Archives of Toxicology最新文献

{"title":"Unraveling the Hsp70-ROS-autophagy axis in pentachlorophenol-challenged lung and liver epithelial cells.","authors":"S Thota, R Begum, D Mutyala, N Bidarimath, M Thakur, B Sarkar, J Morehouse, S Yang, P K Deb, W Dorsey, S Batra","doi":"10.1007/s00204-025-03983-8","DOIUrl":"https://doi.org/10.1007/s00204-025-03983-8","url":null,"abstract":"<p><p>Pentachlorophenol (PCP) was extensively utilized as an organochlorine pesticide and wood preservative in the United States from the 1930s until the Environmental Protection Agency (EPA) imposed restrictions due to concerns about its toxicity and potential carcinogenic properties. Although it is no longer widely used, PCP remains a concern due to its environmental persistence and potential for long-term health effects. Significant occupational and environmental exposures have likely occurred, with the health and economic costs of PCP exposure potentially being substantial given its known toxicity. Notably, PCP exhibits rapid absorption through both the skin and respiratory system and has been shown to cause hepatotoxicity, developmental toxicity, immunotoxicity, irritation, and carcinogenicity in laboratory animal studies. PCP exposure induces oxidative stress, a key mechanism underlying its inflammatory and toxic effects, which can activate cellular stress responses including upregulation of heat shock protein 70 (Hsp70). Previous studies in lung and liver epithelial cells have shown that Hsp70 and oxidative stress play pivotal roles in triggering autophagy. This study establishes the critical role of the Hsp70-reactive oxygen species (ROS)-autophagy axis in regulating cellular responses to PCP exposure in human alveolar (A549) and liver carcinoma (HepG2) epithelial cells. Our research elucidated the molecular mechanisms underlying PCP's cellular effects, demonstrating that its exposure resulted in increased expression of autophagy-related proteins (Beclin-1, LC3B, ATG12, and ATG16), subunits of NADPH oxidase (NCF-1, NCF-2, NOX2, and Rac), and antioxidant proteins (SOD and GPx) in both lung and liver cell types. Notably, PCP augmented the interaction between Hsp70 and the autophagy regulator Beclin-1. Pretreatment with the ROS inhibitor N-acetylcysteine or Hsp70 knockdown markedly reversed PCP-induced responses. Our in-silico protein-protein docking analysis and molecular dynamics simulation studies revealed enhanced interactions and/or stable confirmations maintained throughout the simulations for TLR4-Hsp70 and Hsp70-Beclin-1 complexes in the presence of PCP. These findings provide a strong foundation for future studies, employing in vivo experimental models and human populations to identify promising targets for PCP-induced toxicity and cellular injury. Furthermore, these findings may have far-reaching implications for public health and environmental policy, ultimately leading to the identification of biomarkers and the development of more effective interventions for environmentally induced toxicity and diseases.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydromyricetin restores lysosomal function in Schwann cells to alleviate bortezomib-induced peripheral neuropathy via ERK/TFEB signaling.","authors":"Xiaoliang Liu, Xingxian Zhang, Xinhang Li, Chen Zhang, Huajing Cai, Jiayu Qi, Ke Wang, Xuyun Li, Xiuhua Wu, Ziqi Ye, Gang Chen, Xiangnan Zhang, Jiaying Wu","doi":"10.1007/s00204-025-04030-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04030-2","url":null,"abstract":"<p><p>Bortezomib (BTZ) serves as a first-line drug for multiple myeloma (MM) treatment by reversibly inhibiting of the proteasomes. However, BTZ-induced peripheral neuropathy (BIPN) remains a significant toxicity concern, with its molecular mechanisms not fully elucidated, resulting in limited therapeutic options. Dihydromyricetin (DHM) has been shown to alleviate neuropathic pain, but its potential effect on BIPN has not been investigated. We found that oral administration of DHM (40 mg/kg/day, 200 mg/kg/day) for 2 weeks significantly improved mechanical allodynia, sciatic nerve conduction, and demyelination in a BIPN mouse model (BTZ 1.0 mg/kg, i.v.). BTZ (50 nmol/L) impaired lysosomal function and blocked autophagy flux in both primary cultured rat Schwann cells and RSC96 Schwann cells; these effects were reversed by DHM treatment (3 μmol/L, 10 μmol/L). Mechanistically, DHM facilitated the nuclear translocation of TFEB, a master regulator of lysosomal-related genes, and the protective effects of DHM on Schwann cells were abolished by Tfeb shRNA. Furthermore, BTZ treatment activated ERK signaling, leading to TFEB phosphorylation and impaired nuclear translocation. DHM treatment prevented the BTZ-induced ERK activation, and the protective effects of DHM were compromised by the ERK activator TBHQ. Importantly, DHM did not diminish the efficacy of BTZ against RPMI 8226 myeloma cells. This study demonstrates that DHM mitigates BTZ-induced toxicity on Schwann cells by restoring lysosome-autophagy activity through the ERK-TFEB pathway, highlighting DHM as a promising candidate for improving the adverse reaction of BTZ in the peripheral nervous system.