Pub Date : 2025-11-12DOI: 10.1016/j.etap.2025.104868
Raquel Maroto Cejudo , Denisse Michelle Espinosa Encalada , María Granada Picazo Martínez , Mónica Gómez-Juarez Sango , Fernando Andrés-Pretel , Carlos Cava Valenciano
Introduction
Sevoflurane (SF) has been reported to exhibit topical analgesic/antimicrobial effects. This study evaluated its cytotoxicity on the ocular surface by comparing SF with povidone-iodine (PI) and balanced saline solution (BSS) in an epithelial cell model.
Methods
Cytotoxicity was assessed using the Short-Time Exposure Test (OECD 491) on Seruminstitut Rabbit Cornea (SIRC) cells. Cultures were exposed for 5 min to SF (100 %), PI (5 %) or BSS and viability was determined by the MTT assay. Recovery at 0, 30, and 60 min and the effect of a double SF exposure were also evaluated.
Results
Median viabilities were: 85.3 % for SF, 0.5 % for PI and 97.3 % for BSS (p = 0.005). Significant differences were found between 0 and 30 min (p = 0.021) and 0–60 min (p = 0.038). Double exposure did not significantly modify SF viability (p > 0.05).
Conclusions
SF did not demonstrate significant cytotoxicity in vitro, unlike PI. However, in vivo studies are required to confirm its ocular safety.
{"title":"Evaluation of the ocular cytotoxicity of topical sevoflurane in sirc cells: An in vitro study","authors":"Raquel Maroto Cejudo , Denisse Michelle Espinosa Encalada , María Granada Picazo Martínez , Mónica Gómez-Juarez Sango , Fernando Andrés-Pretel , Carlos Cava Valenciano","doi":"10.1016/j.etap.2025.104868","DOIUrl":"10.1016/j.etap.2025.104868","url":null,"abstract":"<div><h3>Introduction</h3><div>Sevoflurane (SF) has been reported to exhibit topical analgesic/antimicrobial effects. This study evaluated its cytotoxicity on the ocular surface by comparing SF with povidone-iodine (PI) and balanced saline solution (BSS) in an epithelial cell model.</div></div><div><h3>Methods</h3><div>Cytotoxicity was assessed using the Short-Time Exposure Test (OECD 491) on Seruminstitut Rabbit Cornea (SIRC) cells. Cultures were exposed for 5 min to SF (100 %), PI (5 %) or BSS and viability was determined by the MTT assay. Recovery at 0, 30, and 60 min and the effect of a double SF exposure were also evaluated.</div></div><div><h3>Results</h3><div>Median viabilities were: 85.3 % for SF, 0.5 % for PI and 97.3 % for BSS (p = 0.005). Significant differences were found between 0 and 30 min (p = 0.021) and 0–60 min (p = 0.038). Double exposure did not significantly modify SF viability (p > 0.05).</div></div><div><h3>Conclusions</h3><div>SF did not demonstrate significant cytotoxicity in vitro, unlike PI. However, in vivo studies are required to confirm its ocular safety.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104868"},"PeriodicalIF":4.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-12DOI: 10.1016/j.etap.2025.104866
Raya I. Boyd , Doha Shokry, Brayden C. Rennels, Younan Adam, Christine Powell, Samantha Johnson, Michael J. Spinella, Ratnakar Singh
Poly- and perfluoroalkyl substances (PFAS) are of human health concern as epidemiological studies show significant associations with testicular germ cell tumors (TGCTs). Here, the effects of perfluorooctanesulfonic acid (PFOS), lithium bis(trifluoromethylsulfonyl)imide (HQ-115), and hexafluoropropylene oxide dimer acid (GenX) on TGCT cells were investigated. Concentrations (10 nM to 1 µM) modelled PFAS doses in relevant human exposure ranges and acute and short-term timepoints (18 h and 4 days) captured proximal mechanisms of action. Metabolomic studies revealed that HQ-115 altered metabolites associated with steroid biosynthesis and lipid metabolism. Peroxisome-proliferator activation receptor (PPAR) target gene expression was altered upon HQ-115 and GenX exposure. Lastly, PFAS exposure altered the activity of PPARs, in TGCT cells, with the most prominent effects being antagonist activity toward PPARγ. These data support that PFAS may act as fatty acid mimics to modulate fatty acid metabolic and steroidogenic endocrine outcome leading to pro-cancer phenotypes in TGCTs.
