Journal of Toxicological Sciences最新文献_第9页

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway. 抑制VDAC1可通过AMPK/mTOR信号通路抑制双酚A诱导的精原细胞氧化应激和凋亡。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.109

Haixu Wang, Yan Li, Chuang Liu, Tianxiang Lu, Qian Zhai, Hongna Wang, Jianfang Zhang

{"title":"Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway.","authors":"Haixu Wang, Yan Li, Chuang Liu, Tianxiang Lu, Qian Zhai, Hongna Wang, Jianfang Zhang","doi":"10.2131/jts.48.109","DOIUrl":"https://doi.org/10.2131/jts.48.109","url":null,"abstract":"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 the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 μM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 3","pages":"109-119"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10852652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The mechanism of monobutyl phthalate -induced ferroptosis via TNF/IL6/STAT3 signal pathway in TM-3 cells. 邻苯二甲酸一丁酯通过TNF/IL6/STAT3信号通路诱导TM-3细胞铁凋亡的机制

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.299

Xiaoying Guo, Yu Hao, Huiying Ma, Hai Li, Liping Li, Fengmei Yan, Jing Huang, Ling Li

{"title":"The mechanism of monobutyl phthalate -induced ferroptosis via TNF/IL6/STAT3 signal pathway in TM-3 cells.","authors":"Xiaoying Guo, Yu Hao, Huiying Ma, Hai Li, Liping Li, Fengmei Yan, Jing Huang, Ling Li","doi":"10.2131/jts.48.299","DOIUrl":"https://doi.org/10.2131/jts.48.299","url":null,"abstract":"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. In this work, to evaluate the mechanism of MBP-induced ferroptosis in reproductive damage, bioinformation analysis and experimental validation were used. Based on bioinformatics analysis, the interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) genes may be involved in the tumor necrosis factor (TNF) signaling pathway, which controls inflammation. Experimental study validated the significance of IL6 and STAT3 in MBP-induced ferroptosis. Western blotting and quantitative real-time PCR revealed that Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), Tumor necrosis factor-α (TNF-α), IL6, and STAT3 were all elevated with treatment of MBP, but Glutathione peroxidase 4 was significantly decreased. To determine the participation of IL6/STAT3, we added the ferroptosis inhibitor Ferrastain-1 (Fer-1) and the IL6/STAT3 pathway inhibitor Angoline. In conclusion, we found that MBP induced ferroptosis in TM3 cells to damage male reproductive system through the TNF/IL6/STAT signal pathway, resulting in lipid peroxidation and iron metabolite degradation.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 5","pages":"299-310"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9391440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study. 为期两年的吸入研究甲基丙烯酸丁酯对大鼠和小鼠的致癌性和慢性毒性。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.227

Yusuke Furukawa, Shigeyuki Hirai, Tatsuya Kasai, Hideki Senoh, Kenji Takanobu, Toshiaki Sasaki, Hirokazu Kano, Michiharu Matsumoto, Shigetoshi Aiso

{"title":"Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study.","authors":"Yusuke Furukawa, Shigeyuki Hirai, Tatsuya Kasai, Hideki Senoh, Kenji Takanobu, Toshiaki Sasaki, Hirokazu Kano, Michiharu Matsumoto, Shigetoshi Aiso","doi":"10.2131/jts.48.227","DOIUrl":"https://doi.org/10.2131/jts.48.227","url":null,"abstract":"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 the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto's test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher's exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto's test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 5","pages":"227-241"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9396782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lead suppresses perlecan expression via EGFR-ERK1/2-COX-2-PGI₂ pathway in cultured bovine vascular endothelial cells. 铅通过EGFR-ERK1/2-COX-2-PGI2途径抑制培养的牛血管内皮细胞中perlecan的表达。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.655

Takato Hara, Reina Kumagai, Tohru Tanaka, Tsuyoshi Nakano, Tomoya Fujie, Yasuyuki Fujiwara, Chika Yamamoto, Toshiyuki Kaji

