Journal of Applied Toxicology最新文献

{"title":"The Proteome of African Spitting and Non-Spitting Cobra Venoms and Cytotoxicity Against Pancreatic Cancer Cells.","authors":"Benedict C Offor, Beric Muller, Lesetja R Motadi, Lizelle A Piater","doi":"10.1002/jat.4825","DOIUrl":"https://doi.org/10.1002/jat.4825","url":null,"abstract":"<p><p>African cobra (Naja spp.) venom contains toxins dominated by proteins and peptides with inter- and intra-specific variations. There are several FDA-approved drugs from snake venom toxins from other regions, including South America and Asia. Profiling the proteomes of medically important African cobra venoms from different locations will aid in developing more effective anticancer agents. The venoms of spitting cobras (Naja pallida and Naja nigricincta woodi) and non-spitting cobras of the Uraeus subgenus (Naja anchietae, Naja annulifera, and Naja nivea) were fractionated by reverse phase-high performance liquid chromatography (RP-HPLC). Using label-free LC-MS/MS, the venom toxins were identified and grouped into families based on their relative abundance. Venom cytotoxicity of both crude and fractionated samples was tested in pancreatic carcinoma cell lines (MIA PaCa-2) using the Alamar Blue assay. Cell viability analysis revealed a cytotoxic effect of spitting cobra venoms against MIA PaCa-2 cell lines compared to normal MRC-5 cells. Conversely, venoms of non-spitting cobras showed no cytotoxic activity against MIA PaCa-2 cells. Selected RP-HPLC venom fractions from the spitting cobras revealed that N. pallida Fraction 6 and N. n. woodi Fraction 9 at a minimal level were cytotoxic against MIA PaCa-2 cells. LC-MS/MS data showed that while N. pallida Fraction 6 was dominated by basic phospholipase 2 CM-III and Cytotoxin 2, N. n. woodi Fraction 9 was dominated by basic phospholipase 2 CM-III, basic phospholipase 2 CM-II and Cytotoxin 3. These fractions will be purified and studied to determine the mechanisms behind the underlying cytotoxicity against MIA PaCa-2 cells.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Finasteride on Apoptosis, Antioxidants, and Cytokines in Experimental Diabetes Rats.","authors":"Dilek Aksit, Eren Altun, Murat Celebi, Cagla Celebi, Hasan Aksit","doi":"10.1002/jat.4823","DOIUrl":"https://doi.org/10.1002/jat.4823","url":null,"abstract":"<p><p>Diabetes mellitus (DM) is one of the five leading causes of death worldwide. Finasteride is an inhibitor of type 2 5-alpha reductase enzyme. In this study, we aimed to investigate the effects of finasteride on apoptosis, oxidative stress, antioxidants, and cytokines in the liver, kidney, and testis in an experimental diabetes model in rats. Thirty-two male rats were randomly divided into four equal groups as follows: control, finasteride (30 mg/kg 14 days by gastric gavage), diabetes, and diabetes+finasteride. Malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant status (TAS) levels in liver, kidney, and testis tissues, and nitric oxide (NO), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels in blood samples were examined. In addition, tissue sections were evaluated immunohistochemically (B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax)) and histopathologically. Induction of diabetes with streptozotocin resulted in an increase MDA, NO, IL-6, TNF-α levels whereas TAS and SOD decreased compared to the control group. Diabetes+Finasteride group was compared with the diabetes group decrease in MDA, NO, IL-6, TNF-α levels, and increase in TAS and SOD levels were observed. Finasteride suppressed apoptosis through the down regulation of Bax and the induction of the expression of Bcl-2 in the liver and kidney. Finasteride administration ameliorated some histopathological changes and decreased oxidative stress, apoptosis, and inflammation while increasing the antioxidant defense system in the STZ-induced diabetes group. In conclusion, finasteride might show a protective effect by suppressing oxidative stress and apoptosis and downregulation of proinflammatory cytokines in diabetic rats with its antioxidant and antiapoptotic effects. Human trials are needed before clinical application.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and Subacute Toxicity Study of α-Arbutin: An In Vivo Evidence.","authors":"Pooja Mishra, Farogh Ahsan, Tarique Mahmood, Shahzadi Bano, Vaseem Ahamad Ansari, Jyoti Yadav, Jamal Akhtar Ansari, Mohd Masih Uzzaman Khan","doi":"10.1002/jat.4822","DOIUrl":"https://doi.org/10.1002/jat.4822","url":null,"abstract":"<p><p>α-Arbutin, a glucoside of hydroquinone, is utilized as a skin-lightening agent that inhibits human tyrosinase activity. Although it exhibits antioxidant and anti-inflammatory properties, limited research exists on its toxicological effects. This research investigates the oral toxicity of α-arbutin in both acute and subacute settings using Sprague-Dawley rats as test subjects. Female Sprague-Dawley rats underwent acute oral toxicity testing in accordance with OECD TG 425 guidelines. The rats received oral doses of 175, 550, 1750, and 2000 mg/kg. Additionally, a subacute oral toxicity study following OECD TG 407 protocols was