{"title":"The role of lipid metabolism and peroxisome proliferator activation in mediating pro-cancer phenotypes of poly- and perfluoroalkyl substances in testicular cancer","authors":"Raya I. Boyd , Doha Shokry, Brayden C. Rennels, Younan Adam, Christine Powell, Samantha Johnson, Michael J. Spinella, Ratnakar Singh","doi":"10.1016/j.etap.2025.104866","DOIUrl":"10.1016/j.etap.2025.104866","url":null,"abstract":"<div><div>Poly- and perfluoroalkyl substances (PFAS) are of human health concern as epidemiological studies show significant associations with testicular germ cell tumors (TGCTs). Here, the effects of perfluorooctanesulfonic acid (PFOS), lithium bis(trifluoromethylsulfonyl)imide (HQ-115), and hexafluoropropylene oxide dimer acid (GenX) on TGCT cells were investigated. Concentrations (10 nM to 1 µM) modelled PFAS doses in relevant human exposure ranges and acute and short-term timepoints (18 h and 4 days) captured proximal mechanisms of action. Metabolomic studies revealed that HQ-115 altered metabolites associated with steroid biosynthesis and lipid metabolism. Peroxisome-proliferator activation receptor (PPAR) target gene expression was altered upon HQ-115 and GenX exposure. Lastly, PFAS exposure altered the activity of PPARs, in TGCT cells, with the most prominent effects being antagonist activity toward PPARγ. These data support that PFAS may act as fatty acid mimics to modulate fatty acid metabolic and steroidogenic endocrine outcome leading to pro-cancer phenotypes in TGCTs.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104866"},"PeriodicalIF":4.2,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-10DOI: 10.1016/j.etap.2025.104853
Alessandro Giammona , Clarissa Gervasoni , Gianluca Di Iulio , Carmina Sirignano , Stefano Listrani , Matteo Rinaldi , Silvia Canepari , Alessia Lo Dico , Francesca Costabile , Gloria Bertoli
Adverse health effects associated with fine particulate matter (PM2.5) in urban areas can occur even at PM2.5 concentrations below current regulatory limits — a situation increasingly observed in high-income countries. However, the underlying biological mechanisms remain poorly understood. In this study, we investigated the molecular and cellular responses in human bronchial epithelial cells exposed to low PM2.5 using a novel methodology. We first identified specific meteorological conditions that favor low PM2.5 mass concentrations (10 g m−3) combined with high traffic-related aerosol emissions, which we found to correspond to a highly oxidant atmosphere. Under these conditions, PM2.5 samples were collected in the urban background of Rome. The cells were exposed in vitro using a novel methodological approach based on a direct filter-contact model. Our focus was on associating measurable aerosol properties with gene expression pathways related to oxidative stress, inflammation, and their epigenetic modulation through microRNAs. Our findings indicate that exposure to fresh traffic-related aerosols under low PM2.5 concentrations elicited a biphasic gene expression response. The initial response involved the activation of genes such as NRF2, NF-B, CAT1, SOD1, HIF-1, and HMOX1; while a secondary response involved TNF- and GPX4. A strong association was observed between these biological effects and black carbon metrics related to fossil fuel, implicating fresh traffic emissions as key contributors. Additionally, a significant modulation of air pollution-associated microRNAs was observed, even at early times of exposure, suggesting an epigenetic dimension to the cellular stress response. These findings have important implications for future air quality regulations. We provide mechanistic insights into oxidative and epigenetic responses underlying PM2.5 induced biological effects at low PM2.5 levels, emphasizing that neither PM2.5 mass concentration nor its oxidative potential — two metrics currently considered by legislation — are sufficient on their own to explain the observed effects.
与城市地区细颗粒物（PM2.5）相关的不良健康影响，即使PM2.5浓度低于目前的监管限制，也会发生——这种情况在高收入国家越来越多地观察到。然而，潜在的生物学机制仍然知之甚少。在这项研究中，我们使用一种新颖的方法研究了暴露于低PM2.5的人支气管上皮细胞的分子和细胞反应。我们首先确定了有利于低PM2.5质量浓度（<10 μg m - 3）和高交通相关气溶胶排放的特定气象条件，我们发现这与高度氧化的大气相对应。在这些条件下，在罗马城市背景中采集PM2.5样本。使用基于直接过滤器-接触模型的新方法在体外暴露细胞。我们的重点是将可测量的气溶胶特性与氧化应激、炎症及其通过microrna进行表观遗传调节相关的基因表达途径联系起来。我们的研究结果表明，暴露于低PM2.5浓度下的新鲜交通相关气溶胶引发了双相基因表达反应。最初的反应涉及NRF2、NF-κB、CAT1、SOD1、HIF-1α和HMOX1等基因的激活；而继发性反应涉及TNF-α和GPX4。在这些生物效应和与化石燃料相关的黑碳指标之间观察到强烈的关联，这意味着新的交通排放是关键因素。此外，即使在暴露的早期，也观察到与空气污染相关的microrna的显著调节，这表明细胞应激反应的表观遗传维度。这些发现对未来的空气质量法规具有重要意义。我们提供了低PM2.5水平下PM2.5诱导的生物效应的氧化和表观遗传机制，强调PM2.5质量浓度及其氧化电位这两个目前被立法考虑的指标本身都不足以解释所观察到的效应。
