Toxicological Research最新文献

{"title":"In vitro metabolism and inhibitory effect of vonifimod on drug-metabolizing enzymes in human liver preparations.","authors":"Eun Jeong Kim, Min Seo Lee, Yang Hae Park, Bongyong Lee, Hye Suk Lee","doi":"10.1007/s43188-025-00329-5","DOIUrl":"https://doi.org/10.1007/s43188-025-00329-5","url":null,"abstract":"<p><p>Vonifimod is a novel sphingosine-1-phosphate receptor (S1PR) modulator with selectivity for S1PR1 and S1PR4 that is under development for the treatment of autoimmune disease. No reports on vonifimod metabolism exist except for the formation of active vonifimod-phosphate in rats. The in vitro metabolic pathways and drug interaction potentials of vonifimod were characterized by identifying the metabolites of vonifimod in human hepatocytes via liquid chromatography-high-resolution mass spectrometry and determining the inhibitory effects of vonifimod on major cytochrome P450 (CYP) and UDPGA-glucuronosyltransferase (UGT) enzyme activities in human liver microsomes. The incubation of vonifimod with human hepatocytes resulted in the formation of nine metabolites, including hydroxy-vonifimod (M1 and M2), inactive carboxylic acids (M3 - M6), active vonifimod-phosphate (M7), and M3 glucuronides (M3-G1 and M3-G2). ω-Hydroxylation of vonifimod to M2 at the methyl terminus of the decyl chain was catalyzed mainly by CYP4F2 enzymes, which were further oxidized to four carboxylic acid metabolites (M3 - M6). UGT1A7, UGT1A8, UGT1A9, and UGT1A10 catalyzed the formation of M3-G2 from M3. Vonifimod revealed the negligible and weak inhibition of major CYP and UGT enzyme activities at 50 µM in human liver microsomes, suggesting that vonifimod has low potential for drug-drug interactions. These findings suggest hepatic metabolism to be the primary elimination pathway for vonifimod.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 3","pages":"345-359"},"PeriodicalIF":2.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phloroglucinol protects skin cells from particulate matter 2.5-induced oxidative stress and apoptosis.","authors":"Pincha Devage Sameera Madushan Fernando, Kyoung Ah Kang, Mei Jing Piao, Herath Mudiyanselage Udari Lakmini Herath, Herath Mudiyanselage Maheshika Madhuwanthi Senavirathna, Mee Jung Ahn, Changlim Hyun, Jin Won Hyun","doi":"10.1007/s43188-025-00324-w","DOIUrl":"https://doi.org/10.1007/s43188-025-00324-w","url":null,"abstract":"<p><p>Particulate matter 2.5 (PM_2.5) is an air pollutant that causes skin inflammation and aging. Phloroglucinol (PG) is a naturally occurring polyphenol with strong antioxidant potential that is widely used in pharmaceutical production. Information regarding the protective effect of PG against PM_2.5-induced cellular damage is lacking; therefore, this study evaluated the protective effect of PG against the detrimental effects of PM_2.5. PG reduced cellular reactive oxygen species levels in a dose-dependent manner. Furthermore, PG reduced PM_2.5-induced 8-hydroxydeoxyguanosine, protein carbonylation, 8-isoprostane, interleukin (IL)-6, and IL-1β levels. PG reduced PM_2.5-induced apoptosis by inhibiting the expression of pro-apoptotic proteins and mitochondrial membrane depolarization. PG restored PM_2.5-impaired nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (Ho-1) protein expression. Furthermore, PG reduced PM_2.5-induced mitogen-activated protein kinase pathway-related protein expression. Assessment of mouse skin tissue further confirmed that PG could restore PM_2.5-reduced Nrf2 and Ho-1 expression and reduce PM_2.5-induced thickening of the mouse epidermis. Overall, PG exhibited a strong potential to reduce PM_2.5-mediated skin cell damage by activating the antioxidant defense system.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"251-260"},"PeriodicalIF":2.