Journal of Applied Toxicology最新文献

{"title":"Functionalized Polystyrene Nanoplastics Drive Distinct Mitochondrial Bioenergetic and Phenotypic Responses in Rainbow Trout Gill Epithelia.","authors":"Lissett G Diaz, Rebecca Klaper","doi":"10.1002/jat.70170","DOIUrl":"10.1002/jat.70170","url":null,"abstract":"<p><p>Nanoplastics are emerging contaminants of concern in freshwater ecosystems and have been shown to be ingested and assimilated in fish gill tissues. Understanding the interactions of nanoplastics in fish gill cells and how these interactions influence bioenergetics is essential. In particular, the mitochondria are vulnerable due to their critical role in energy production, lipid metabolism, redox regulation, apoptosis, and much more. Surface charge is a key determinant in nano-bio interactions, mediating mechanisms of toxicity by influencing uptake and subsequent subcellular organelle responses. In our previous study, we found a possible mode of action governing the phenotypic response in positively charged nanoparticles specific to the mitochondria. In this study, we investigated the bioenergetic and morphological effects of surface functionalized polystyrene nanoplastics (PS NPs)-amine-functionalized (PS-NH₂) and carboxyl-modified (PS-COOH) PS NPs-in rainbow trout gill epithelia (RTgill-W1). Using the Seahorse XF Mito Stress Test and high-content imaging, we demonstrated that PS-NH₂ NPs, which are positively charged, caused dose-dependent declines in basal and maximal oxygen consumption rates (OCRs), increased proton leak, and reduced ATP-linked respiration, indicating disruption of mitochondrial respiration. Conversely, PS-COOH NPs exhibited minimal effects on mitochondrial function. Extracellular acidification rate (ECAR) analysis revealed impaired glycolytic compensation in sublethal PS-NH₂-treated cells. Phenotypic profiling demonstrated that morphological data distinguished treatment groups by distinct clusters based on similarity and revealed a more comprehensive understanding of nano-induced cellular stress than bioenergetics measurements alone. Future nanotoxicological studies should implement multiparametric approaches to expand beyond traditional endpoints, including the use of other environmentally relevant nanoplastics in aquatic organisms.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4160-4174"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633489","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":"Genotoxic and Biochemical Responses of the Amphibian Rhinella arenarum Under Exposure to the Herbicide 2,4-Dichlorophenoxyacetic Acid (2,4-D).","authors":"Milagros R R Laborde, Celeste Ruiz de Arcaute, Sonia Soloneski","doi":"10.1002/jat.70194","DOIUrl":"10.1002/jat.70194","url":null,"abstract":"<p><p>The widespread use of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), an analogue to the hormone auxin, raises concerns regarding its potential impact on aquatic organisms, particularly amphibians. Thus, this study aimed to evaluate the genotoxic and oxidative effects of an environmentally relevant concentration of 2,4-D on Rhinella arenarum tadpoles. To this end, tadpoles were acutely exposed to 5 μg/L of 2,4-D under laboratory conditions using the microformulation Dedalo Elite (30% a.i.). Genotoxicity was assessed via the alkaline comet assay, measuring DNA single- and double-strand breaks. Oxidative balance was evaluated by determining catalase (CAT) and glutathione S-transferase (GST) activities, along with reduced glutathione (GSH) levels. The results demonstrated that, after exposure, tadpoles showed significant increases in DNA damage, with 3.32- and 2.92-fold increases at 48 and 96 h, respectively. The 48-h exposure increased DNA damage, but extended exposure (96 h) had a lesser effect. In addition, after 96 h of exposure, CAT activity was significantly reduced (43.8%), and GSH levels decreased by 29.8%, indicating the induction of oxidative stress. These findings highlight the sensitivity of R. arenarum tadpoles to sublethal 2,4-D concentrations and emphasise the ecological relevance of assessing early life stage responses in amphibians. Our results add to the growing evidence on the risks posed by widely used auxinic herbicides, with detrimental effects on cellular integrity that may compromise the early life stages of freshwater species in their natural environments.