{"title":"Cellular responses of human bronchial epithelial cells following short-term exposure to oxidative particulate matter","authors":"Alessandro Giammona , Clarissa Gervasoni , Gianluca Di Iulio , Carmina Sirignano , Stefano Listrani , Matteo Rinaldi , Silvia Canepari , Alessia Lo Dico , Francesca Costabile , Gloria Bertoli","doi":"10.1016/j.etap.2025.104853","DOIUrl":"10.1016/j.etap.2025.104853","url":null,"abstract":"<div><div>Adverse health effects associated with fine particulate matter (PM<sub>2.5</sub>) in urban areas can occur even at PM<sub>2.5</sub> concentrations below current regulatory limits — a situation increasingly observed in high-income countries. However, the underlying biological mechanisms remain poorly understood. In this study, we investigated the molecular and cellular responses in human bronchial epithelial cells exposed to low PM<sub>2.5</sub> using a novel methodology. We first identified specific meteorological conditions that favor low PM<sub>2.5</sub> mass concentrations (<span><math><mo><</mo></math></span>10 <span><math><mi>μ</mi></math></span>g m<sup>−3</sup>) combined with high traffic-related aerosol emissions, which we found to correspond to a highly oxidant atmosphere. Under these conditions, PM<sub>2.5</sub> samples were collected in the urban background of Rome. The cells were exposed <em>in vitro</em> using a novel methodological approach based on a direct filter-contact model. Our focus was on associating measurable aerosol properties with gene expression pathways related to oxidative stress, inflammation, and their epigenetic modulation through microRNAs. Our findings indicate that exposure to fresh traffic-related aerosols under low PM<sub>2.5</sub> concentrations elicited a biphasic gene expression response. The initial response involved the activation of genes such as <em>NRF2</em>, <em>NF-</em><span><math><mi>κ</mi></math></span><em>B</em>, <em>CAT1</em>, <em>SOD1</em>, <em>HIF-1</em><span><math><mi>α</mi></math></span>, and <em>HMOX1</em>; while a secondary response involved <em>TNF-</em><span><math><mi>α</mi></math></span> and <em>GPX4</em>. A strong association was observed between these biological effects and black carbon metrics related to fossil fuel, implicating fresh traffic emissions as key contributors. Additionally, a significant modulation of air pollution-associated microRNAs was observed, even at early times of exposure, suggesting an epigenetic dimension to the cellular stress response. These findings have important implications for future air quality regulations. We provide mechanistic insights into oxidative and epigenetic responses underlying PM<sub>2.5</sub> induced biological effects at low PM<sub>2.5</sub> levels, emphasizing that neither PM<sub>2.5</sub> mass concentration nor its oxidative potential — two metrics currently considered by legislation — are sufficient on their own to explain the observed effects.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104853"},"PeriodicalIF":4.2,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.etap.2025.104864
Sofia Neves , Solange A. Pacheco , Fátima Vaz , Cristina Valentim-Coelho , Joana Saraiva , Peter James , Tânia Simões , Deborah Penque
Chronic exposure to second-hand smoke (SHS) contributes to the development of health issues, including cancer and cardiovascular diseases. Molecular mechanisms underlying SHS-related diseases remain poorly understood, highlighting the need for reliable risk assessment biomarkers. Herein, we demonstrate that the plasma proteome of individuals exposed to SHS undergoes significant modulation. Butyrylcholinesterase (BChE) and Vitamin D-binding protein (GC) that are involved in the physiological response to circulating toxic substances, as well as key mediators of systemic inflammation, including Complement C1r subcomponent (C1R), Complement C1q subcomponent subunit C (C1QC), Histidine-rich glycoprotein (HRG), and Vitamin K-dependent protein S (PROS1), were found to be significantly modulated in SHS-exposed individuals. Moreover, strong indicators of a pro-atherothrombotic response such Apolipoprotein A-IV (APOA4) and Alpha-2-antiplasmin (SERPINF2), were also differentially expressed. These findings provide novel insights into the biological pathways linking SHS-exposure to cardiovascular risks, and suggest a panel of candidate proteins with potential utility as SHS-risk assessment biomarkers.
