sought for functional liver cells. Many of the earlier in vitro hepatotoxicity studies were carried out using hepatoma-derived cell lines. These cell lines have overcome some of
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Melatonin therapy reverses lead exposure-induced testicular damage in rats despite the lack of effect on serum testosterone levels. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Marco A Gallegos-Reyes,Alejandro R Antaño-Martínez,Yolanda Alcaraz-Contreras,Jorge A Alegría-Torres,Juvencio Robles,Eunice Yáñez-Barrientos,Minerva Martinez-Alfaro
Lead (Pb) exposure induces testicular damage and infertility. The aim of this study was to analyze and compare the therapeutic effects of antioxidants or vitamin D and calcium, which have previously been shown to reduce the toxic effects of Pb co-exposure, in rats. Rats were exposed to Pb for 28 days and subsequently treated with antioxidant (melatonin, silymarin), vitamin D and calcium (VitDCa) or
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Effects of inhalation of multi-walled carbon nanotube (MWCNT) on respiratory syncytial virus (RSV) infection in mice. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Aki Miyauchi,Toshi Akashi,Satoshi Yokota,Yuhji Taquahashi,Akihiko Hirose,Motoki Hojo,Hiroki Yoshida,Masahiko Kurokawa,Wataru Watanabe
Multi-walled carbon nanotubes (MWCNTs), a kind of nanomaterial, are widely used in battery electrodes and composite materials, but the adverse effects associated with their accumulation in the living body have not been sufficiently investigated. MWCNTs are a fibrous material with molecules similar to asbestos fibers, and there are concerns about its effects on the respiratory system. In this study
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Organophosphate agent action at the fatty acid amide hydrolase enhancing anandamide-induced apoptosis in NG108-15 cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takehito Terajima,Hirofumi Inoue,Kenji Shimomura,Fuki Iwasaki,Aya Sasaki,Yuki Ito,Michihiro Kamijima,Motohiro Tomizawa
Organophosphate (OP) agents are continuously utilized in large amount throughout the globe for crop protection and public health, thereby creating a potential concern on human health. OP agent as an anticholinesterase also acts on the endocannabinoid (EC)-hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to reveal unexpected adverse effects including ADHD-like
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Preclinical in vitro evaluation of immune suppression induced by GYM329, Fc-engineered sweeping antibody. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yoshika Iwata,Hitoshi Katada,Momoko Okuda,Yoshiaki Doi,Tim Jang Ching,Asako Harada,Akira Takeiri,Masaki Honda,Masayuki Mishima
Fc-engineering is commonly used to improve the therapeutic potency of antibody (Ab) treatments. Because FcγRIIb is the only inhibitory FcγR that contains an immunoreceptor tyrosine-based inhibition motif (ITIM), Fc-engineered Abs with enhanced binding affinity to FcγRIIb might provide immune suppression in clinical contexts. GYM329 is an anti-latent myostatin Fc-engineered Ab with increased affinity
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Pathogenesis of selective damage of granule cell layer in cerebellum of rats exposed to methylmercury. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ke Du,Takashi Hirooka,Yu Sasaki,Akira Yasutake,Takato Hara,Chika Yamamoto,Yasuyuki Fujiwara,Yo Shinoda,Tomoya Fujie,Shogo Katsuda,Komyo Eto,Toshiyuki Kaji
Granule cell-selective toxicity of methylmercury in the cerebellum is one of the main unresolved issues in the pathogenesis of Minamata disease. Rats were orally administered methylmercury chloride (10 mg/kg/day) for 5 consecutive days, and their brains were harvested on days 1, 7, 14, 21, or 28 after the last administration for histological examination of the cerebellum. It was found that methylmercury
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Corilagin attenuates morphine-induced BV2 microglial activation and inflammation via regulating TLR2-mediated endoplasmic reticulum stress. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Sen Guan,Fan Miao,Dongmei Wang,Jie Hu,Huimiao Wang