{"title":"Lead suppresses perlecan expression via EGFR-ERK1/2-COX-2-PGI2 pathway in cultured bovine vascular endothelial cells.","authors":"Takato Hara, Reina Kumagai, Tohru Tanaka, Tsuyoshi Nakano, Tomoya Fujie, Yasuyuki Fujiwara, Chika Yamamoto, Toshiyuki Kaji","doi":"10.2131/jts.48.655","DOIUrl":"10.2131/jts.48.655","url":null,"abstract":"Vascular endothelial cell growth is essential for the repair of intimal injury. Perlecan, a large heparan sulfate proteoglycan, intensifies fibroblast growth factor-2 (FGF-2) signaling as a co-receptor for FGF-2 and its receptor, and promotes the proliferation of vascular endothelial cells. Previously, we reported that 2 µM of lead, a toxic heavy metal, downregulated perlecan core protein expression and then suppressed the growth of vascular endothelial cells. However, since the mechanisms involved in the repression of perlecan by lead remains unclear, we analyzed its detailed signaling pathway using cultured bovine aortic endothelial cells. Our findings indicate that 2 µM of lead inhibited protein tyrosine phosphatase (PTP) activity and induced cyclooxygenase-2 (COX-2) via phosphorylation of the epidermal growth factor receptor (EGFR) and its downstream extracellular signal-regulated kinases (ERK1/2). In addition, among the prostanoids regulated by COX-2, prostaglandin I2 (PGI2) specifically contributes to the downregulation of perlecan expression by lead. This study revealed an intracellular pathway-the EGFR-ERK1/2-COX-2-PGI2 pathway activated by inhibition of PTP by lead-as a pathway that downregulates endothelial perlecan synthesis. The pathway is suggested to serve as a mechanism for the repression of perlecan expression, which leads to a delay in cell proliferation by lead.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 12","pages":"655-663"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Behavioral effects induced by the oral administration of acetamiprid in male mice during the postnatal lactation period or adulthood. 产后哺乳期和成年期口服乙酰氨脒对雄性小鼠行为的影响。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.203

Hirokatsu Saito, Kentaro Tanemura, Yusuke Furukawa, Takahiro Sasaki, Jun Kanno, Satoshi Kitajima

{"title":"Behavioral effects induced by the oral administration of acetamiprid in male mice during the postnatal lactation period or adulthood.","authors":"Hirokatsu Saito, Kentaro Tanemura, Yusuke Furukawa, Takahiro Sasaki, Jun Kanno, Satoshi Kitajima","doi":"10.2131/jts.48.203","DOIUrl":"https://doi.org/10.2131/jts.48.203","url":null,"abstract":"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 mice to ACE (10 mg/kg) orally when they were two (postnatal lactation) or 11 weeks old (adult). We examined the effects of ACE on the central nervous system using the mouse behavioral test battery, consisting of the open field test, light/dark transition test, elevated plus-maze test, contextual/cued fear conditioning test, and pre-pulse inhibition test at 12-13 weeks old. In the mouse behavioral test battery, learning memory abnormalities were detected in the mature treatment group. In addition, learning memory and emotional abnormalities were detected in the postnatal lactation treatment group. These results suggest that the behavioral effects of postnatal lactation treatment with ACE were qualitatively different from the behavioral abnormalities in the mature treatment group.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 4","pages":"203-210"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9294542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events. 氟烷麻醉犬对质子泵抑制剂急性电药理学作用的体内分析:心血管不良事件的转化研究。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.375

Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama

{"title":"In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.","authors":"Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama","doi":"10.2131/jts.48.375","DOIUrl":"https://doi.org/10.2131/jts.48.375","url":null,"abstract":"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 doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 7","pages":"375-385"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10121233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effects of perfluorooctane sulfonate (PFOS) on cognitive behavior and autophagy of male mice. 全氟辛烷磺酸对雄性小鼠认知行为和自噬的影响。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.513

Aojia Zhou, Li Wang, Xuejiao Pi, Cheng Fan, Wenwen Chen, Ziping Wang, Shuang Rong, Ting Wang

{"title":"Effects of perfluorooctane sulfonate (PFOS) on cognitive behavior and autophagy of male mice.","authors":"Aojia Zhou, Li Wang, Xuejiao Pi, Cheng Fan, Wenwen Chen, Ziping Wang, Shuang Rong, Ting Wang","doi":"10.2131/jts.48.513","DOIUrl":"https://doi.org/10.2131/jts.48.513","url":null,"abstract":"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, cognitive function and anxiety-like behavior were evaluated by a series of behavioral tests. The underling mechanisms of PFOS on impaired behaviors were evaluated by HE/Nissl staining, electron microscopy observation and western blot analysis. The results indicated that PFOS-exposed mice exhibited significant cognitive impairment, anxiety, neuronal degeneration and the abnormities of synaptic ultrastructure in the cortex and hippocampus. Western blot analysis indicated that PFOS exposure increased microtubule-associated protein light chain 3 (LC3) and decreased p62 protein levels, which may be associated with activation of autophagy leading to neuron damage. In summary, our results suggest that chronic exposure to PFOS adversely affects cognitive-related behavior in mice. These findings provide new mechanistic insights into PFOS-induced neurotoxicity.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 9","pages":"513-526"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10148836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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. 利用三明治长期冷冻培养的人肝细胞构建扩展的功能性胆管，并应用肝细胞预测药物和食物相关化合物的胆汁排泄。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.251