长期接触二手烟会导致健康问题的发展，包括癌症和心血管疾病。shs相关疾病的分子机制尚不清楚，因此需要可靠的风险评估生物标志物。在此，我们证明了暴露于SHS的个体的血浆蛋白质组经历了显著的调节。研究发现，参与循环有毒物质生理反应的丁基胆碱酯酶（BChE）和维生素d结合蛋白（GC），以及全身性炎症的关键介质，包括补体C1r亚组分（C1r）、补体C1q亚组分亚基C （C1QC）、富组氨酸糖蛋白（HRG）和维生素k依赖性蛋白S (PROS1)，在shs暴露个体中被显著调节。此外，促动脉粥样硬化血栓反应的强指标，如载脂蛋白a- iv （APOA4）和α -2抗纤溶蛋白（serinf2），也有差异表达。这些发现为将shs暴露与心血管风险联系起来的生物学途径提供了新的见解，并提出了一组具有潜在效用的候选蛋白作为shs风险评估生物标志物。
{"title":"Second-hand smoke exposure modulates plasma proteins linked to detoxification, inflammation and atherothrombosis","authors":"Sofia Neves , Solange A. Pacheco , Fátima Vaz , Cristina Valentim-Coelho , Joana Saraiva , Peter James , Tânia Simões , Deborah Penque","doi":"10.1016/j.etap.2025.104864","DOIUrl":"10.1016/j.etap.2025.104864","url":null,"abstract":"<div><div>Chronic exposure to second-hand smoke (SHS) contributes to the development of health issues, including cancer and cardiovascular diseases. Molecular mechanisms underlying SHS-related diseases remain poorly understood, highlighting the need for reliable risk assessment biomarkers. Herein, we demonstrate that the plasma proteome of individuals exposed to SHS undergoes significant modulation. Butyrylcholinesterase (BChE) and Vitamin <span>D</span>-binding protein (GC) that are involved in the physiological response to circulating toxic substances, as well as key mediators of systemic inflammation, including Complement C1r subcomponent (C1R), Complement C1q subcomponent subunit C (C1QC), Histidine-rich glycoprotein (HRG), and Vitamin K-dependent protein S (PROS1), were found to be significantly modulated in SHS-exposed individuals. Moreover, strong indicators of a pro-atherothrombotic response such Apolipoprotein A-IV (APOA4) and Alpha-2-antiplasmin (SERPINF2), were also differentially expressed. These findings provide novel insights into the biological pathways linking SHS-exposure to cardiovascular risks, and suggest a panel of candidate proteins with potential utility as SHS-risk assessment biomarkers.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104864"},"PeriodicalIF":4.2,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.etap.2025.104863
Stefano Magni , Andrea Binelli , Lara Nigro , Eva Roubeau Dumont , Emmanuel Eysseric , Riccardo Sbarberi , Luca Del Giacco , Alberto Diana , Camilla Della Torre , Christian Gagnon , François Gagné
This study focuses on the sub-lethal effects of three key tire rubber-derived contaminants (TRDCs) used as vulcanizing agents and antioxidants in the tire production: 1,3-diphenylguanidine (DPG), N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), and its byproduct 6PPD-quinone (6PPD-q). Effects were assessed at the concentration of 500 ng/L on Danio rerio (zebrafish) larvae, from 0 to 120 h post fertilization, through a wide battery of biomarkers, proteomics, as well as imaging techniques for the inflammation detection. No significant effects were observed on larvae concerning apical endpoints, such as viability and morphological alterations, in all experimental groups. However, DPG exposure led to the most widespread biomarker responses among the tested compounds, with a significant induction of superoxide dismutase, ethoxyresorufin-O-deethylase and glutathione-S-transferase. To obtain a toxicity scale of tested TRDCs, based on used biomarkers, each endpoint was integrated in the Biomarker Response Index. This approach indicated that 6PPD-q and DPG were more toxic than 6PPD. Coherently, proteomic analysis revealed the modulation of 8 proteins with the DPG treatment, 7 with 6PPD-q and only 4 impacted proteins in the treatment with 6PPD. Other evidence, which considers also the effects of TRDC mixture, is necessary to better investigate the main toxic chemicals related to tire in aquatic ecosystems.