Morphine-induced microglia activation and neuroinflammation have been considered as the contributors of morphine tolerance. Corilagin (Cori) has been reported to exhibit strong anti-inflammatory property. The present study aims to investigate whether and how Cori alleviates morphine-induced neuroinflammation and microglia activation. Mouse BV-2 cells were exposed to different concentrations of Cori
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In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ryuichi Kambayashi,Ai Goto,Hiroko Izumi-Nakaseko,Yoshinori Takei,Atsushi Sugiyama
Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic
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Proteasome and p62/SQSTM1 are involved in methylmercury toxicity mitigation in mouse embryonic fibroblast cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yasukazu Takanezawa,Ryosuke Nakamura,Yuka Ohshiro,Shimpei Uraguchi,Masako Kiyono
Methylmercury (MeHg), an environmental pollutant, disrupts and impairs cellular function. MeHg binds to various cellular proteins, causing dysfunction and misfolding, which are considered underlying causes of MeHg toxicity. The p62 protein, also termed SQSTM1, is a ubiquitin-binding protein that targets ubiquitinated substrates to undergo autophagy and plays a key role in ameliorating MeHg toxicity
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Evaluation of MTT reducers and strongly colored substances in the Short Time Exposure test method for assessing eye irritation potential. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takayuki Abo,Yuuki Deguchi,Takuo Yuki,Yutaka Takahashi,Masaaki Miyazawa,Hitoshi Sakaguchi
The Short Time Exposure (STE) test evaluates eye irritation potential using a 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MTT assays may underpredict results for some substances that directly reduce MTT (i.e., MTT reducers) or interfere with absorbance because of their strong color (i.e., strongly colored substances). Based on previous research, we selected 25 substances
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Propofol improves ischemia reperfusion-induced liver fibrosis by regulating lncRNA HOXA11-AS. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Jia Luo,Jitong Liu,Yan Mou,Feng Luo,Qian Liao,Yongqiong Liao
Liver ischemia reperfusion (IR) injury induces hepatic stellate cell (HSC) activation and liver fibrosis. Propofol (PRO) possesses a positive protective effect on liver ischemia reperfusion injury. We aimed to investigate PRO function and mechanism in IR-induced liver fibrosis. A mice model of liver IR was established. Hematoxylin-eosin (HE) staining was utilized to evaluate liver tissue's pathological
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Evaluation of neurotoxicity of anticancer drugs using nematode Caenorhabditis elegans as a model organism. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yuko Sakaguchi,Marin Mizukami,Yamashiro Hiroka,Kayuko Miyasaka,Kyoko Niwa,Koji Arizono,Nobuhiro Ichikawa
It is well established that platinum-based drugs, including oxaliplatin (L-OHP) and cisplatin (CDDP), as well as microtubule inhibitors paclitaxel (PTX) and vincristine (VCR), are associated with chemotherapy-induced peripheral neuropathy (CIPN). In this study, we examined and compared the characteristics of neuropathies induced by L-OHP, CDDP, PTX, and VCR to evaluate whether Caenorhabditis elegans
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Early detection of hepatocarcinogens in rats by immunohistochemistry of γ-H2AX. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takeshi Toyoda,Mizuki Sone,Kohei Matsushita,Hirotoshi Akane,Jun-Ichi Akagi,Tomomi Morikawa,Yasuko Mizuta,Young-Man Cho,Kumiko Ogawa
We have developed an early detection method for bladder carcinogens with high sensitivity and specificity using immunohistochemistry of γ-H2AX, a well-known marker of DNA damage. To investigate the potential application of γ-H2AX as a biomarker for early detection of hepatocarcinogens, we examined γ-H2AX formation in the liver of rats treated with several different chemicals for 28 days. Six-week-old
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Human gut microbiota influences drug-metabolizing enzyme hepatic Cyp3a: A human flora-associated mice study. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Masao Togao,Takashi Kurakawa,Shinnosuke Tajima,Gaku Wagai,Yuki Ohta-Takada,Jun Otsuka,Akinobu Kurita,Koji Kawakami
