Toxicology最新文献

{"title":"Chronic exposure to polystyrene microplastics triggers osteoporosis by breaking the balance of osteoblast and osteoclast differentiation","authors":"Chun Pan ,&nbsp;Runyang Hong ,&nbsp;Kehan Wang ,&nbsp;Yujie Shi ,&nbsp;Zhencheng Fan ,&nbsp;Tingting Liu ,&nbsp;Hao Chen","doi":"10.1016/j.tox.2024.154017","DOIUrl":"10.1016/j.tox.2024.154017","url":null,"abstract":"<div><div>Plastic pollution is becoming more and more serious, and microplastics (MPs) formed by degradation from plastics significantly threaten the health of animals and humans. However, it remains unknown how MPs interfere with bone homeostasis by regulating the function of bone marrow mesenchymal stem cells (BMSCs). In order to simulate the toxic impacts of long-term low-dose MPs on the skeletal system, we constructed a 6-month drinking water model of mice exposed to MPs. We found that the bone microstructure in the femur of mice exposed to MPs was destroyed, the quantity of bone trabeculae decreased sharply and the bone mass decreased significantly, accompanied by the decrease of bone formation and the activation of osteoclasts. In addition, RNA sequencing showed NF-κB pathway was activated in MPs-treated BMSCs, manifested as significantly up-regulated inflammatory factors, accelerated the senescence of BMSCs, and inhibited their osteogenic differentiation and extracellular mineralization. Senescent BMSCs induced by MPs led to the overproduction of RANKL, which contributed to the production of more osteoclasts. Importantly, the administration of NF-κB inhibitors <em>in vivo</em> markedly diminished MPs-induced BMSCs senescence and impaired osteogenic differentiation. Meanwhile, the secretion of RANKL caused by MPs was reversed, and osteoclast formation was significantly reduced. In summary, our data innovatively reveal the core mechanism of MPs in bone balance. By promoting the NF-κB signaling pathway, it significantly accelerates the aging of BMSCs, causes a decrease in bone formation, and promotes osteoclast formation through RANKL.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154017"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFR-TKIs induce acneiform rash and xerosis via Caspase-3/GSDME-mediated pyroptosis of keratinocytes and sebocytes.","authors":"Huiling Zhu, Qiuyun She, Hongmei Li, Ning Zhang, Weining Huang, Yingping Xu, Zhongrong Liu, Yunsheng Liang","doi":"10.1016/j.tox.2024.154018","DOIUrl":"https://doi.org/10.1016/j.tox.2024.154018","url":null,"abstract":"<p><p>Skin toxicities are the most common adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). While EGFR-TKIs induce pyroptosis in lung cancer cells through Gasdermin E (GSDME) activation, it is unknown whether they can similarly affect skin cells. In this study, we used immunohistochemistry to demonstrate that in acneiform rash, the N-terminus of GSDME (GSDME-N) is predominantly expressed in the basal layer of the follicular epithelium and sebocytes, while it is absent in the interfollicular epidermis. In contrast, in cases of xerosis or secondary eczematous rash, GSDME-N was significantly expressed in the basal layer of the interfollicular epidermis and weakly or partially positive in the follicular epithelium. Bright-field microscopy of HaCaT and SZ95 cells treated with afatinib revealed cell swelling and large bubble formation, while scanning electron microscopy showed a reduction in microvilli and membrane pores formation. Transmission electron microscopy further revealed multiple membrane pores and decreased cytoplasmic density. Importantly, we found that GSDME is cleaved during afatinib-induced pyroptosis via caspase-3 activation. ELISA analysis further confirmed that afatinib-treated cells released elevated levels of HMGB1 and IL-1α. Meanwhile, inhibition of caspase-3 activity or knockdown of GSDME both suppressed afatinib-induced pyroptosis, while GSDME elimination did not affect caspase-3 activation. These results indicate that afatinib-induced pyroptosis in keratinocytes and sebocytes is mediated by the caspase-3/GSDME pathway. Our findings suggest that GSDME-dependent pyroptosis in HaCaT and SZ95 cells contributes to the development of acneiform rash and xerosis, highlighting the need for further investigation into the underlying mechanisms.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154018"},"PeriodicalIF":4.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic analysis of human iPSC-derived sympathetic neurons identifies proteostasis collapse as a molecular signature following subtoxic rotenone exposure","authors":"Tamar Gordon ,&nbsp;Mahmood Ali Saleh ,&nbsp;Metsada Pasmanik-Chor ,&nbsp;Gad D. Vatine ,&nbsp;Avraham Ashkenazi","doi":"10.1016/j.tox.2024.154015","DOIUrl":"10.1016/j.tox.2024.154015","url":null,"abstract":"<div><div>Rotenone is a toxic isoflavone and an inhibitor of the mitochondrial respiratory chain. Rotenone is commonly used due to its piscicidal and pesticidal properties. The peripheral nervous system (PNS) lacks protective barriers and is exposed to many environmental substances due to its long-reaching structure. A causal association between rotenone and human PNS dysfunction