本研究重点研究了轮胎生产中作为硫化剂和抗氧化剂的三种关键轮胎橡胶衍生污染物（trdc）： 1,3-二苯基胍（DPG）、N-（1,3-二甲基丁基）-N ' -苯基-对苯二胺（6PPD）及其副产物6PPD-醌（6PPD-q）的亚致死效应。通过广泛的生物标志物、蛋白质组学和炎症检测成像技术，评估了500 ng/L浓度对斑马鱼（Danio rerio）幼虫在受精后0至120 h的影响。在所有实验组中，对幼虫的生存力和形态变化等尖端端点均无显著影响。然而，DPG暴露导致了测试化合物中最广泛的生物标志物反应，显著诱导了超氧化物歧化酶、乙氧基间苯二酚- o -去乙基化酶和谷胱甘肽- s -转移酶。为了获得测试trdc的毒性等级，基于使用的生物标志物，将每个终点整合到生物标志物反应指数中。该方法表明6PPD-q和DPG的毒性大于6PPD。蛋白质组学分析一致显示，DPG处理可调节8个蛋白，6PPD-q处理可调节7个蛋白，6PPD处理仅影响4个蛋白。为了更好地调查水生生态系统中与轮胎有关的主要有毒化学物质，有必要提供其他证据，这些证据也考虑了TRDC混合物的影响。
{"title":"Assessment of the sub-lethal effects induced by three tire rubber-derived contaminants on zebrafish larvae","authors":"Stefano Magni , Andrea Binelli , Lara Nigro , Eva Roubeau Dumont , Emmanuel Eysseric , Riccardo Sbarberi , Luca Del Giacco , Alberto Diana , Camilla Della Torre , Christian Gagnon , François Gagné","doi":"10.1016/j.etap.2025.104863","DOIUrl":"10.1016/j.etap.2025.104863","url":null,"abstract":"<div><div>This study focuses on the sub-lethal effects of three key tire rubber-derived contaminants (TRDCs) used as vulcanizing agents and antioxidants in the tire production: 1,3-diphenylguanidine (DPG), N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD), and its byproduct 6PPD-quinone (6PPD-q). Effects were assessed at the concentration of 500 ng/L on <em>Danio rerio</em> (zebrafish) larvae, from 0 to 120 h post fertilization, through a wide battery of biomarkers, proteomics, as well as imaging techniques for the inflammation detection<em>.</em> No significant effects were observed on larvae concerning apical endpoints, such as viability and morphological alterations, in all experimental groups. However, DPG exposure led to the most widespread biomarker responses among the tested compounds, with a significant induction of superoxide dismutase, ethoxyresorufin-O-deethylase and glutathione-S-transferase. To obtain a toxicity scale of tested TRDCs, based on used biomarkers, each endpoint was integrated in the Biomarker Response Index. This approach indicated that 6PPD-q and DPG were more toxic than 6PPD. Coherently, proteomic analysis revealed the modulation of 8 proteins with the DPG treatment, 7 with 6PPD-q and only 4 impacted proteins in the treatment with 6PPD. Other evidence, which considers also the effects of TRDC mixture, is necessary to better investigate the main toxic chemicals related to tire in aquatic ecosystems.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104863"},"PeriodicalIF":4.2,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145461653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.etap.2025.104862
R. Kondati , M. Thakur , D. Mutyala , W. Dorsey , S. Batra
Pentachlorophenol (PCP), its metabolite tetrachlorohydroquinone (TCHQ), and the co-occurring pollutant hexachlorobenzene (HCB) remain a toxicological concern due to their environmental persistence and bioaccumulation. Both PCP and TCHQ exhibit well-documented toxicities and have likely contributed to substantial occupational and environmental exposures worldwide, owing to their efficient absorption through multiple routes. While HCB, although not a PCP metabolite, similarly poses long-term toxicological risks. These toxicants exhibit distinct toxicological profiles, underscoring their relevance as environmental health hazards. Our previous studies have demonstrated that PCP exposure activates the Hsp70-ROS-autophagy axis in submerged lung alveolar epithelial (A549) monolayers, highlighting its role in initiating early cellular stress responses. Building on our prior investigations, this study evaluates the cellular mechanisms activated by PCP, its metabolite TCHQ, and the co-occurring pollutant HCB at a higher occupationally relevant concentration using submerged monolayer (2D) and 3D air-liquid interface (ALI) models. The computational insights from the STITCH-based network prompted us to validate these links in A549 cells exposed to PCP, TCHQ, and HCB. All tested compounds induced the expression of PANoptosis and RNA granule markers, alongside inflammatory cytokine/chemokine production, implicating integrated cell death pathways and post-transcriptional regulatory mechanisms jointly mediate cellular responses under these conditions. Remarkably, wound healing (in vitro scratch) assays indicated preserved epithelial cell migration capacity despite robust inflammatory and PANoptotic signaling, highlighting a dynamic balance between cellular stress and regenerative resilience. Overall, this study elucidates the role of PANoptosis and RNA granule dynamics as central mediators of toxicant-induced inflammation, providing a mechanistic framework for evaluating the cellular effects of chlorinated environmental pollutants such as PCP and related compounds.