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4199-4210"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645604","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":"Biological Response of Silver Nanoparticles Covered With Ilex paraguariensis Extract or Polyvinylpyrrolidone: A Nanotoxicological Study.","authors":"Ayelen M Sosa, Daniela Maza Vega, Natasha L Monzón, Lorena R García, E Malen Saint Martin, David E Ybarra, Laura Cogoi, María Del Rosario Alonso, María F Troncoso, Johanna G Miquet, Jorge Montanari M, Carolina S Martinez, M Jimena Prieto","doi":"10.1002/jat.70159","DOIUrl":"10.1002/jat.70159","url":null,"abstract":"<p><p>The development of nanomaterials and the search for alternatives that reduce adverse effects have become a central focus in the scientific community. However, this progress has not been accompanied by exhaustive nanotoxicological studies, often leading to the assumption that the addition of natural or inert components minimizes the harmful effects of nanostructures. Silver nanoparticles (AgNPs), widely used for their antimicrobial properties, are known to be cytotoxic and potentially harmful to the environment and human health. To mitigate these risks, in this study core-shell nanoparticles were synthesized using coatings of either natural ilex paraguariensis (yerba mate [YM]) extract or synthetic polyvinylpyrrolidone (PVP) to evaluate whether additives confer a safer alternative. Both formulations were fully characterized for dynamic light scattering, zeta potential, and spectroscopy UV-visible. Then, these formulations were evaluated for cytotoxicity in vitro using human skin and liver cell lines and assessed in vivo using the zebrafish model to determine general and organ-specific toxicity. Results showed that AgNPs-YM induced toxicity across all tested concentrations in both in vitro and in vivo systems, with the highest concentration causing mortality, organ damage, and increased production of reactive oxygen species (ROS). In contrast, AgNPs-PVP exhibited significantly lower toxicity under the same conditions. These findings demonstrate that natural-origin coatings do not guarantee safety, and highlight the need for the implementation of exhaustive toxicological screening prior to the validation of new nanomaterials.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"3933-3948"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147468149","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":"Colonic Barrier Dysfunction and Inflammation Induced by Nano-/Micro-Plastics Fibers in Mice via the FAK/NF-κB/iNOS and TLR4/NF-κB/iNOS Pathways.","authors":"Yuting Li, Shibo Bao, Puyang Huang, Jiahui Wang, Hongfeng Li, Yahong Liu, Kai Wang, Jianjun Du, Lingjun Yan, Guowei Pan, Wei Sun","doi":"10.1002/jat.70196","DOIUrl":"10.1002/jat.70196","url":null,"abstract":"<p><p>As emerging environmental contaminants, nano- and micro-plastics (NMPs) have drawn increasing research attention due to potential hazards to organisms. Particle shape is a key factor influencing the toxic effects of NMPs, and NMPs of different shapes cause varying degrees of tissue damage. We investigated the specific mechanisms of polystyrene NMPs (PS-NMPs) with different shapes underlying damage to the colonic intestinal barrier. We divided 120 five-week-old male C57BL/6J mice into seven groups that were orally exposed to different doses of PS-NMPs for 5 weeks. Hematoxylin and eosin staining showed that both shapes of PS-NMPs induced colon pathological injuries, with more pronounced damage in the PS-Fibers groups. DAO and D-LA levels were increased in the medium- and high-dose groups. In all PS-Fibers groups, DAO and D-LA levels were significantly elevated. Immunohistochemical analysis revealed discontinuous distribution and reduced expression of ZO-1 and occludin in the PS-NMPs groups. Alcian blue-periodic acid-Schiff staining results indicated that both types of PS-NMPs significantly reduced the number of goblet cells. The levels of ZO-1, occludin, MUC2, and E-cadherin were significantly decreased in the high-dose PS-Beads group and all PS-Fibers groups. The expression of pro-inflammatory cytokines was significantly increased in the high-dose PS-Beads group and all PS-Fibers groups. Mechanistically, PS-Fibers induced colonic intestinal barrier damage by activating both the TLR4/NF-κB/iNOS and FAK/NF-κB/iNOS pathways, whereas PS-Beads induced damage primarily via the TLR4/NF-κB/iNOS pathway. These findings highlight the effect of differently shaped PS-NMPs on affecting colonic barrier function, thereby providing new insights into the adverse health effects of NMPs.