is currently a subject of investigation. Here, we treated human induced pluripotent stem cell (iPSC)-derived peripheral sympathetic neurons with a subtoxic dose of rotenone (10 µg/L) that is considered safe for human health and is permitted for environmental use. Indeed, no overt toxicity was observed in the human peripheral neurons and neurite morphology was intact in the treated neurons. Surprisingly, we detected significant changes in the proteome of rotenone-exposed sympathetic neurons with a signature of protein homeostasis (proteostasis) collapse. Screening the proteostasis modules of protein translation, proteolysis, and chaperones, revealed severe perturbations in clusters of autophagy regulators. Our proteomic profiling reveals compromised proteostasis as a consequence of low-dose non-toxic exposure to rotenone, which can disrupt the ability of the PNS to cope with proteotoxic stress. Exposed individuals may have varying degrees of tolerance to such vulnerabilities but they may eventually progress into peripheral neuropathies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154015"},"PeriodicalIF":4.8,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrabromobisphenol A induced p38-MAPK/AMPKα activation downstream-triggered CHOP signal contributing to neuronal apoptosis and death","authors":"Jui-Ming Liu ,&nbsp;Shing-Hwa Liu ,&nbsp;Shih-Chang Fu ,&nbsp;Wei-Cheng Lai ,&nbsp;Kai-Min Fang ,&nbsp;Ken-An Lin ,&nbsp;Jun-An Ke ,&nbsp;Chun-Ying Kuo ,&nbsp;Chin-Chuan Su ,&nbsp;Ya-Wen Chen","doi":"10.1016/j.tox.2024.154014","DOIUrl":"10.1016/j.tox.2024.154014","url":null,"abstract":"<div><div>Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, −7, −9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and −7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and −7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and −7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154014"},"PeriodicalIF":4.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient analysis of toxicity and mechanisms of Acetyl tributyl citrate on aging with network toxicology and molecular docking strategy","authors":"Qiu Zheng ,&nbsp;Qingping Peng ,&nbsp;Jianlin Shen ,&nbsp;Huan Liu","doi":"10.1016/j.tox.2024.154009","DOIUrl":"10.1016/j.tox.2024.154009","url":null,"abstract":"<div><div>The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154009"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project)","authors":"Laura Micheli ,&nbsp;David Balayssac ,&nbsp;Jérôme Busserolles ,&nbsp;Cristelle Dalbos ,&nbsp;Laetitia Prival ,&nbsp;Damien Richard ,&nbsp;Mercedes Quintana ,&nbsp;Lorenzo Di Cesare Mannelli ,&nbsp;Alessandra Toti ,&nbsp;Clara Ciampi ,&nbsp;Carla Ghelardini ,&nbsp;Katerina Vlasakova ,&nbsp;Warren E. Glaab ,&nbsp;Yang Hu ,&nbsp;Irena Loryan ,&nbsp;Olivier Perrault ,&nbsp;Mohamed Slaoui ,&nbsp;Kuno Wuersch ,&nbsp;Eric Johnson ,&nbsp;Wilfried Frieauff ,&nbsp;Diethilde Theil","doi":"10.1016/j.tox.2024.153998","DOIUrl":"10.1016/j.tox.2024.153998","url":null,"abstract":"<div><div>Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153998"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing","authors":"Malene Lislien ,&nbsp;Eliska Kuchovska ,&nbsp;Julia Kapr ,&nbsp;Nur Duale ,&nbsp;Jill Mari Andersen ,&nbsp;Hubert Dirven ,&nbsp;Oddvar Myhre ,&nbsp;Ellen Fritsche ,&nbsp;Katharina Koch ,&nbsp;Marcin W. Wojewodzic","doi":"10.1016/j.tox.2024.154000","DOIUrl":"10.1016/j.tox.2024.154000","url":null,"abstract":"<div><div>The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current <em>in vivo</em> testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days. Using high-throughput RNA sequencing, we compared gene expression profiles of 2D and 3D models at three developmental stages (3, 14, and 21 days of differentiation). Both models exhibit maturation towards post-mitotic neurons, with the 3D model maturing faster and showing a higher prevalence of GABAergic neurons, while the 2D model is enriched with glutamatergic neurons. Both models demonstrate broad applicability domains, including excitatory and inhibitory neurons, astrocytes, and key endocrine and especially the understudied cholinergic receptors. Comparison with human fetal brain samples confirms their physiological relevance. This study provides novel in-depth applicability insights into the temporal and dimensional aspects of hiPSC-derived neural models for DNT testing. The complementary use of these two models is highlighted: the 2D model excels in synaptogenesis assessment, while the 3D model is particularly suited for neural network formation as observed as well in previous functional studies with these models. This research marks a significant advancement in developing human-relevant, high-throughput DNT assays for regulatory purposes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154000"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review of the proline mimic azetidine-2-carboxylic acid (A2C)","authors":"Kenneth J. Rodgers,&nbsp;James Kabalan,&nbsp;Connor R. Phillips","doi":"10.1016/j.tox.2024.153999","DOIUrl":"10.1016/j.tox.2024.153999","url":null,"abstract":"<div><div>The imino acid azetidine-2-carboxylic acid (A2C), a