{"title":"Persistent environmental toxicants PCP, TCHQ, and HCB drive PANoptosis and RNA granule remodeling in human lung epithelial cells","authors":"R. Kondati , M. Thakur , D. Mutyala , W. Dorsey , S. Batra","doi":"10.1016/j.etap.2025.104862","DOIUrl":"10.1016/j.etap.2025.104862","url":null,"abstract":"<div><div>Pentachlorophenol (PCP), its metabolite tetrachlorohydroquinone (TCHQ), and the co-occurring pollutant hexachlorobenzene (HCB) remain a toxicological concern due to their environmental persistence and bioaccumulation. Both PCP and TCHQ exhibit well-documented toxicities and have likely contributed to substantial occupational and environmental exposures worldwide, owing to their efficient absorption through multiple routes. While HCB, although not a PCP metabolite, similarly poses long-term toxicological risks. These toxicants exhibit distinct toxicological profiles, underscoring their relevance as environmental health hazards. Our previous studies have demonstrated that PCP exposure activates the Hsp70-ROS-autophagy axis in submerged lung alveolar epithelial (A549) monolayers, highlighting its role in initiating early cellular stress responses. Building on our prior investigations, this study evaluates the cellular mechanisms activated by PCP, its metabolite TCHQ, and the co-occurring pollutant HCB at a higher occupationally relevant concentration using submerged monolayer (2D) and 3D air-liquid interface (ALI) models. The computational insights from the STITCH-based network prompted us to validate these links in A549 cells exposed to PCP, TCHQ, and HCB. All tested compounds induced the expression of PANoptosis and RNA granule markers, alongside inflammatory cytokine/chemokine production, implicating integrated cell death pathways and post-transcriptional regulatory mechanisms jointly mediate cellular responses under these conditions. Remarkably, wound healing (in vitro scratch) assays indicated preserved epithelial cell migration capacity despite robust inflammatory and PANoptotic signaling, highlighting a dynamic balance between cellular stress and regenerative resilience. Overall, this study elucidates the role of PANoptosis and RNA granule dynamics as central mediators of toxicant-induced inflammation, providing a mechanistic framework for evaluating the cellular effects of chlorinated environmental pollutants such as PCP and related compounds.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"121 ","pages":"Article 104862"},"PeriodicalIF":4.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1016/j.etap.2025.104861
Tuğba Tezcan , Selin Özkan-Kotiloğlu , Mukaddes Asena Yıldırım , Mustafa Danışman , H. Ceren Bozmaoğlu , Kenan Can Tok , İrem Kar , Mehmet Gümüştaş , İnci Özgür-İlhan , Halit Sinan Süzen , Dilek Kaya-Akyüzlü
This study investigated whether hsa-miR-29a-3p expression affects diazepam (DZP) metabolism by modulating CYP2C19 gene expression in patients with alcohol withdrawal syndrome (AWS). Blood samples were obtained from 75 male AWS patients. hsa-miR-29a-3p expression was quantified using qRT-PCR, and plasma DZP and its active metabolite nordiazepam (NDZP) levels were measured via HPLC. No significant correlations were found between hsa-miR-29a-3p expression and DZP dose, plasma DZP/NDZP levels, dose-adjusted or weight-adjusted concentrations, or the metabolite-to-parent drug ratio. However, hsa-miR-29a-3p expression levels were significantly higher in patients exhibiting confusion (p = 0.016) and excessive fatigue (p = 0.039). Although hsa-miR-29a-3p did not appear to influence diazepam biotransformation directly, this study is the first to report a potential link between elevated hsa-miR-29a-3p expression and neuropsychiatric symptoms in AWS, suggesting a possible role of this microRNA in the clinical presentation of alcohol withdrawal.
{"title":"Evaluation of hsa-miR-29a-3p expression and diazepam biotransformation via CYP2C19 in alcohol withdrawal syndrome","authors":"Tuğba Tezcan , Selin Özkan-Kotiloğlu , Mukaddes Asena Yıldırım , Mustafa Danışman , H. Ceren Bozmaoğlu , Kenan Can Tok , İrem Kar , Mehmet Gümüştaş , İnci Özgür-İlhan , Halit Sinan Süzen , Dilek Kaya-Akyüzlü","doi":"10.1016/j.etap.2025.104861","DOIUrl":"10.1016/j.etap.2025.104861","url":null,"abstract":"<div><div>This study investigated whether <em>hsa-miR-29a-3p</em> expression affects diazepam (DZP) metabolism by modulating <em>CYP2C19</em> gene expression in patients with alcohol withdrawal syndrome (AWS). Blood samples were obtained from 75 male AWS patients. <em>hsa-miR-29a-3p</em> expression was quantified using qRT-PCR, and plasma DZP and its active metabolite nordiazepam (NDZP) levels were measured via HPLC. No significant correlations were found between <em>hsa-miR-29a-3p</em> expression and DZP dose, plasma DZP/NDZP levels, dose-adjusted or weight-adjusted concentrations, or the metabolite-to-parent drug ratio. However, <em>hsa-miR-29a-3p</em> expression levels were significantly higher in patients exhibiting confusion (p = 0.016) and excessive fatigue (p = 0.039). Although <em>hsa-miR-29a-3p</em> did not appear to influence diazepam biotransformation directly, this study is the first to report a potential link between elevated <em>hsa-miR-29a-3p</em> expression and neuropsychiatric symptoms in AWS, suggesting a possible role of this microRNA in the clinical presentation of alcohol withdrawal.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104861"},"PeriodicalIF":4.2,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.etap.2025.104857