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4144-4159"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147592316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Half a Century of Per- and Polyfluoroalkyl Substances in Northern Gannet Eggs: Impact of Regulations.","authors":"Anaïs Fournier, Anaïs Kerric, Raphaël A Lavoie","doi":"10.1002/jat.70175","DOIUrl":"10.1002/jat.70175","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS), known as \"forever chemicals\", are persistent organic pollutants that have been widely used in the industry across the globe for many decades. Their chemical stability, bioaccumulation, and toxicity pose major environmental and health risks. This study examines temporal trends in the concentrations of 17 PFASs in northern gannet (Morus bassanus) eggs from the Gulf of St. Lawrence, Canada, over a 55-year period (1969-2024). Analyses include 13 perfluoroalkyl carboxylic acids (PFCAs) and four perfluoroalkyl sulfonic acids (PFSAs). Stable isotopes of carbon (δ¹³C) and nitrogen (δ¹⁵N), lipid content, and moisture content were analyzed. Generalized additive models (GAMs), adjusted for lipids and for both lipids and δ¹⁵N, were applied to assess how chemical properties, industrial use, regulatory actions, and trophic dynamics influence PFAS trends. Perfluorooctanesulfonic acid (PFOS) was the dominant compound throughout the study period, peaking in the mid-1990s and declining thereafter due to regulatory measures and voluntary phase-outs. However, PFOS and other PFASs show high persistence, with estimated ecological half-lives for ∑₁₇PFASs of 60 years with lipid correction and 36 years after lipid and δ¹⁵N correction. Some long-chain PFCAs, such as perfluorododecanoic acid (PFDoA; 12 carbons) and perfluorotridecanoic acid (PFTrDA; 13 carbons), have shown a delayed response to regulations. Moreover, PFOS and PFOS + perfluorohexanesulfonic acid (PFHxS) concentrations in northern gannet eggs remained above established toxicological thresholds for 30 years, indicating ecotoxicological risks for marine top predators. These findings highlight the persistent nature of PFAS contamination and underline the importance of regulations, long-term research, and risk assessment.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4085-4098"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147529326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Short-Term 5-MeO-DiPT Exposure on the Brain Metabolome of Zebrafish (Danio rerio).","authors":"Yin Tang, Yanjiao Wang, Liang Meng, Sen Zhao","doi":"10.1002/jat.70178","DOIUrl":"10.1002/jat.70178","url":null,"abstract":"<p><p>5-MeO-DiPT (5-methoxy-N,N-diisopropyltryptamine) has been preliminarily reported to exhibit short-term hallucinogenic effects on humans. However, the connection between its toxic mechanism and behavioral changes remains unexplored. Therefore, this study used zebrafish as the research subject to investigate the metabolic characteristics of 5-MeO-DiPT and its perturbation effects on the metabolic network of organisms and verified the specific impacts of this perturbation through behavioral studies. It is shown that 27 metabolites with significant changes were detected in the brain of zebrafish after being exposed to 5-MeO-DiPT for a short period. The concentration of eight metabolites is increased, whereas the other 19 show a downward trend. Additionally, nine core metabolic pathways were significantly perturbed (p < 0.05). It is indicated that 5-MeO-DiPT disrupted the homeostasis of neurotransmitters, interfered with amino acid metabolism and lipid peroxidation reactions, causing a series of damages to the organism's neural conduction, immune response, and energy metabolism. Its potential carcinogenic risk and the mechanism of inducing metabolic syndrome deserve attention. Filling the theoretical gap in the research of the metabolic mechanism of this drug provides a reference basis for the next step of its research direction.