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards prospective identification of respiratory sensitizers: effects of piperazine, chloramine-T, and toluene-diisocyanate in an air-liquid interface model comprising human bronchial epithelial cells.","authors":"Evert Duistermaat, Véronique M P de Bruijn, Jolanda P Vermeulen, Eric R Gremmer, Rob J Vandebriel","doi":"10.1007/s00204-025-04029-9","DOIUrl":"https://doi.org/10.1007/s00204-025-04029-9","url":null,"abstract":"<p><p>Exposure to respiratory sensitizers (RSs) is the leading cause of occupational asthma. Although the prospective identification of RSs is important, there currently exists no OECD-approved test guideline for this endpoint. The adverse outcome pathway for respiratory sensitization consists of key event (KE) 1: binding of the respiratory sensitizer to a protein, KE2: activation of lung epithelial cells, KE3: activation of dendritic cells, and KE4: T-cell response. Here, we focused on KE2 by investigating whether measuring this KE could contribute to prospectively identify respiratory sensitizers. To mimic real-life exposure, cells were exposed via the air. We used an air-liquid interface model comprising the human bronchial epithelial cell line Calu-3. Exposure to the RS piperazine (3, 18, and 100 mg/m³) dose-dependently increased IL-6 production at dose levels that did not affect the other parameters tested (barrier integrity, cell metabolism, cytotoxicity, and IL-8 production). IL-6 has been linked to asthma in humans. Exposure to the RS chloramine-T (30, 300, and 3000 ng/cm²) showed only minor effects on the parameters tested. Exposure to the RS 2,4-toluene diisocyanate (10, 33, and 100 mg/m³) at the highest dose level clearly affected all parameters tested. Disrupted barrier function has been linked to asthma. In conclusion, this study may possibly suggest that different respiratory sensitizers may differentially impact KE2. Further research is needed to elucidate this.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker-based approach to human exposure assessment of furan in food.","authors":"C Kalisch, M Reiter, A Mally","doi":"10.1007/s00204-025-04022-2","DOIUrl":"https://doi.org/10.1007/s00204-025-04022-2","url":null,"abstract":"<p><p>Humans are continuously exposed to furan, a hepatotoxic and carcinogenic process-related food contaminant. Considerable uncertainties associated with current exposure estimates based on the content of furan in food underscore the need to explore biomarker monitoring as an alternative or complementary approach to furan exposure assessment. Previous work in rats demonstrated a linear correlation between furan dose and several urinary furan metabolites, whereby N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-L-cysteinylglycine (GSH-BDA), the glutathione (GSH) conjugate of the reactive furan metabolite cis-2-butene-1,4-dial (BDA), was identified as a specific biomarker of exogenous furan exposure. To further test the validity of GSH-BDA as a biomarker of furan exposure, the present study was designed to monitor urinary excretion of furan metabolites in human volunteers after consumption of diets with low vs. high furan content using stable isotope dilution LC-MS/MS, and to investigate if analysis of GSH-BDA in human urine is suitable for translating biomarker levels into probable daily intakes. Ten healthy volunteers (n = 5/sex) consumed a low-furan diet for three days (day 1-3), followed by consumption of foods with high furan content for three days (day 4-6) and returned to a low-furan diet for a further three days (7-9). Urinary GSH-BDA excretion significantly increased during periods of a high-furan diet, and rapidly declined upon returning to a low-furan diet. Probable daily intakes estimated from GSH-BDA excretion in non-smoking subjects and excretion rates previously determined in F344/DuCrl rats ranged from 0.05 to 0.31 µg/kg bw/d during periods of low-furan diet and increased to 0.18-1.20 µg/kg bw/d during consumption of a high-furan