Gabriel O. Ostapchuk , Analía Ale , Victoria S. Andrade , Gisela L. Poletta , Luciana Montalto , Florencia M. Rojas Molina , Martín F. Desimone , Paolo N. Catalano
Silica nanoparticles (SiNP) have a high global production volume, but their toxicity is far from being completely understood. In this study, we synthesized SiNP with distinct morphological features: dense SiNP (dSiNP), conventional mesoporous SiNP (MSN), and two types of flower-like dendritic mesoporous SiNP with a stellate lamellar structure: one using ibuprofen (FLW-IBU) and one using sodium salicylate (FLW-NaSal) as auxiliary templates. To assess their toxicological impact, we conducted a 96-hour bioassay exposing the freshwater bivalve Limnoperna fortunei to 10 µg/mL of these varied SiNP. Exposure to dSiNP increased superoxide dismutase and glutathione S-transferase enzyme activities in the soft tissue of bivalves. Lipid peroxidation levels also augmented following exposure to both dSiNP and MSN. We observed no significant alterations in tissular damage markers across treatments. Neither FLW-IBU nor FLW-NaSal induced any deleterious effect, indicating they are less detrimental to L. fortunei. These findings contribute to the safe-by-design development of nanomaterials.
{"title":"Impact of morphologically tuned silica nanoparticles on the invasive freshwater bivalve Limnoperna fortunei","authors":"Gabriel O. Ostapchuk , Analía Ale , Victoria S. Andrade , Gisela L. Poletta , Luciana Montalto , Florencia M. Rojas Molina , Martín F. Desimone , Paolo N. Catalano","doi":"10.1016/j.etap.2025.104857","DOIUrl":"10.1016/j.etap.2025.104857","url":null,"abstract":"<div><div>Silica nanoparticles (SiNP) have a high global production volume, but their toxicity is far from being completely understood. In this study, we synthesized SiNP with distinct morphological features: dense SiNP (dSiNP), conventional mesoporous SiNP (MSN), and two types of flower-like dendritic mesoporous SiNP with a stellate lamellar structure: one using ibuprofen (FLW-IBU) and one using sodium salicylate (FLW-NaSal) as auxiliary templates. To assess their toxicological impact, we conducted a 96-hour bioassay exposing the freshwater bivalve <em>Limnoperna fortunei</em> to 10 µg/mL of these varied SiNP. Exposure to dSiNP increased superoxide dismutase and glutathione S-transferase enzyme activities in the soft tissue of bivalves. Lipid peroxidation levels also augmented following exposure to both dSiNP and MSN. We observed no significant alterations in tissular damage markers across treatments. Neither FLW-IBU nor FLW-NaSal induced any deleterious effect, indicating they are less detrimental to <em>L. fortunei</em>. These findings contribute to the safe-by-design development of nanomaterials.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104857"},"PeriodicalIF":4.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145383645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.etap.2025.104858
Mengya Si , Muhammad Nadeem Khan , Hazrat Bilal , Muhammad Shafiq , Sabir Khan , Xiaoling Guo , Meimei Wang , Jilong Wu , Wang Zhen , Fen Yao , Adela Jing Li , Xiaoyang Jiao
Neonicotinoids (NEOs) and their metabolites impact neuronal function; however, their effects on neurotransmitters remain unexplored. We analyzed cerebrospinal fluid (CSF) from leukemia patients with differing concentrations of N-desmethyl-acetamiprid (N-dm-ACE) for neurotransmitter profiling. Neurotransmitters and biomarkers were measured in CSF, blood, and serum from 39 patients (19 low and 20 high N-dm-ACE) across three age groups: children, adults, and elders. Significant differences (p ≤ 0.05) in neurotransmitters were found among groups, including glutamic acid (253.45 ± 388.16 & 101.11 ± 52.79), aspartic acid (79.64 ± 87.46 & 0.00), tryptophan (325.89 ± 76.47 & 508.09 ± 331.35), and tyrosine (984.41 ± 348.78 ng/mL). Regression analysis indicated that N-dm-ACE is significantly (p < 0.05) positively associated with serum total proteins and negatively with betaine-aldehyde-chloride and ornithine. This suggests that increased accumulation of N-dm-ACE in the CNS may elevate the risk of neurological or neurotoxic conditions. Further studies are needed to better understand the intricate relationship between NEOs, particularly N-dm-ACE, and brain health.