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Artificial intelligence‑based quantitative analysis of hepatic fibrosis in carbon tetrachloride-induced mouse model of metabolic dysfunction-associated steatohepatitis.","authors":"Jin-Hee Lee, Myung-Hwa Yang, Gyeongjin Han, Won Hoon Jung, Myung Ae Bae, Ji-Seok Han, Tae-Sung Koo, Jae-Woo Cho","doi":"10.1007/s43188-025-00326-8","DOIUrl":"https://doi.org/10.1007/s43188-025-00326-8","url":null,"abstract":"<p><p>Liver fibrosis, a major histopathological indicator of chronic liver injury, is also a key feature of metabolic dysfunction-associated steatohepatitis. Its quantitative assessment in preclinical toxicology is frequently inconsistent and subjective. This study aimed to develop and validate multi-scale, patch-based convolutional neural network classification algorithms for automated fibrosis quantification in a carbon tetrachloride (CCl₄)-induced mouse model. We sought to determine the optimal patch size for accurate predictions. Accordingly, male C57BL/6 mice (n = 19) were categorized into the following three groups: vehicle control (n = 5), high-fat diet (HFD) and CCl₄ positive control (n = 9), and HFD and CCl₄ with elafibranor (ELA) treatment (n = 5). Liver tissues were stained with Sirius-red, digitized as whole slide images, and cropped into patches of 32 × 32, 64 × 64, or 128 × 128 pixels. Each algorithm was trained, validated, and tested in an 8:1:1 ratio over 40 epochs with a batch size of 32 to classify fibrotic, normal, and background regions. All models performed robustly, with validation accuracies exceeding 98% and F1-scores above 0.96. Particularly, the 32 × 32 model exhibited the highest correlation with pathologist's measurements (Spearman's <i>r</i> = 0.9609; <i>p</i> < 0.05) and the most accurate estimation of absolute fibrotic area compared to expert assessments. This model also accurately detected the antifibrotic effects of ELA. These findings establish that the 32 × 32 patch-based classification approach provides a rapid, reproducible, and objective method for liver fibrosis quantification in preclinical toxicology, with strong potential for integration into digital pathology workflows.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00326-8.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"235-250"},"PeriodicalIF":2.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug induced TdP risks classification assay using electro-mechanical models of human ventricle based on CiPA framework.","authors":"Aulia Khamas Heikhmakhtiar, Ali Ikhsanul Qauli, Yunendah Nur Fu'adah, Muhammad Adnan Pramudito, Iga Narendra Pramawijaya, Aroli Marcellinus, Kim Yoo Seok, Frederique Jos Vanheusden, Ki Moo Lim","doi":"10.1007/s43188-025-00320-0","DOIUrl":"https://doi.org/10.1007/s43188-025-00320-0","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Predicting drug-induced cardiac toxicity is critical for drug safety assays, especially when evaluating risks of inducing Torsade de Pointes (TdP). This study proposes an integrated electromechanical model of myocytes for TdP risk assessment, extending the CiPA framework. Human electrophysiological models of CiPAORdv1.0, ORD, and ToR were integrated with a Land mechanical ventricle model. Twenty-seven parameters were observed, including the net current ( &lt;math&gt;&lt;mrow&gt;&lt;mi&gt;qNet&lt;/mi&gt;&lt;/mrow&gt; &lt;/math&gt; ), inward current ( &lt;math&gt;&lt;mrow&gt;&lt;mi&gt;qInward&lt;/mi&gt;&lt;/mrow&gt; &lt;/math&gt; ), action potential profile, intracellular calcium profile, and tension profile. We used ordinal logistic regression with 12 drugs as training dataset and validated using unseen data from the remaining 16 drugs following the protocol from the FDA. We observed that the electromechanical model improved the TdP risk classification in most of the parameters derived from the action potential, Calcium Transient ( &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;Ca&lt;/mi&gt;&lt;/mrow&gt; &lt;mi&gt;i&lt;/mi&gt;&lt;/msub&gt; &lt;/math&gt; )&lt;i&gt;,&lt;/i&gt; and tension profile. The CiPAORdv1.0 + Land not only preserved &lt;math&gt;&lt;mrow&gt;&lt;mi&gt;qNet&lt;/mi&gt;&lt;/mrow&gt; &lt;/math&gt; performance but improved the classification performance using &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;APD&lt;/mi&gt;&lt;/mrow&gt; &lt;mn&gt;50&lt;/mn&gt;&lt;/msub&gt; &lt;/math&gt; , &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;APD&lt;/mi&gt;&lt;/mrow&gt; &lt;mn&gt;90&lt;/mn&gt;&lt;/msub&gt; &lt;/math&gt; &lt;i&gt;,&lt;/i&gt; &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;CaD&lt;/mi&gt;&lt;/mrow&gt; &lt;mn&gt;90&lt;/mn&gt;&lt;/msub&gt; &lt;/math&gt; &lt;i&gt;,&lt;/i&gt; &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;Ca&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;tri&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; &lt;i&gt;,&lt;/i&gt; &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;ti&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;tri&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; , and &lt;math&gt;&lt;mrow&gt;&lt;mi&gt;EMW&lt;/mi&gt;&lt;/mrow&gt; &lt;/math&gt; . On the other hand, ToR + Land model improved the parameter of &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;CaTD&lt;/mi&gt;&lt;/mrow&gt; &lt;mn&gt;50&lt;/mn&gt;&lt;/msub&gt; &lt;/math&gt; and &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;CaD&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mn&gt;50&lt;/mn&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mi&gt;t&lt;/mi&gt; &lt;mi&gt;p&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; . The ORD + Land model showed some improvement in &lt;math&gt;&lt;msub&gt;&lt;mi&gt;V&lt;/mi&gt; &lt;mrow&gt;&lt;mi&gt;max&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; , and some well for other parameters including &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;CaTD&lt;/mi&gt;&lt;/mrow&gt; &lt;mn&gt;90&lt;/mn&gt;&lt;/msub&gt; &lt;/math&gt; &lt;i&gt;,&lt;/i&gt; &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;CaD&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mn&gt;90&lt;/mn&gt; &lt;mo&gt;,&lt;/mo&gt; &lt;mi&gt;t&lt;/mi&gt; &lt;mi&gt;p&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; &lt;i&gt;,&lt;/i&gt; &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;Ca&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;tri&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; and &lt;math&gt; &lt;msub&gt;&lt;mrow&gt;&lt;mi&gt;ti&lt;/mi&gt;&lt;/mrow&gt; &lt;mrow&gt;&lt;mi&gt;tri&lt;/mi&gt;&lt;/mrow&gt; &lt;/msub&gt; &lt;/math&gt; . This work highlights the advantage of an electromechanical ventricular model for assessing drug-induced TdP risk compared to an electrophysiological model. Overall, the coupled models improved the TdP classification performance based on APD and calcium as well as tension profile. Further optimization of the models and inclusion of more drugs in training the models can improve interpretability and predictive accuracy for TdP risk assessment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Supplementary information: &lt;/strong&gt;The online version contains supplementary material available at 10.1007/s4318","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"217-233"},"PeriodicalIF":2.3,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid ecotoxicity and genotoxicity assessment using <i>Macropodus ocellatus</i> cells.","authors":"Minseon Kim, Ji Ho Park, Byeonghyeon So, Hojun Lee, Jee Hee Yoon, Yoo Jin Lee, Duyeol Kim, Hyung Wook Kwon, Jihae Park, Taejun Han, Sekyung Oh, Yun Haeng Lee, Joon Tae Park","doi":"10.1007/s43188-025-00325-9","DOIUrl":"https://doi.org/10.1007/s43188-025-00325-9","url":null,"abstract":"<p><p>Toxic substances can cause serious harm to aquatic organisms and humans who consume them. Rapid ecotoxicity assessment and genotoxicity assessment should be performed simultaneously to detect potential harm caused by toxic substances. In a previous study, an ecotoxicity and genotoxicity assessment system was established by treating fish cells derived from <i>Cyprinus carpio</i> (<i>C. carpio</i>) with toxic substances in a medium containing 1% fetal bovine serum (FBS) for 6 h. In this study, these conditions (1% FBS/6 h) were applied to fish cells derived from <i>Macropodus ocellatus</i> (<i>M. ocellatus</i>). Surprisingly, the new assessment tool using <i>M. ocellatus</i> cells provided ecotoxicity and genotoxicity data similar to those of <i>C. carpio</i> cells. In addition, the new assessment tool demonstrated its suitability as an assessment platform by demonstrating ecotoxicity and genotoxicity for substances known to be genotoxic (fluxapyroxad, fipronil, clarithromycin, 2,4-di-tert-butylphenol, perfluorooctanoic acid, prochloraz, abamectin, and climbazole). In conclusion, this study established an ecotoxicity and genotoxicity assessment system that can rapidly generate data. This assessment platform can be used as a tool to analyze a large number of toxins within a given period of time.