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4175-4185"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633435","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 Biocide Triclosan Drives the Inflammatory Responses in Epithelial Cells and Macrophages via ROS-Mediated Activation of ERK/NF-κB Signaling Pathways.","authors":"Amritha Das, Sneha Bhandari, Nayanika Datta, Sehal Mishra, Santanu Kar Mahapatra, Subbiah Rajasekaran","doi":"10.1002/jat.70202","DOIUrl":"10.1002/jat.70202","url":null,"abstract":"<p><p>Triclosan (TCS) is an antimicrobial agent that is commonly spread and detected in various environmental matrices and organisms, including human tissues and biological fluids. A sustained inflammatory response is an important initial event in various disease developments. TCS-induced inflammatory response and its fundamental molecular mechanisms remain largely unexplored. In this current study, the impact of TCS exposure on inflammatory activation was investigated in both noncancerous (BEAS-2B) and cancerous (A549) lung epithelial cells in addition to murine macrophages (J774). The results revealed that TCS treatment could significantly induce various pro-inflammatory mediators' expression that includes cytokines and chemokines, in all cell types compared to the corresponding vehicle-treated cells. Further, TCS-mediated inflammatory response is associated with reactive oxygen species (ROS)-mediated activation of extracellular-signal-regulated kinase (ERK)1/2 and nuclear factor-kappa B (NF-κB) p65 signaling pathways. Scavenging of TCS-induced ROS by N-acetylcysteine (NAC) could mitigate signaling pathways activation. As expected, inhibitors specific for ERK1/2 (PD98059) and NF-κB p65 (IMD0354) signaling pathways efficiently attenuated TCS-induced inflammatory response in BEAS-2B cells. Thus, ROS/ERK/NF-κB axis contributes to the TCS-induced inflammatory response. Further, animal studies are required for a better understanding of TCS-mediated inflammatory response in various organs, including the lungs.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4211-4222"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644964","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":"Phthalate Esters in Different Beverages From Lagos and Ogun States, Nigeria: Concentrations and Health Risk Assessment.","authors":"Adewale M Taiwo, Joshua O Marcus, Olufunmilayo O Olayinka, Caroline A Akinremi, Bayonle I Ojo, Tunde M Hassan, Temitope M Osobamiro, Patrick Ssebugere","doi":"10.1002/jat.70182","DOIUrl":"10.1002/jat.70182","url":null,"abstract":"<p><p>Phthalate esters (PAEs) are widely used additives in polymeric materials to enhance the flexibility and durability of plastics such as polyethylene terephthalate (PET). Under elevated temperatures, these compounds may migrate from packaging materials into beverages, posing potential health risks including endocrine disruption and increased susceptibility to chronic diseases such as cancer. Despite the widespread consumption of bottled and packaged beverages in Nigeria, information on phthalate contamination remains limited. This study therefore presents the first comprehensive assessment of six PAEs (dimethyl phthalate [DMP], diethyl phthalate [DEP], dibutyl phthalate [DBP], butyl benzyl phthalate [BBP], bis(2-ethylhexyl) phthalate [DEHP], and di-n-octyl phthalate [DNOP]) in beverages marketed in Lagos and Ogun States, Nigeria. PAEs were analyzed using gas chromatography-mass spectrometry, enabling sensitive detection of trace contaminants. Concentrations ranged 0.016-0.020 mg L^-1 for DMP, < 0.001-0.001 mg L^-1 for DEP, < 0.001-0.010 mg L^-1 for DBP, 0.104-0.153 mg L^-1 for BBP, <0.001 mg L^-1 for DEHP, and 0.555-1.501 mg L^-1 for DNOP. DNOP and BBP were the most prevalent compounds, with DNOP ranging from 0.555 ± 0.442 mg L^-1 in orange drinks to 1.501 ± 2.490 mg L^-1 in bottled water, while BBP ranged from 0.104 ± 0.010 mg L^-1 in energy drinks to 0.153 ± 0.136 mg L^-1 in cola drinks. Health risk assessment indicated negligible non-carcinogenic risk for most phthalates (hazard quotient < 1). However, DNOP exceeded safety thresholds across all age groups, suggesting potential cumulative exposure, particularly for infants. BBP accounted for most estimated lifetime cancer risk, highlighting the need for improved packaging practices and regulatory monitoring in tropical environments where elevated temperatures may enhance plasticizer migration.