Several studies revealed that gut microbiota affects the hepatic drug-metabolizing enzyme cytochrome P450 (Cyp). We hypothesized that individual gut microbiota variations could contribute to CYP activity. Human flora-associated (HFA) mice are established from germ-free mice using human feces and are often used to determine the effect of the human gut microbiota on the host. This study generated two
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Construction of extended and functional bile canaliculi using long-term sandwich-cultured cryopreserved human hepatocytes and the application of hepatocytes for predicting the biliary excretion of pharmaceutical and food-related compounds. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takashi Kitaguchi,Shinichiro Horiuchi,Yukie Kuroda,Katsutoshi Ohno,Kazuhiro Kobayashi,Mitsuru Tanaka,Seiichi Ishida
The biliary excretion of pharmaceutical and food-related compounds is an important factor for assessing pharmacokinetics and toxicities in humans, and a highly predictive in vitro method for human biliary excretion is required. We have developed a simple in vitro culture method for generating extended and functional bile canaliculi using cryopreserved human hepatocytes. We evaluated the uptake of compounds
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Simulation-based risk assessment for the leakage of toxic substances in a chemical plant and the effects on the human body: ethanol as a working model. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Akio Horiguchi,Satoshi Numazawa
Chemical plants must handle a wide variety of hazardous substances. To ensure safety in such plants, it is necessary to conduct extensive and highly accurate risk assessments. In this study, we aimed at developing a method that enables flexible and accurate risk assessment. We combined two different simulation tools to reproduce the phenomena of toxic gas leakage and diffusion as well as its impact
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The mechanism of monobutyl phthalate -induced ferroptosis via TNF/IL6/STAT3 signal pathway in TM-3 cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Xiaoying Guo,Yu Hao,Huiying Ma,Hai Li,Liping Li,Fengmei Yan,Jing Huang,Ling Li
As a common environmental endocrine disruptor, monobutyl phthalate (MBP) has been connected to reports of ROS accumulation, sperm destruction and reproductive damage. However, the specific mechanism of reproductive injury caused by MBP remains uncertain. Ferroptosis is a non-apoptotic, controlled oxidative damage-related cell death that is usually connected with reactive oxygen species and lipid peroxidation
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Oxidative stress-induced TET1 upregulation mediates active DNA demethylation in human gastric epithelial cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Mengna Zuo,Jianing He,Qianxi Yin,Xiaoying He,Ying Liu,Yang Liu,Jiwei Liu,Shujun Liu,Libing Ma
The gastrointestinal (GI) tract is more vulnerable to effects by the outside environment, and experiences oxidative stress. A wide diversity of GI disorders can be partially attributed to oxidative stress. However, the mechanism of oxidative stress-caused GI pathological changes is not clear. In the present study, human gastric epithelial cells (hGECs) were treated with hydrogen peroxide (H2O2), and
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Oxidative stress and cellular toxicity induced by dihydropyrazine: a comparative study with other Maillard reaction products. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yuu Miyauchi,Haruna Koba,Madoka Sawai,Hisao Kansui,Shinji Takechi
Glycation products are generated during the Maillard reaction, a non-enzymatic reaction between reducing sugars and the amino groups of proteins, which accumulate in the body with aging and cause many diseases. Herein, we have focused on dihydropyrazines (DHPs), which are glycation products formed by the dimerization of D-glucosamine or 5-aminolevulinic acid, and have reported that DHPs can produce
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Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yusuke Furukawa,Shigeyuki Hirai,Tatsuya Kasai,Hideki Senoh,Kenji Takanobu,Toshiaki Sasaki,Hirokazu Kano,Michiharu Matsumoto,Shigetoshi Aiso
We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in