performed on both male and female rats. In this study, the animals were given daily oral doses of 250, 500, 1000, and 2000 mg/kg for 28 days. During acute and subacute oral toxicity assessments, no deaths or observable changes in behavior were noted at the administered doses. Examination of gross anatomy showed a significant decrease in the relative spleen weight of rats given α-arbutin at 250 mg/kg compared to the control group. Male rats treated with α-arbutin exhibited markedly non-significantly increased levels of AST, ALT, and chloride ions. In contrast, mean corpuscular hemoglobin concentration levels notably decreased at lower α-arbutin doses relative to the control group. Brain histopathology of male rats revealed moderate inflammation with pyknotic nuclei, whereas the cortex showed extensive epithelial cell necrosis following the administration of 2000 mg/kg of α-arbutin. The results showed that when given for a short time, α-arbutin is nontoxic till 2000 mg/kg. The median lethal dose (LD₅₀) of α-arbutin is more than 2000 mg/kg. A long-term toxicity study may be performed to validate the result. This study evaluated the acute and subacute oral toxicity of α-arbutin in Sprague-Dawley rats. No mortality or significant behavioral changes were observed up to 2000 mg/kg. However, at higher doses, male rats exhibited elevated liver enzymes and chloride ions, along with brain inflammation and cortical necrosis. Overall, α-arbutin showed no remarkable toxicity at tested doses, with an LD₅₀ exceeding 2000 mg/kg, warranting further long-term safety assessments.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic Exploration of Potential Toxicity Targets and Molecular Mechanisms of Emerging Short-Chain PFAS Substitutes: PFBA- and PFBS-Induced Hepatocellular Carcinoma Based on Toxicity Network Analysis, Machine Learning, and Biomimetic Calculations.","authors":"Zirui Zhang, Jin Wang, Zhongyi Zhang, Qianrong Gan, Yunliang He, Donghui Chen, Yong Zhang, Mei Zhao","doi":"10.1002/jat.4818","DOIUrl":"https://doi.org/10.1002/jat.4818","url":null,"abstract":"<p><p>Perfluorobutanoic acid (PFBA) and perfluorobutanesulfonic acid (PFBS) are short-chain alternatives to traditional perfluoroalkyl and polyfluoroalkyl substances (PFASs). Long-term exposure to these pollutants is closely associated with hepatocellular carcinoma (HCC). However, the toxic targets and mechanisms underlying PFBA- and PFBS-induced HCC remain unclear. To address this knowledge gap, this study employed a multifaceted approach encompassing network toxicology, molecular docking, and molecular dynamic simulation. Thirty-six core targets associated with PFBA- and PFBS-induced HCC were identified, and 12 key genes were initially screened through network toxicity analysis. Subsequently, based on the TCGA and ICGC datasets, three classical algorithms were applied to screen key genes: PPARG, ESR1, and ALB. Further exploration of the HCC-related dataset from the GEO database identified six critical genes: PPARG, ESR1, CD36, ABCA1, ACACA, and ALB. Survival analysis and ROC analysis based on the TCGA dataset revealed and validated the strong association between the expression levels of key genes (PPARG, ESR1, and ACACA). Single-gene GSEA showed that these three key genes may induce HCC through multiple biological pathways via interfering with the normal growth and development of hepatocytes and promoting inflammation and cell proliferation. Ultimately, molecular dynamics demonstrated the strong binding affinities between PFBA, PFBS, and the three protein receptors, with the best stability and flexibility of the interaction between PFBS and PPARG. These findings provide insights into the theoretical foundation for applying network toxicology, molecular docking, and molecular dynamic simulations in environmental pollutant research.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the Mechanistic Approach of Aflatoxin Contaminated Food on Neurodegenerative Diseases-A Novel Approach.","authors":"Ajay Elangovan, Arya Singh, Mahalaxmi Iyer, Sindduja Muthu Kumar, Masako Kinoshita, Jayalakshmi Krishnan, Jyoti Parkash, Neelakshi Verma, Mukesh Kumar Yadav, Arvinder Wander, Dibbanti HariKrishna Reddy, Balachandar Vellingiri","doi":"10.1002/jat.4817","DOIUrl":"https://doi.org/10.1002/jat.4817","url":null,"abstract":"<p><p>Aflatoxins (AFs) are a group of toxic secondary metabolites and a dietary toxin produced predominantly by Aspergillus species such as Aspergillus flavus and Aspergillus parasiticus. The four most common and harmful forms of AFs include Aflatoxin B1 (AFB1), Aflatoxin B2 (AFB2), Aflatoxin G1 (AFG1), and Aflatoxin G2 (AFG2), which pose a significant health threat due to their widespread contamination of food and feed products. Particularly, AFB1 has raised a major global health concern. Noxious neurological outcomes have been associated with chronic exposure to AF-contaminated food, contributing to development of neuropathies, demyelinating diseases, and cognitive decline. Disrupted tight junctions of blood-brain barrier (BBB) said to have implicated by AFs toxicity by directly damaging brain endothelial cells. Compromised