Takashi Kitaguchi, Shinichiro Horiuchi, Yukie Kuroda, Katsutoshi Ohno, Kazuhiro Kobayashi, Mitsuru Tanaka, Seiichi Ishida

{"title":"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.","authors":"Takashi Kitaguchi, Shinichiro Horiuchi, Yukie Kuroda, Katsutoshi Ohno, Kazuhiro Kobayashi, Mitsuru Tanaka, Seiichi Ishida","doi":"10.2131/jts.48.251","DOIUrl":"https://doi.org/10.2131/jts.48.251","url":null,"abstract":"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 by hepatocytes and bile canaliculi, and the biliary excretion index (BEI) was calculated. After 21 days of culture, the presence of extended and functional bile canaliculi was confirmed by the uptake of two fluorescent substrates. Positive BEIs were observed for taurocholic acid-d4, rosuvastatin, pitavastatin, pravastatin, valsartan, olmesartan, and topotecan (reported biliary-excreted compounds in humans), but no difference in BEI was observed for salicylic acid (a nonbiliary-excreted compound). Furthermore, 8 of 21 food-related compounds with specific structures and reported biliary transporter involvement exhibited positive BEIs. The developed in vitro system was characterized by functional bile canaliculus-like structures, and it could be applied to the prediction of the biliary excretion of pharmaceutical and food-related compounds.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 5","pages":"251-261"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9396783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Development of a GCN-based model to predict in vitro phototoxicity from the chemical structure and HOMO-LUMO gap. 从化学结构和HOMO-LUMO间隙预测基于gcn的体外光毒性模型的建立。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.243

Yoshinobu Igarashi, Suyong Re, Ryosuke Kojima, Yasushi Okuno, Hiroshi Yamada

{"title":"Development of a GCN-based model to predict in vitro phototoxicity from the chemical structure and HOMO-LUMO gap.","authors":"Yoshinobu Igarashi, Suyong Re, Ryosuke Kojima, Yasushi Okuno, Hiroshi Yamada","doi":"10.2131/jts.48.243","DOIUrl":"https://doi.org/10.2131/jts.48.243","url":null,"abstract":"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 relationship (QSAR) models for phototoxicity have been developed, in silico technology to evaluate phototoxicity has not been well established. In this study, we attempted to develop an artificial intelligence (AI) model to predict the in vitro Neutral Red Uptake Phototoxicity Test results from a chemical structure and its derived information. To accomplish this, we utilized an open-source software library, kMoL. kMoL employs a graph convolutional neural networks (GCN) approach, which allows it to learn the data for the specified chemical structure. kMoL also utilizes the integrated gradient (IG) method, enabling it to visually display the substructures contributing to any positive results. To construct this AI model, we used only the chemical structure as a basis, then added the descriptors and the HOMO-LUMO gap, which was obtained from quantum chemical calculations. As a result, the assortment of chemical structures and the HOMO-LUMO gap produced an AI model with high discrimination performance, and an F1 score of 0.857. Additionally, our AI model could visualize the substructures involved in phototoxicity using the IG method. Our AI model can be applied as a toxicity screening method and could enhance productivity in drug development.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 5","pages":"243-249"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9396784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epigenetic mutagen-like environmental chemicals alter neural differentiation of human induced pluripotent stem cells. 表观遗传诱变剂样环境化学物质改变人类诱导多能干细胞的神经分化。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2023-01-01 DOI: 10.2131/jts.48.571

Yoshikazu Arai, Koichiro Nishino

{"title":"Epigenetic mutagen-like environmental chemicals alter neural differentiation of human induced pluripotent stem cells.","authors":"Yoshikazu Arai, Koichiro Nishino","doi":"10.2131/jts.48.571","DOIUrl":"https://doi.org/10.2131/jts.48.571","url":null,"abstract":"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, and selenium) detected in the serum of pregnant mothers on neural development using human neurospheres (NSphs) differentiated from induced pluripotent stem cells. Exposure to each chemical at serum concentrations revealed no effects on NSph development. However, combined exposure to the five chemicals caused a significant decrease in NSph size and altered gene expression and neural differentiation. Thus, we next focused on DNA methylation to investigate changes in NSph properties caused by chemical exposure. Combined exposure to chemicals had extremely small effects on the DNA methylation status of NSphs at individual gene loci. However, stochastic changes in methylation status caused by chemical exposure were significantly accumulated throughout the entire genome. These results suggest that the five chemicals acted as epimutagens that alter the epigenetic status during human neural development at the biological level. Taken together, we showed for the first time, the epimutagen-induced alterations in neural differentiation at serum concentrations using an in vitro human neuronal model.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"48 11","pages":"571-583"},"PeriodicalIF":2.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71424665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0