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Development of a GCN-based model to predict in vitro phototoxicity from the chemical structure and HOMO-LUMO gap. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yoshinobu Igarashi,Suyong Re,Ryosuke Kojima,Yasushi Okuno,Hiroshi Yamada
The interaction between sunlight and drugs can lead to phototoxicity in patients who have received such drugs. Phototoxicity assessment is a regulatory requirement globally and one of the main toxicity screening steps in the early stages of drug discovery. An in silico-in vitro approach has been utilized mainly for toxicology assessments at these stages. Although several quantitative structure-activity
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Experience in the treatment of chlorfenapyr poisoning. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Benhe Wu,Fei Xue,Mingfeng Lu,Aiwen Ma,Lu Fan
In China, the extensive use of the pesticide chlorfenapyr has led to an increase in chlorfenapyr poisoning. However, there are limited reports on chlorfenapyr poisoning, and most of them are fatal cases. This study retrospectively analyzed four patients admitted to the emergency room after chlorfenapyr intake and detected different concentrations of chlorfenapyr in their plasma. Among them, one patient
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Behavioral effects induced by the oral administration of acetamiprid in male mice during the postnatal lactation period or adulthood. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Hirokatsu Saito,Kentaro Tanemura,Yusuke Furukawa,Takahiro Sasaki,Jun Kanno,Satoshi Kitajima
Acetamiprid (ACE), a neonicotinoid chemical, is widely used as a pesticide due to its rapid insecticidal activity. Although neonicotinoids exert very low toxicity in mammals, the effects of early exposure to neonicotinoids on the adult central nervous system are poorly understood. This study investigated the effects of ACE exposure in early life on brain function in adult mice. We exposed male C57BL/6N
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Exposure to bisphenol A or its phenolic analogs during early life induces different types of anxiety-like behaviors after maturity in male mice. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Takahiro Sasaki,Hirokatsu Saito,Yusuke Furukawa,Takashi Tominaga,Satoshi Kitajima,Jun Kanno,Kentaro Tanemura
Products used in daily life contain multiple chemicals capable of inducing endocrine disruption in animals, including humans. One such typical substance is bisphenol A (BPA). BPA has been widely used in epoxy resins and polycarbonate plastics and can exert several adverse effects. Furthermore, given their structural similarity to BPA, phenolic analogs of BPA, i.e., synthetic phenolic antioxidants (SPAs)
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The toxicity assessment of neorudin in cynomolgus monkeys. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yu-Bin Liu,Bo-Yuan Ren,Xing-Chen Zhou,Lin Zhang,Yun Liu,Can Zheng,Jin-Feng Wei,Chu-Tse Wu,Ji-de Jin
In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively.
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Toxicity manifestations and sex differences due to MARTA olanzapine. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Natsumi Hattori-Usami,Asuka Kaizaki-Mitsumoto,Takashi Ashino,Masayuki Yamamoto,Satoshi Numazawa
Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic
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Both osmolality-dependent and independent mechanisms are associated with acute hyperglycemia-induced cardiovascular adverse reactions: Analysis of the mutual interactions leading to cardiovascular phenotypes in dogs. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ryuichi Kambayashi,Hiroko Izumi-Nakaseko,Ai Goto,Yoshinori Takei,Akio Matsumoto,Ulrike Lorch,Jörg Täubel,Atsushi Sugiyama
Acute hyperglycemia causes various cardiovascular responses; however, the underlying pathophysiology in vivo is myriad and complex, of which mutual interactions remain poorly understood. We analyzed the cardiovascular effects of acute hyperglycemia in comparison with those of hyperosmolality alone. Three g/kg of D-glucose (n = 4) or D-mannitol (n = 4) was intravenously infused to isoflurane-anesthetized
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Tributyltin activates the Keap1-Nrf2 pathway via a macroautophagy-independent reduction in Keap1. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Misaki Hatano,Shunichi Hatamiya,Masatsugu Miyara,Yaichiro Kotake