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4132-4143"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581148","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":"Bisphenol A Induces Endothelial Dysfunction via Oxidative Stress-Driven Ferroptosis and Nrf2 Suppression.","authors":"S Yukta, R Jayasuriya, K L Milan, S Sahabudeen, Gaku Ichihara, K M Ramkumar","doi":"10.1002/jat.70145","DOIUrl":"10.1002/jat.70145","url":null,"abstract":"<p><p>Bisphenol A (BPA), a widespread environmental contaminant, induces endothelial dysfunction through multiple mechanisms; however, its role in triggering ferroptosis remains largely unexplored. In this study, we investigated the effect of BPA on ferroptosis induction in endothelial cells and its association with Nrf2 signaling and endothelial dysfunction. Human endothelial cells were exposed to BPA (10, 50, and 100 μM) for 24 h, and the expression of ferroptosis markers (GPX4, SLC7A11, ACSL4, TFR1, FPN, FTH), Nrf2 and its downstream antioxidant enzymes (SOD2, HO-1, NQO1, CAT), oxidative stress markers (P22PHOX, TXNIP), inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-18), and endothelial dysfunction markers (ENDO-1, ICAM-1, VCAM-1, vWF) were assessed by qRT-PCR and western blotting. BPA exposure downregulated GPX4, SLC7A11, FPN, and FTH while upregulating ACSL4 and TFR1, indicating ferroptotic activation. Ferroptosis induction was further confirmed by FerroOrange staining, demonstrating increased labile intracellular iron accumulation in BPA-treated endothelial cells. Concurrently, Nrf2 expression and nuclear translocation were suppressed, accompanied by Keap1 upregulation, reduced levels of antioxidant enzymes, and elevated oxidative stress and proinflammatory cytokine levels. Markers of endothelial dysfunction increased significantly at higher BPA concentrations (50-100 μM). Collectively, these findings identify ferroptosis as a critical mediator of BPA-induced endothelial dysfunction through disruption of Nrf2 signaling, highlighting potential therapeutic targets for BPA-associated cardiovascular pathologies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"3949-3960"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473890","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":"Evaluation of DNA/Chromosome Integrity and Cell Death in Human Metabolically Noncompetent and Competent Cells Exposed to N'-(3,5-Difluorobenzylidene)Pyridine-4-Carbohydrazide.","authors":"Larissa Ribeiro Canuto Santos, Jéssica Natalia Barbosa de Almeida, Camila Cavalleiro Frias, Wanda Pereira Almeida, Edson Luis Maistro","doi":"10.1002/jat.70171","DOIUrl":"10.1002/jat.70171","url":null,"abstract":"<p><p>The N-acylhydrazone scaffold is recognized as a privileged structure for the design of bioactive substances with increasing applications in medicinal chemistry research. Ensuring the safety of newly developed molecules is a critical step for both human health and environmental protection. Accordingly, this study aimed to evaluate the cytotoxic and genotoxic properties of N'-(3,5-difluorobenzylidene)pyridine-4-carbohydrazide in two cellular models: nonmetabolizing leukocytes and metabolically active hepatic cells (HepG2/C3A). The resazurin-based cytotoxicity analysis, performed with concentrations between 1 and 600 μg/mL, indicated that only the uppermost concentration caused a marked decrease in viability of both cell populations after 48 h of incubation. Regarding genotoxicity at 50, 100, and 200 μg/mL concentrations, no DNA damage was detected in the comet assay, but in the micronucleus test, a significant increase in chromosome alterations in leukocytes at 200 μg/mL concentration was detected, with a decrease in cell proliferation in both cell types. The data indicate that, at the concentrations where the biological effects of acylhydrazone were previously observed, the substance appeared to be safe, but at higher concentrations and/or during chronic exposure, caution and further studies are needed.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":"4076-4084"},"PeriodicalIF":3.1,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}