BBB leads to the formation of DNA adducts, mitochondrial dysfunction, and impaired oxidative phosphorylation, contributing to oxidative stress in neuronal cells. AFs disrupt neuronal signaling pathways by generating reactive oxygen species (ROS) and initiating chronic inflammation, impairing cognitive function and motor control. Mounting evidences suggests that these factors trigger neurological disorders especially neurodegenerative disorders. Neuroprotective compounds, such as hesperetin, N-acetylcysteine (NAC), curcumin, and artichoke extract, have shown promise in counteracting AF-induced neurotoxicity. These compounds could reduce oxidative stress, attenuate inflammation, and support mitochondrial function, offering potential therapeutic strategies to mitigate AF-induced neurodegeneration. This review focuses on the molecular pathways through which AFs exert neurotoxic effects, highlighting their role in the onset of neurodegenerative diseases and potential neuroprotective compounds for therapies have been highlighted.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Do Gadolinium-Based Contrasts Represent a High Risk for Genotoxicity in Mammalian Cells? A Systematic Review.","authors":"Thiago Guedes Pinto, Rogerio Aparecido Dedivits, Daniel Araki Ribeiro","doi":"10.1002/jat.4814","DOIUrl":"https://doi.org/10.1002/jat.4814","url":null,"abstract":"<p><p>The scientific rationale for this review stems from the increasing global use of gadolinium-based contrast agents in medical imaging and the concerns over the long-term environmental accumulation of gadolinium waste, which may pose biological risks. The primary objective was to determine whether gadolinium exposure induces genetic damage in mammalian cells, regardless of the assay method used, and to assess the quality of the studies available in the literature. Genotoxicity was measured through assays such as the micronucleus test, comet assay, chromosomal aberration, and sister chromatid exchange. A total of 17 studies were included being 11 studies (out of 17) with positive genotoxic effects, suggesting that gadolinium can induce DNA damage. Most of the studies (12 out of 17) were rated as \"strong\" or \"moderate\" in quality, providing reliable evidence for these findings. This review advances the current understanding of gadolinium's potential health risks by highlighting its genotoxic effects.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute and Subacute Toxicity of Synthetic Pyridone Analogs in Albino Rats: Analysis of Basic Parameters.","authors":"Vaishali Singh, Lalhruaizela, Ranjeet Maurya, Ved Prakash Singh, Rajesh Kumar Kharwar","doi":"10.1002/jat.4819","DOIUrl":"https://doi.org/10.1002/jat.4819","url":null,"abstract":"<p><p>1,4-Dihydropyridones and its derivatives possess biological and pharmacological activities. However, at present there is no information regarding toxicity and biological as well as pharmacological potentials of Compound 1 [Ethyl-5-cyano-2-methyl-4-(2-nitrophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylate], Compound 2 [Ethyl 4-(4-chlorophenyl)-5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate], and Compound 3 [Ethyl-5-cyano-2-methyl-6-oxo-4-phenyl-1,6-dihydropyridine-3-carboxylate]. We evaluated acute and subacute toxicity of Compounds 1, 2, and 3. To achieve the proposed objective, rats were orally administrated with different doses of 1, 2, and 3. For acute oral toxicity animals were administered single oral dose of 10, 20, 50, and 100 mg/100 g bw and for subacute oral toxicity animals were administered oral dose of 1 and 10 mg/100 g bw for 28 days. Common physiological endpoints such as food and water consumption, stool weight and mortality were observed up to 14 and 28 days. Variation in bw, food and water consumption, stool weight, hematological, biochemical, organ weight, and histopathology was observed. In acute study, administration of Compound 2 lead to the mortality of one female rat. However, no mortality was noted in males. Normal physiological endpoints were noted in males as well as female rats. No significant change was noted in any parameters after treatment with acute and subacute doses. After oral administration of Compound 1 and Compound 3 no significant variation was noted in any groups of the animals. All compounds showed no toxic potential for either acute or subacute dose. Further studies are required to check biological and pharmacological efficiency of the compounds.