Tributyltin (TBT) is an environmental chemical, which was used as an antifouling agent for ships. Although its use has been banned, it is still persistently present in ocean sediments. Although TBT reportedly causes various toxicity in mammals, few studies on the mechanisms of biological response against TBT toxicity exist. The well-established Keap1-Nrf2 pathway is activated as a cytoprotective mechanism
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Amelioration of lipopolysaccharides-induced impairment of fear memory acquisition by alpha-glycosyl isoquercitrin through suppression of neuroinflammation in rats. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Qian Tang,Kazumi Takashima,Wen Zeng,Hiromu Okano,Xinyu Zou,Yasunori Takahashi,Ryota Ojiro,Shunsuke Ozawa,Mihoko Koyanagi,Robert R Maronpot,Toshinori Yoshida,Makoto Shibutani
This study investigated the role of neuroinflammation in a lipopolysaccharides (LPS)-induced cognitive dysfunction model in rats using an antioxidant, α-glycosyl isoquercitrin (AGIQ). Six-week-old rats were dietary treated with 0.5% (w/w) AGIQ for 38 days, and LPS at 1 mg/kg body weight was administered intraperitoneally once daily on Days 8 and 10. On Day 11, LPS alone increased or tended to increase
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Effects of early-life tosufloxacin tosilate hydrate administration on growth rate, neurobehavior, and gut microbiota at adulthood in male mice. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ayano Hasegawa,Takahiro Sasaki,Jahidul Islam,Takashi Tominaga,Tomonori Nochi,Kenshiro Hara,Kentaro Tanemura
Reportedly, antibiotics, which are frequently prescribed in children, have long-term effects owing to gut microbiota dysregulation. Tosufloxacin tosilate hydrate (TFLX) is the first orally administered new quinolone with high efficacy and broad-spectrum action approved as an antibacterial agent for pediatric use in Japan. However, studies on the effects of its early-stage administration are limited
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Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Run Wang,Pengfei Liu,Fan Li,Hui Qiao
Dexmedetomidine (DEX) has been demonstrated to protect against ropivacaine (Ropi)-induced neuronal damages. This study was conducted to explore the protective role of DEX in Ropi-induced neuronal pyroptosis and provide a strategy to eliminate Ropi-induced neurotoxicity. The impacts of different concentrations of Ropi and DEX on neurotoxicity in SK-N-SH cells were evaluated by cell counting kit-8 assay
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Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Haixu Wang,Yan Li,Chuang Liu,Tianxiang Lu,Qian Zhai,Hongna Wang,Jianfang Zhang
Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls
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Establishment of hyperoxic cell culture system for predicting drug-induced liver injury: reducing accumulated lipids in hepatocytes derived from chimeric mice with humanized liver. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yuya Ohtsuki,Seigo Sanoh,Mikaru Yamao,Yuha Kojima,Yaichiro Kotake,Chise Tateno
Drug-induced liver injury (DILI) is a major adverse reaction. Species-specific differences between humans and laboratory animals make it difficult to establish evaluation models that can accurately predict DILI in the preclinical phase. Chimeric mice with humanized liver are potential predictive models for understanding DILI. Chimeric mice generated by transplanting human hepatocytes into urokinase-type
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Benzo(a)pyrene-induced mitochondrial respiration and glycolysis disturbance in human neuroblastoma cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yi Lyu,Jin Yang,LiXia Cheng,ZhaoFei Li,JinPing Zheng
Mammalian cells generate ATP through mitochondrial respiration and glycolysis. Mitochondria not only play a key role in cell energy metabolism but also in cell cycle regulation. As a neurotoxic pollutant, benzo(a)pyrene (BaP) can trigger neuronal oxidative damage and apoptosis. However, the features of BaP-induced energy metabolism disturbance in SH-SY5Y cells has rarely been addressed. This study