proline homologue, was first identified in liliaceous plants in 1955. Its ability to exchange for proline in protein synthesis is responsible for its teratogenic effects and has made it a very useful tool for generating non-native proteins to study proteotoxic stress and ER stress. The tRNA synthetases from some A2C-producing plants can discriminate between proline and A2C, but for most plants and for mammalian cells, A2C is mistakenly used in protein synthesis in place of proline and can avoid cell proof-reading mechanisms. Human exposure to A2C would be very limited had it not been for the development of sugar beets as an alternative source of dietary sucrose to sugar cane, and the widespread use of the plentiful byproducts as livestock fodder. Fodder beets, a very high yielding forage crop, are also used as livestock fodder particularly for lactating cows. It is therefore possible for A2C to enter the human food chain and impact human health. It was hypothesised that its ability to replace proline in protein synthesis generates immunogenic neo-epitopes in myelin basic protein and could therefore be a causative factor for multiple sclerosis. In this review we discuss the distribution of A2C in nature, what is known about its toxicity, and the impact of the proline to A2C exchange on protein structure and function and in particular the proteins collagen and myelin basic protein. We summarise analytical approaches that can be used to quantify A2C in complex biological samples and the adaptations made by some organisms to avoid its toxic effects. We summarise the evidence for human exposure to A2C and the geographical and temporal links to higher incidences of MS. Finally, we highlight gaps in our knowledge that require addressing before we can determine if this non-protein amino acid is a threat to human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153999"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to polystyrene nanoplastics promotes premature cellular senescence through mitochondrial ROS production and dysfunction in pre-differentiated skeletal myoblasts","authors":"EunJin Bang ,&nbsp;Hyun Hwangbo ,&nbsp;Hyesook Lee ,&nbsp;Cheol Park ,&nbsp;Su Hyun Hong ,&nbsp;Hyuk Soon Kim ,&nbsp;Youngmi Jung ,&nbsp;Young-Min Hyun ,&nbsp;Jin Won Hyun ,&nbsp;Gi-Young Kim ,&nbsp;Yung Hyun Choi","doi":"10.1016/j.tox.2024.154002","DOIUrl":"10.1016/j.tox.2024.154002","url":null,"abstract":"<div><div>Nanoplastics (NPs) are emerging environmental contaminants present in atmospheric, freshwater, and aquatic environments. NPs can rapidly permeate cell membranes and build up in human tissues and organs, causing a potential threat to human health. As the skeletal muscle undergoes aging, myogenesis gradually deteriorates, leading to loss of muscle mass. While previous studies have demonstrated the adverse and toxic effects of polystyrene (PS)-NPs, gaps remain in understanding aging effects and specific mechanisms by PS-NPs in pre-differentiated myoblasts. In this study, we investigated the cellular internalization, aggregation, and senescent effects of PS-NPs using an <em>in vitro</em> model of pre-differentiated C2C12 myoblasts. Pre-differentiated C2C12 myoblasts were exposed to increasing concentrations of PS-NPs and internalization was observed in myoblasts using flow cytometry and transmission electron microscopy (TEM). We further investigated whether internalization of these PS-NPs at sublethal cytotoxic concentrations led to an increase in senescence hallmarks, such as increased β-galactosidase activity, increased expression of p16, p21 and senescence-related secretory phenotypes, and cell cycle arrest. In addition, PS-NP treatment caused notable mitochondrial superoxide production and damage, including mitochondrial membrane depolarization, content loss, fragmentation, and decreased ATP production. Rotenone, a mitochondrial function inhibitor, and exacerbated PS-NP-induced cell proliferation inhibition, whereas Mito-TEMPO, a mitochondrial superoxide scavenger, restored the cell proliferation rate and rescued cellular senescence. Therefore, our findings indicate the senescent effects of PS-NPs through mitochondrial superoxide production and dysfunction in pre-differentiated myoblasts.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154002"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders","authors":"Yasuyuki Higashi ,&nbsp;Chinatsu Nishida ,&nbsp;Hiroto Izumi ,&nbsp;Kazuma Sato ,&nbsp;Naoki Kawai ,&nbsp;Taisuke Tomonaga ,&nbsp;Toshiki Morimoto ,&nbsp;Kei Yamasaki ,&nbsp;Ke-Yong Wang ,&nbsp;Hidenori Higashi ,&nbsp;Akihiro Moriyama ,&nbsp;Jun-Ichi Takeshita ,&nbsp;Takuma Kojima ,&nbsp;Kazuo Sakurai ,&nbsp;Kazuhiro Yatera ,&nbsp;Yasuo Morimoto","doi":"10.1016/j.tox.2024.154001","DOIUrl":"10.1016/j.tox.2024.154001","url":null,"abstract":"<div><div>Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m³ for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m³ for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m³ CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m³. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154001"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}