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of a 3D Human Cornea-Like Epithelium for Eye Irritation Assessment of Contact Lens Solutions.","authors":"Xian He, Li Fang, Xianhua Chen, Ziyang Zhang, Senting Zhou, Danning Qi, Xu Weng, Xinyi Lin, Nana Gao, Fei Hu, Xin Lu","doi":"10.1002/jat.4820","DOIUrl":"https://doi.org/10.1002/jat.4820","url":null,"abstract":"<p><p>Currently, medical device eye irritation testing relies on the Draize eye test in rabbits, which presents significant challenges regarding animal welfare and variations across laboratories. This research explores the application of the commercially available three-dimensional reconstructed human corneal epithelial tissue (Skinovo-Ocular) in eye irritation evaluation. The model is developed by culturing immortalized human corneal epithelial cells at a liquid-air interface, resembling the morphology and induction of biological indicators found in human corneal tissue. We evaluated the eye irritation effect of 30 minimum reference chemicals according to OECD Performance Standards. The results revealed a sensitivity of 100%, specificity of 66.7%, and accuracy of 83.3%, indicating predictive performance comparable to other reference methods. Furthermore, we conducted analyses including trans-epithelial electrical resistance, cytokine secretion, and histology, thereby enhancing our understanding of the mechanisms underlying eye irritation assessment in this model. Additionally, we tested various contact lens solutions and compared the results with rabbit in vivo experiments, demonstrating the model's potential for analyzing the eye irritation of mixtures. This model shows promise as an alternative for eye irritation analysis of medical devices, further reducing the reliance on experimental animals.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Permethrin Affects Freshwater Mussels: Physiological, Biochemical, and Histopathological Analyses?","authors":"Reyhan Gençer, Pınar Arslan Yüce, Aysel Çağlan Günal","doi":"10.1002/jat.4821","DOIUrl":"https://doi.org/10.1002/jat.4821","url":null,"abstract":"<p><p>Freshwater mussel Unio delicatus is a species found in aquatic ecosystems in countries bordering the Mediterranean Sea. Permethrin is a synthetic pyrethroid and a widely used chemical in domestic, industrial, and agricultural areas due to its insecticidal properties. Therefore, it is one of the substances that inevitably contaminate aquatic ecosystems and is a chemical whose effects on different types of nontarget aquatic organisms are investigated. In the present study, the sublethal effects of permethrin on the physiological, biochemical, and histological properties of U. delicatus were investigated with two different exposure times. Permethrin was less toxic than other commonly used insecticides against U. delicatus, and its 96-h LC₅₀ value was 119.4430 μg/L. In 96-h and 7-day exposure to permethrin with ¹/₁₀, ¹/₅₀, and ¹/₁₀₀ concentrations, a decrease in total hemocyte count occurred compared to control groups, whereas hemolymph fluid biochemical parameters showed an increase in total antioxidant and total oxidant levels depending on the concentration. In addition to these biochemical results, there were changes in total glutathione, advanced oxidative protein products, and malondialdehyde levels in the gill and digestive gland tissues compared to the control groups. In the gill, digestive gland, connective tissue, and ovaries, ¹/₁₀ and ¹/₅₀ concentrations of LC₅₀ caused pathological findings in both exposure periods. All these data showed that permethrin has significant sublethal effects on U. delicatus. The results of this study provided a comprehensive understanding of the effects of permethrin on nontarget organisms such as U. delicatus.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome Analysis Suggests Chronic Toxic Effects of 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide in Daphnia magna via Induction of Endoplasmic Reticulum Stress.","authors":"Haruka Ito, Megumi Matsumoto, Keisuke Mitsukuni, Tomohiro Suzuki, Hitoshi Miyakawa","doi":"10.1002/jat.4816","DOIUrl":"https://doi.org/10.1002/jat.4816","url":null,"abstract":"<p><p>Plastics have revolutionized modern life, yet their persistence in the environment poses a growing ecological threat. Biodegradable plastics, like polycaprolactone (PCL), offer a promising alternative, but their degradation can release toxic byproducts. In this study, we evaluated the ecotoxicological impact of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a carbodiimide-based additive used to stabilize PCL, using Daphnia magna as a model organism. Chronic toxicity assays revealed that EDC exposure at concentrations as low as 1 mg/L significantly impaired reproduction, and concentrations above 7.5 mg/L caused complete lethality. To clarify the underlying molecular mechanisms, RNA-seq analysis was conducted using four developmental stages. Surprisingly, the highest number of differentially expressed genes appeared at Day 2, prior to visible phenotypic changes. Gene ontology and pathway analysis revealed that EDC exposure induced endoplasmic reticulum (ER) stress, indicated by suppressed ribosomal gene expression and enhanced protein folding and degradation pathways. Concurrently, sphingolipid metabolism and glutathione metabolism were altered, suggesting adaptive responses to maintain cellular homeostasis. These findings suggest that EDC leaching from degrading plastics can cause profound cellular and organismal toxicity, even at environmentally relevant concentrations. Our study highlights the need to assess the toxicity of not only intact polymers, but also their degradation byproducts, offering essential insights for safer plastic chemistry and for environmental risk evaluation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}