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Plasma membrane damage triggered by benzalkonium chloride and cetylpyridinium chloride induces G0/G1 cell cycle arrest via Cdc6 reduction in human lung epithelial cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Sanae Kanno,Seishiro Hirano,Jun Monma-Otaki,Hideaki Kato,Mamiko Fukuta,Yoshimi Nakamura,Yasuhiro Aoki
Quaternary ammonium compounds, including benzalkonium chloride (BAC) and cetylpyridinium chloride (CPC), are widely used as disinfectants. Increased use of inhalable products containing BAC or CPC has raised concerns for lung toxicity. This study sought to elucidate the microstructure of plasma membrane damage caused by BAC and CPC and the subsequent mechanism by which the damage is mediated, as assessed
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Lipopolysaccharide administration increases the susceptibility of mitochondrial permeability transition pore opening via altering adenine nucleotide translocase conformation in the mouse liver. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Ryota Nakajima,Akinori Takemura,Yugo Ikeyama,Kousei Ito
Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, induces various biological reactions in vivo. Our previous study suggested that LPS administration disrupts respiratory chain complex activities, enhances reactive oxygen species production, especially in the liver mitochondria, and sensitizes mitochondrial permeability transition (MPT) pore opening in rats. However
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Establishment of an in vitro cholestasis risk assessment system using two-dimensional cultured HepaRG cells and 12 bile acids. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Toshihisa Koga,Kenji Takeuchi,Ken Umehara
Drug-induced liver injury (DILI) is a major cause of market withdrawal or drug-development discontinuation because of safety concerns. In this study, we focused on drug-induced cholestasis (DIC) to establish an in vitro cytotoxicity test system and analyze its sensitivity using two-dimensional (2-D) cultured HepaRG cells and 12 types of bile acids (BAs) present in the human serum. First, to detect
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Methylthioacetic acid, a derivative of aroma compounds from Cucumis melo var. conomon dose-dependently triggers differentiation and apoptosis of RCM-1 human colorectal cancer cells. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Miyu Kamimura,Azusa Sasaki,Yui Otani,Yasushi Nakamura,Takako Nakamura,Kouji Kuramochi,Toshio Imai,Nakao Kubo,Shigehisa Okamoto
Methylthioacetic acid (MTA) is an acid-hydrolyzed derivative of a natural aroma compound, methylthioacetic acid ethyl ester isolated from Cucumis melo var. conomon (Katsura-uri, Japanese Picking Melon), and induces a villiform-like structure dome in RCM-1 human colorectal cancer cell culture. Thus far, the physiological and molecular properties of MTA-mediated dome formation remain unknown. Herein
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Rapid derivatization of phosphorus-containing amino acid herbicides in plasma and urine using microwave heating. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Hiroyuki Mohri,Kazuko Mohri,Akinaga Gohda,Yuji Ishii
We developed a derivatization technique that involves microwave heating to reduce the overall forensic analysis time of phosphorus-containing amino acid herbicides (PAAHs). Combined with an extraction method that uses titanium (IV) oxide (TiO2), we were able to obtain a practical analytical method for PAAHs and their metabolites in samples intended for poisoning cases. The optimized derivatization
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Effect of microsampling (50 μL) on toxicological evaluation of methapyrilene, a hepatotoxic substance, in a collaborative 28-day study in female rats. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Norimichi Hattori,Hideaki Yokoyama,Asuka Takumi,Sayaka Kawaguchi,Koki Yamaguchi,Taishi Shimazaki,Yusuke Shibui,Kosuke Saito,Yoshiro Saito
Although microsampling of blood is recommended to promote the 3Rs in toxicokinetic (TK) evaluation, there are few reports applying microsampling in actual toxicity evaluation. Here, we assessed the effects of microsampling on toxicological evaluation of methapyrilene hydrochloride, a hepatotoxic substance. Female SD rats received methapyrilene hydrochloride orally at dose levels of 0 (vehicle), 10