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00325-9.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"199-216"},"PeriodicalIF":2.3,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of alternative cell models to BALB/c 3T3 for in vitro neutral red uptake phototoxicity test of pharmaceuticals: NIH 3T3 and HaCaT cells.","authors":"Jee-Hyun Hwang, Jeong-Hyun Hong, Kyung-Min Lim","doi":"10.1007/s43188-025-00323-x","DOIUrl":"https://doi.org/10.1007/s43188-025-00323-x","url":null,"abstract":"<p><p>Phototoxicity assessment is a critical component of preclinical safety assessment of pharmaceuticals with potential photosensitivity. 3T3 Neutral Red Uptake (NRU) Phototoxicity test, OECD Test Guideline 432, has been widely used as a reference method but concerns about oversensitivity to UVA, insufficient cell attachment and resultant difficulties in achieving the acceptance criteria is raised, which is mainly attributable to aged and over-sensitized BALB/c 3T3 cell line. Here, we compared BALB/c 3T3, NIH 3T3, and HaCaT cell lines for in vitro NRU phototoxicity test using 3 phototoxic pharmaceuticals and non-phototoxic chemicals with well-established photo-reactivity profiles. BALB/c 3T3 cells showed oversensitivity to UVA, which often showed decreased viability below 80% of non-irradiated control. Cell counts were increased to 2 × 10⁴ cells to meet the viability criteria. With established experimental condition, in vitro phototoxicity tests were done with three cell lines. While all three cell lines succeeded in distinguishing phototoxic pharmaceuticals, significant differences were noted in sensitivity metrics: BALB/c 3T3 displayed the highest responsiveness, whereas NIH 3T3 exhibited moderate sensitivity followed by HaCaT. In addition, NIH 3T3 and HaCaT showed higher tolerance to UV-induced damages, uniform adherence to culture surface, and minimal well-to-well variability, thereby improving assay reproducibility. Collectively, these findings demonstrated that NIH 3T3 and HaCaT cells can be used as better alternatives to BALB/c 3T3 in the in vitro phototoxicity test.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"187-197"},"PeriodicalIF":2.3,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A decrease in Atp8a2 expression in Purkinje cells mediated acrylamide-induced cerebellar pathology in rats.","authors":"Kai Yan, Wenhui Liu, Siqi Xu, Lifang Li, Jiaqi Zhang, Zhoutong Luo, Guoying Li, Junhua Yang","doi":"10.1007/s43188-025-00322-y","DOIUrl":"https://doi.org/10.1007/s43188-025-00322-y","url":null,"abstract":"<p><p>Atp8a2 is a type of phospholipid flippases, highly expressed in the cerebellum, functioning to maintain the stability and normal function of the cytomembrane by transporting phosphatidylserine into the cytoplasmic membrane. Atp8a2 mutations and knockout can cause neuronal PS externalization and cerebellar ataxia. The cerebellar damage caused by acrylamide (ACR) exposure has similar pathological features to the symptoms caused by Atp8a2 mutations and knockout. However, the expression of Atp8a2 in the cerebellum and whether Atp8a2 alterations are involved in the pathogenesis of ACR neurotoxicity remain unclear. Here, we find that gavage of 0.5 mg/kg and higher doses of ACR decreased Atp8a2 expression in male SD rats' Purkinje cells, while the loss of Purkinje cells was observed only at 20 mg/kg. The upregulation of Atp8a2 blocks phosphatidylserine externalization and the loss of Purkinje cells and mitigates the increase in the number of microglia in SD rats exposed to 20 mg/kg ACR. These suggest that Atp8a2 expression is sensitive to the neurotoxicity of ACR, and decreased Atp8a2 expression is involved in the mechanism of ACR-induced cerebellar injury. This study provides a new important clue for understanding the mechanism of ACR-induced cerebellar lesions and evaluating dose standards for ACR neurotoxicity.