diet. These estimates are in good agreement with exposures reported by the European Food Safety Authority (EFSA), which range between 0.11 to 0.75 µg/kg bw per day (minimum LB to maximum UB) for the average adult and 0.20 to 1.22 µg/kg bw per day (minimum LB to maximum UB) for highly exposed adult consumers (95th percentile). Interestingly, higher excretion of GSH-BDA was observed in smoking compared to non-smoking individuals, highlighting tobacco smoke as a significant source of furan exposure and confounding factor when estimating furan exposure via diet. In contrast to GSH-BDA, high urinary background levels of lysine adducts of BDA and BDA-derived cysteine-lysine crosslinks limit their suitability as biomarkers of exogenous furan exposure.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific differences in toxicology: does the sex make the poison?","authors":"Charlotte Esser, Doreen Reichert","doi":"10.1007/s00204-025-04021-3","DOIUrl":"https://doi.org/10.1007/s00204-025-04021-3","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative in vitro-to-in vivo extrapolation of human adrenergic and trace amine-associated receptor 1 potencies of pre-workout supplement ingredients using physiologically based kinetic modelling-based reverse dosimetry.","authors":"Nicole E T Pinckaers, W Matthijs Blankesteijn, Anastasiya Mircheva, Ans Punt, Antoon Opperhuizen, Frederik-Jan van Schooten, Misha Vrolijk","doi":"10.1007/s00204-025-03992-7","DOIUrl":"https://doi.org/10.1007/s00204-025-03992-7","url":null,"abstract":"<p><p>The present study predicts effective doses of a set of phenethylamine (PEA) analogues that are frequently present in pre-workout and weight-loss food supplements, to prioritize these compounds for further risk assessment. In vitro determined EC₅₀ values of PEA analogues for multiple human adrenergic receptor (ADR) subtypes (ADRα_1A, α_1B, α_1D, α_2A, β₁, β₂) and trace-amine associated receptor 1 (TAAR1) were extrapolated to human ED₅₀ values by using physiologically based kinetic (PBK) modelling-based reverse dosimetry combined with in silico and in vitro determined PBK model input parameters. The predicted ED₅₀ values of the studied PEAs for activation of ADRα_1A/B/D, ADRα_2A, ADRβ₁ and TAAR1 were within a range of 0.914-29.7 mg/kg body weight (bw), 139-234 mg/kg bw, 0.0839-38.8 mg/kg bw and 0.995-264 mg/kg bw, respectively. Comparison of the predicted ED₅₀ values with reported intake values revealed that particularly the exposure of the PEA analogues higenamine, isopropyloctopamine, β-methylphenethylamine and p-synephrine is in the same range or exceeds the predicted ED₅₀ values. This suggests that these PEAs can (in)directly affect the cardiovascular system after the intake of food supplements. These PEA analogues should therefore be considered as high priority compounds for further risk assessment. In conclusion, our study shows that the use of quantitative in vitro-to-in vivo extrapolation (QIVIVE) of adrenergic and TAAR1 potencies using a generic PBK model can serve as an efficient prioritization method for a whole set of chemical analogues.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A silence catalyst: CCL5-mediated intercellular communication in cancer.","authors":"Wei-Ting Hu, Ming Li, Pei-Jun Ma, Ding Yang, Xiao-Dong Liu, Yun Wang","doi":"10.1007/s00204-025-04036-w","DOIUrl":"https://doi.org/10.1007/s00204-025-04036-w","url":null,"abstract":"<p><p>Chemokine CCL5 (RANTES), as a key mediator of intercellular communication in cancers, and its role in cancer development, metastasis and immune escape has received increasing attention. CCL5 and its receptors are important components of the tumor microenvironment and play a tumor promoting role in different ways by triggering signaling pathways through binding to the primary receptor CCR5. CCL5 was viewed as indispensable \"gate keepers\" of immunity and inflammation, it remains unclear of CCL5-mediated intercellular communication. Therefore, in this review, we summarize the latest information on the origin, structure, and characterization of CCL5 and role of CCL5 in the tumor microenvironment. It includes CCL5-mediated intercellular communication through exosomes, microvesicles and others in breast, lung, and ovarian cancers. CCL5 has a multifaceted role in cancer and has potential applications as a biomarker for cancer diagnosis and prognosis, which provides theoretical bases and therapeutic targets for the development of new cancer therapeutic strategies.