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Species differences in activation of TRPA1 by resin additive-related chemicals relevant to indoor air quality. J. Toxicol. Sci. (IF 2.0) Pub Date : 2023-01-01 Yoko Mori,Toshiko Tanaka-Kagawa,Maiko Tahara,Tsuyoshi Kawakami,Akira Aoki,Yoshinori Okamoto,Takashi Isobe,Susumu Ohkawara,Nobumitsu Hanioka,Kenichi Azuma,Shinobu Sakai,Hideto Jinno
Transient Receptor Potential Ankyrin 1 (TRPA1), which is expressed in the airways, has causative and exacerbating roles in respiratory diseases. TRPA1 is known as a target of sick building syndrome-related air pollutants, such as formaldehyde. Thus, an in vitro TRPA1 activation assay would be useful for predicting the potential risk of air pollution. In this study, we used human TRPA1 (hTRPA1)- and
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Involvement of Npas2 and Per2 modifications in zinc-induced acute diurnal toxicity in mice. J. Toxicol. Sci. (IF 2.0) Pub Date : 2022-01-01 Hiroki Yoshioka,Sarah Tominaga,Masumi Suzui,Yasuro Shinohara,Tohru Maeda,Nobuhiko Miura
Zinc (Zn) is one of the most essential trace elements in the body and an integral part of many enzyme systems. Zn deficiency is characterized by growth retardation, loss of appetite, and impaired immune function. In contrast, Zn overdoses can be associated with liver, kidney, and stomach damage. We focused on the "chronotoxicity," or the relationship between injection time and severity of chemical
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Triphenylbismuth dichloride inhibits human glyoxalase I and induces cytotoxicity in cultured cancer cell lines. J. Toxicol. Sci. (IF 2.0) Pub Date : 2022-01-01 Ryoko Takasawa,Akane Jona,Manami Inoue,Miku Azuma,Haruka Akahane,Yuto Ueno,Yuki Nakagawa,Ryusei Chimori,Yasunari Mano,Yuki Murata,Shuji Yasuike,Toshiyuki Kaji
Organobismuth compounds, i.e., organic-inorganic hybrid molecules composed of an organic structure and bismuth metal, have been reported to induce cytotoxicity in cancer cells; however, the target proteins associated with this cytotoxicity have not been elucidated. Herein, we investigated the inhibitory effect of five organobismuth compounds on human glyoxalase I (hGLO I), a promising target candidate
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2,3',4,4',5-Pentachlorobiphenyl induced thyroid dysfunction by increasing mitochondrial oxidative stress. J. Toxicol. Sci. (IF 2.0) Pub Date : 2022-01-01 Wenli Xu,Xiaoxia Zhu,Li Wang,Guoxian Ding,Xiaodong Wang,Yunlu Sheng,Shan Lv,Jing Yu,Juan Liu,Yu Duan
Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) and are associated with thyroid diseases. Our previous study reported that 2,3',4,4',5-Pentachlorobiphenyl (PCB118) could induce thyroid dysfunction and the rat thyroid tissues exhibit abnormal mitochondrial ultrastructure. However, the more specific effects of PCB118 on mitochondria and the relationship between mitochondria
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Forward and reverse dosimetry for aniline and 2,6-dimethylaniline in humans extrapolated from humanized-liver mouse data using simplified physiologically based pharmacokinetic models. J. Toxicol. Sci. (IF 2.0) Pub Date : 2022-01-01 Tomonori Miura,Shotaro Uehara,Makiko Shimizu,Hiroshi Suemizu,Hiroshi Yamazaki
Although human urinary aniline and 2,6-dimethylaniline were unexpectedly detected in biomonitoring data, little is known about the daily intake doses of aniline and 2,6-dimethylaniline in the living environment or their relation to tolerable daily intake (TDI) values in humans. In the current study, to evaluate the daily oral intake of aniline and 2,6-dimethylaniline in humans, forward and reverse
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Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide induces ferroptosis in neuroblastoma cells through redox imbalance. J. Toxicol. Sci. (IF 2.0) Pub Date : 2022-01-01 Yi Lyu,Xue-Ke Ren,Can-Can Guo,Zhao-Fei Li,Jin-Ping Zheng
As a widespread environmental pollutant, benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE)-induced neurotoxicity has received increasing attention. Studies have shown that BPDE-induced neurodegeneration is due partly to neuronal apoptosis. Unlike apoptosis, ferroptosis is a non-apoptotic form of programmed cell death, but its specific role in the neurotoxicity of BPDE remains unclear. In this work, we investigated