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00322-y.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"171-186"},"PeriodicalIF":2.3,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bisphenol AF induces mouse spermatogonia apoptosis via reactive oxygen species-mediated Beclin-1 cleavage.","authors":"Hyo Jin Gu, Gil Un Han, Seul Gi Kim, Sung-Hwan Moon, Seung Hee Shin, Buom-Yong Ryu","doi":"10.1007/s43188-025-00321-z","DOIUrl":"https://doi.org/10.1007/s43188-025-00321-z","url":null,"abstract":"<p><p>Oxidative stress plays an essential role in homeostasis, cell signaling, and host defense mechanisms. However, excessive levels are harmful and cause DNA damage, lipid peroxidation, and mitochondrial dysfunction, ultimately causing cell death. Oxiapoptophagy, a cell death mechanism driven by excessive reactive oxygen species (ROS), involves both apoptosis and autophagy. This study investigated the mechanisms underlying bisphenol AF (BPAF)-induced cell death in mouse GC-1 spermatogonia (spg), using 7-ketocholesterol (7KC) as a reference oxiapoptophagy inducer. Both 7KC and BPAF inhibited GC-1 spg proliferation with comparable half-maximal inhibitory concentration (IC₅₀): 16.9 µM for 7KC and 16.5 µM for BPAF. However, BPAF induced significantly higher ROS levels than 7KC. At 20 µM, BPAF predominantly triggered apoptosis, whereas 7KC mainly promoted autophagy. BPAF evidently increased cleaved Beclin-1 levels, suggesting a transition from autophagy to apoptosis and implicating Beclin-1 cleavage as key modulator of apoptosis. Furthermore, the ROS scavenger N-acetyl cysteine (NAC) reduced BPAF-induced ROS production, suppressed Beclin-1 cleavage, and partially restored GC-1 spg proliferation. Collectively, these findings demonstrate that BPAF-induced spermatogonia toxicity is mediated by ROS and regulated through Beclin-1 cleavage, underscoring the need for further investigation of BPAF's reproductive toxicity and the development of strategies to protect male reproductive health.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 1","pages":"113-125"},"PeriodicalIF":2.3,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12770039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deficiency of the voltage‑gated proton channel Hv1 aggravates lung damage induced by exposure to carboxylated carbon black and carboxylated carbon black@lead.","authors":"Shangrong Zhang, Ji Chen, Jie Li, Xin Ming, Jingya Li, Zijian Ma, Qing Liu, Shuanglin Jiang, Xiaoqing Wu, Hongcheng Wang, Yong Liu","doi":"10.1007/s43188-025-00319-7","DOIUrl":"https://doi.org/10.1007/s43188-025-00319-7","url":null,"abstract":"<p><p>Black carbon has attracted significant attention because of its severe health hazards. Carbon black (CB), a commercially available standardized particulate material, is widely used as a surrogate model in toxicological studies. The voltage-gated proton channel Hv1, encoded by the <i>Hvcn1</i> gene, is specifically expressed in lung epithelial cells and regulates the generation of reactive oxygen species. However, the role of Hv1 in lung homeostasis remains unclear. In this study, we constructed an Hv1 knockout (KO) mouse model via CRISPR/Cas9 technology to investigate the impact of channel deficiency on lung injury induced by exposure to CB particles. Our findings revealed that Hv1 deficiency significantly exacerbated lung injury caused by CB particles compared with that in wild-type (WT) mice. Specifically, Hv1 knockout mice presented significantly elevated levels of inflammatory and cytokine factors in bronchoalveolar lavage fluid (BALF). Further analysis demonstrated that Hv1 deficiency led to increased malondialdehyde content and decreased superoxide