{"title":"Investigation of N-desmethyl-acetamiprid-induced neurotransmitter disturbances in cerebrospinal fluid from leukemia patients","authors":"Mengya Si , Muhammad Nadeem Khan , Hazrat Bilal , Muhammad Shafiq , Sabir Khan , Xiaoling Guo , Meimei Wang , Jilong Wu , Wang Zhen , Fen Yao , Adela Jing Li , Xiaoyang Jiao","doi":"10.1016/j.etap.2025.104858","DOIUrl":"10.1016/j.etap.2025.104858","url":null,"abstract":"<div><div>Neonicotinoids (NEOs) and their metabolites impact neuronal function; however, their effects on neurotransmitters remain unexplored. We analyzed cerebrospinal fluid (CSF) from leukemia patients with differing concentrations of N-desmethyl-acetamiprid (N-dm-ACE) for neurotransmitter profiling. Neurotransmitters and biomarkers were measured in CSF, blood, and serum from 39 patients (19 low and 20 high N-dm-ACE) across three age groups: children, adults, and elders. Significant differences (p ≤ 0.05) in neurotransmitters were found among groups, including glutamic acid (253.45 ± 388.16 & 101.11 ± 52.79), aspartic acid (79.64 ± 87.46 & 0.00), tryptophan (325.89 ± 76.47 & 508.09 ± 331.35), and tyrosine (984.41 ± 348.78 ng/mL). Regression analysis indicated that N-dm-ACE is significantly (p < 0.05) positively associated with serum total proteins and negatively with betaine-aldehyde-chloride and ornithine. This suggests that increased accumulation of N-dm-ACE in the CNS may elevate the risk of neurological or neurotoxic conditions. Further studies are needed to better understand the intricate relationship between NEOs, particularly N-dm-ACE, and brain health.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104858"},"PeriodicalIF":4.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145383644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1016/j.etap.2025.104859
Wei Zhang , Hui Chen , Yanshu Li , Qian Zhu , Kangtai Liu , Xinran Liu , Yan Wang , Gaochun Zhu
Lead (Pb) facilitates neurological deficits. Silybin is a flavonoid with neuroprotective properties. Heterogeneous nuclear ribonucleoprotein U (hnRNP U) has been implicated in neurodevelopmental disorders and predicted to regulate Repressor Element-1 Silencing Transcription (REST) expression. STAT3 can form a complex with hnRNP U and is inhibited by Silybin. We aim to elucidate the role of hnRNP U/STAT3 in Pb neurotoxicity and the neuroprotective effects of Silybin in Pb-exposed rats. We found that Pb increased the nuclear protein levels of hnRNP U and STAT3 and REST expression, which Silybin can partially reverse. Silencing hnRNP U reduced REST expression. Inhibiting STAT3 blocked hnRNP U nuclear transport. Silybin improves Pb-induced learning and memory impairment. Silybin reduced the expression of hnRNP U and NFκB. Inhibiting NFκB reduced hnRNP U expression. These suggest that Silybin improves Pb-induced learning and memory impairment by antagonizing STAT3/hnRNP U/REST and hnRNP U/NFκB.
{"title":"Silybin ameliorates Pb-induced learning and memory impairment by inhibiting STAT3/hnRNP U/REST and NFκB/hnRNP U","authors":"Wei Zhang , Hui Chen , Yanshu Li , Qian Zhu , Kangtai Liu , Xinran Liu , Yan Wang , Gaochun Zhu","doi":"10.1016/j.etap.2025.104859","DOIUrl":"10.1016/j.etap.2025.104859","url":null,"abstract":"<div><div>Lead (Pb) facilitates neurological deficits. Silybin is a flavonoid with neuroprotective properties. Heterogeneous nuclear ribonucleoprotein U (hnRNP U) has been implicated in neurodevelopmental disorders and predicted to regulate Repressor Element-1 Silencing Transcription (REST) expression. STAT3 can form a complex with hnRNP U and is inhibited by Silybin. We aim to elucidate the role of hnRNP U/STAT3 in Pb neurotoxicity and the neuroprotective effects of Silybin in Pb-exposed rats. We found that Pb increased the nuclear protein levels of hnRNP U and STAT3 and REST expression, which Silybin can partially reverse. Silencing hnRNP U reduced REST expression. Inhibiting STAT3 blocked hnRNP U nuclear transport. Silybin improves Pb-induced learning and memory impairment. Silybin reduced the expression of hnRNP U and NFκB. Inhibiting NFκB reduced hnRNP U expression. These suggest that Silybin improves Pb-induced learning and memory impairment by antagonizing STAT3/hnRNP U/REST and hnRNP U/NFκB.</div></div>","PeriodicalId":11775,"journal":{"name":"Environmental toxicology and pharmacology","volume":"120 ","pages":"Article 104859"},"PeriodicalIF":4.2,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145396813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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