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vernonia amygdalina displays otoprotective effects via antioxidant pathway on cisplatin-induced hair cell loss in zebrafish.","authors":"Hsinlin Cheng, Yuxuan Wu, Jiannjou Yang","doi":"10.1007/s00204-025-04038-8","DOIUrl":"https://doi.org/10.1007/s00204-025-04038-8","url":null,"abstract":"<p><p>Iatrogenic hearing loss is defined as irreversible cochlear hair cell injury resulting from medical intervention, such as cisplatin, which leads to the overproduction of reactive oxygen species (ROS). Vernonia amygdalina (VA), a medicinal herb, has recently been found to exerted pharmacotherapeutic potential due to its antioxidant activity. In the present study, we used a transgenic zebrafish line (pvalb3b: TagGFP) as an in vivo screening platform for discovering compounds or agents with potential otoprotective ability and a combination of behavioral methods for assessing the physiological outcome. The 1 h of 250 μM cisplatin treatment induced severs injury to lateral-line hair cell that triggered a drastic cell death response. Five readouts were conducted as the parameters of VA ultrasonic water extract (VAUWE) protection against cisplatin ototoxicity: (1) radical-scavenging ability, (2) hair cell viability, (3) mechanotransduction (MET) channel functionality, (4) apoptosis, (5) antioxidant defense, and (6) locomotor behavior. Our results demonstrated that 1-h pretreatment of VAUWE with non-toxic concentrations (1.0 mg/ml and 2.0 mg/ml) increases hair cell viability by blocking cisplatin entry through the MET channel and subsequently ameliorates apoptotic cell death. Regarding molecular mechanisms, VAUWE also modulates the expression of antioxidant enzyme gene, which collectively contributes to restoring impaired swimming behavior induced by cisplatin ototoxicity. The findings of the present study might highlight the in vivo protective role of VAUWE on modulating cisplatin-induced hair cell damage in transgenic zebrafish, which further informs preclinical foundations for developing potential otoprotectants against iatrogenic hearing loss.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cleavage fragments and asbestos fibers: better characterization of minerals and improved cell models are needed to elucidate toxicity differences.","authors":"Ann Wylie, Brooke Mossman, Andrey Korchevskiy","doi":"10.1007/s00204-025-04039-7","DOIUrl":"https://doi.org/10.1007/s00204-025-04039-7","url":null,"abstract":"","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hazard characterization of the mycotoxins enniatins and beauvericin to identify data gaps and improve risk assessment for human health.","authors":"Anne-Cathrin Behr, Christiane Kruse Fæste, Amaya Azqueta, Ana M Tavares, Anastasia Spyropoulou, Anita Solhaug, Ann-Karin Olsen, Ariane Vettorazzi, Birgit Mertens, Bojana Zegura, Camille Streel, Dieynaba Ndiaye, Eliana Spilioti, Estelle Dubreil, Franca Maria Buratti, Francesco Crudo, Gunnar Sundstøl Eriksen, Igor Snapkow, João Paulo Teixeira, Josef D Rasinger, Julie Sanders, Kyriaki Machera, Lada Ivanova, Laurent Gaté, Ludovic Le Hegarat, Matjaz Novak, Nicola M Smith, Sabrina Tait, Sónia Fraga, Sonja Hager, Doris Marko, Albert Braeuning, Henriqueta Louro, Maria João Silva, Hubert Dirven, Jessica Dietrich","doi":"10.1007/s00204-025-03988-3","DOIUrl":"https://doi.org/10.1007/s00204-025-03988-3","url":null,"abstract":"<p><p>Enniatins (ENNs) and beauvericin (BEA) are cyclic hexadepsipeptide fungal metabolites which have demonstrated antibiotic, antimycotic, and insecticidal activities. The substantial toxic potentials of these mycotoxins are associated with their ionophoric molecular properties and relatively high lipophilicities. ENNs occur extensively in grain and grain-derived products and are considered a food safety issue by the European Food Safety Authority (EFSA). The tolerable daily intake and maximum levels for ENNs in humans and animals remain unestablished due to key toxicological and toxicokinetic data gaps, preventing full risk assessment. Aiming to find critical data gaps impeding hazard characterization and risk evaluation, this review presents a comprehensive summary of the existing information from in vitro and in vivo studies on toxicokinetic characteristics and cytotoxic, genotoxic, immunotoxic, endocrine, reproductive and developmental effects of the most prevalent ENN analogues (ENN A, A1, B, B1) and BEA. The missing information identified showed that additional studies on ENNs and BEA have to be performed before sufficient data for an in-depth hazard characterisation of these mycotoxins become available.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}