dismutase activity in the BALF of mice exposed to CB particles, indicating increased oxidative stress. Histopathological staining and immunohistochemical experiments confirmed that the absence of the proton channel resulted in thickened alveolar walls, exacerbated inflammatory cell infiltration, and increased fibrous protein deposition in lung tissues. Further immunohistochemical analysis revealed that, compared with WT mice, Hv1 KO mice presented significantly decreased E-cadherin expression and increased vimentin and α-SMA expression in lung tissue after CB particle exposure. Furthermore, exposure to CB particles significantly elevated transforming growth factor-beta 1 levels in the BALF of Hv1 KO mice relative to WT controls. Collectively, these findings demonstrate that Hv1 deficiency potentiates particulate matter-induced lung injury by exacerbating pulmonary inflammation, oxidative stress, and epithelial‒mesenchymal transition. This study establishes Hv1 as a critical protective factor against particulate matter-induced lung damage and highlights its potential as a therapeutic target for preventing and treating particulate matter-associated pulmonary disorders.</p><p><strong>Graphical abstract: </strong></p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00319-7.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 1","pages":"99-111"},"PeriodicalIF":2.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12770054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Alanine alleviated non-alcoholic fatty liver disease via regulation of hepatic sulfur-amino acid metabolism in mice.","authors":"Joohee Lee, Sou-Hyun Kim, Jiwon Hwang, Young-Suk Jung, Doyoung Kwon","doi":"10.1007/s43188-025-00313-z","DOIUrl":"https://doi.org/10.1007/s43188-025-00313-z","url":null,"abstract":"<p><p>β-Alanine is a non-essential β-amino acid used as a dietary supplement for improvement of exercise performance. The hepatic influence of β-alanine has been controversial in previous studies and its effects on nonalcoholic fatty liver disease (NAFLD) are uncertain. In the present study, we examined the role of β-alanine on diet-induced NAFLD in mice and determined the hepatic S-amino acid (SAA) metabolism to identify the cellular mechanisms. Male C57BL/6 mice were provided with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 2 weeks to induce NAFLD, and simultaneously supplemented with β-alanine (3%, w/v) in drinking water. CDAHFD-induced liver injury, steatosis, and oxidative stress as shown by the increased serum alanine aminotransferase and aspartate aminotransferase activities, and hepatic triglyceride and lipid peroxide levels, respectively, but β-alanine alleviated these changes. The CDAHFD promoted significant changes in SAA metabolites, including reduced S-adenosylmethionine (SAM) and hypotaurine levels, and elevated homocysteine and taurine levels in the liver. β-Alanine attenuated the decrement of the SAM induced by the CDAHFD via the restoration of methionine adenosyltransferase activity, which appeared to ameliorate fat accumulation by stimulating hepatic lipid export via very-low-density lipoprotein secretion. Moreover, the induction of fatty acid β-oxidation, as shown by the elevations of peroxisome proliferator-activated receptor-gamma coactivator 1-α, carnitine palmitoyltransferase 1A, and acyl-CoA dehydrogenase medium chain proteins, may contribute to the anti-steatogenic effect of β-alanine. Normalizations of hepatic homocysteine and hypotaurine levels due to the restorations of cystathionine β-synthase and cysteine sulfinic acid decarboxylase, respectively, along with increased glutathione levels may be the mechanisms of inhibition of CDAHFD-induced oxidative stress by β-alanine. These results suggest that β-alanine can improve NAFLD via its antioxidant and anti-steatotic effects by restoring hepatic SAA metabolism.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 1","pages":"47-58"},"PeriodicalIF":2.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12770030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}