{"title":"An Evaluation of Oral Subchronic Toxicity of Maizinol (UP165), a Zea mays Leaf Extract.","authors":"J Kyle Weston, Barry S Lynch, James A Akingbasote","doi":"10.1002/jat.4882","DOIUrl":"https://doi.org/10.1002/jat.4882","url":null,"abstract":"<p><p>Maize (Zea mays) has been consumed by humans for millennia and represents the third most abundant crop grown globally. Maize and maize-derived products have a long history of safe consumption from bread and other cereal products in human diets worldwide. Aside from key dietary components like carbohydrates and proteins, the corn plant contains endogenous biomolecules like benzoxazinoids. Benzoxazinoids are a group of secondary metabolites produced in monocotyledons and some species of dicotyledons from the Acanthaceae, Ranunculaceae, Scrophulariaceae, Plantaginaceae, and Lamiaceae families, and benzoxazinoids play a vital role in plant physiology. The current research aims to evaluate the safety of Maizinol (UP165), an ethanolic corn leaf extract containing 0.2%-0.3% of the benzoxazinoid, benzoxazolinone 6-methoxy-2-benzoxazolinone (6-MBOA) in Sprague Dawley rats. Animals were orally dosed with 0-, 750-, 1500-, or 3000-mg Maizinol/kg body weight/day for 90 days and observed for mortality and morbidity. Results revealed that Maizinol was well tolerated at all tested doses, as no significant effects were observed in hematological, biochemical, and histological endpoints at all doses. A subchronic 90-day toxicity no-observed-adverse-effect level for UP165 in Sprague Dawley rats was determined to be 3000 mg/kg body weight/day.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130968","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":"Effects of Hydroxychloroquine Used in Fracture Healing on Oxidative Stress and DNA Damage in Rat Tissues.","authors":"Elçin Bakır, Aysun Ökçesiz Hacıseyitoğlu, Salih Varol, Fazile Cantürk Tan, Kaan Gürbüz, Duran Topak, Ayşe Eken","doi":"10.1002/jat.4938","DOIUrl":"https://doi.org/10.1002/jat.4938","url":null,"abstract":"<p><p>Hydroxychloroquine is an aminoquinoline derivative drug widely used in the treatment of autoimmune diseases, rheumatoid arthritis, and malaria. In 2020, it was approved by the FDA for the treatment of COVID-19, despite a lack of clear evidence of efficacy/safety based solely on in vitro data. In our previous study, we demonstrated that orally administered hydroxychloroquine in rats impaired bone fracture healing, attributing this to increased oxidative stress in the blood. In this study, based on our previous results, we aimed to investigate the effects of the drug on oxidative stress and DNA damage that may develop over time in liver, kidney, and brain tissues in the same model. In the study, antioxidant enzyme activities and lipid peroxidation were measured as parameters of oxidative stress, and the Comet assay was used to determine potential DNA damage in rat tissues. While a dose-independent increase was observed in MDA levels in the liver and brain, the level of MDA in the kidney increased dose-dependently. DNA damage results were also consistent with MDA levels. Although oxidative damage due to bone fracture formation in the control groups showed a time-dependent change, it was not statistically significant. Our findings clearly demonstrate that hydroxychloroquine causes oxidative stress and DNA damage in the liver, kidney, and brain tissues of rats with bone fracture.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124719","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}
Abdullah Tasci, Ecem Deniz Kirkpantur Tasci, Cansu Arslan Turan, Tuba Cimilli Ozturk
{"title":"Acute Pioglitazone Intoxication in Rats: Lack of Protective Effect of Intravenous Lipid Emulsion-A Pilot Study.","authors":"Abdullah Tasci, Ecem Deniz Kirkpantur Tasci, Cansu Arslan Turan, Tuba Cimilli Ozturk","doi":"10.1002/jat.4939","DOIUrl":"https://doi.org/10.1002/jat.4939","url":null,"abstract":"<p><p>Intravenous lipid emulsion (ILE) is an established antidote for local anesthetic systemic toxicity and has been tested in various lipophilic drug intoxications, but its efficacy in pioglitazone toxicity remains unclear. This study evaluated the biochemical and histopathological effects of pioglitazone and the potential protective role of ILE in an animal model. Thirty-two male Sprague-Dawley rats were randomly assigned to four groups (n = 8): control, ILE (12.4 mL/kg, 20% IV), pioglitazone (PIO; ½ LD<sub>50</sub>, 1000 mg/kg), and PIO + ILE. ILE (or saline) was administered intravenously over ~2 min immediately after pioglitazone, with matched volume and duration. Animals were observed for 24 h with free access to food and water. At 24 h, rats were decapitated, and blood and tissue samples were analyzed. Pioglitazone induced significant hepatic and renal injury (both p < 0.001), while cardiac changes were minimal and nonsignificant. ILE administration did not reduce liver or kidney injury. The ILE-only group showed higher renal injury versus controls (p < 0.001). Serum biochemistry revealed increased BUN and creatinine in PIO + ILE compared with Control and ILE (adjusted p < 0.05), with no difference between PIO and PIO + ILE. ILE failed to reverse hepatic or renal injury in acute pioglitazone toxicity and was associated with potential nephrotoxic effects. These findings suggest limited utility of ILE for pioglitazone overdose, likely reflecting drug physicochemical properties (moderate lipophilicity and high protein binding) and timing/dosing constraints. Caution is warranted, particularly regarding renal effects.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124683","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}
Chibuisi Gideon Alimba, Samuel Oluwasegun Adesida, Wasiu Mathew Owonikoko, Ayodeji Ojo Oteyola
{"title":"Micro (Nano)plastics Vitiation of Genetic Material: Systematic Review of Genotoxic Biomarkers and Model Bioindicators.","authors":"Chibuisi Gideon Alimba, Samuel Oluwasegun Adesida, Wasiu Mathew Owonikoko, Ayodeji Ojo Oteyola","doi":"10.1002/jat.4928","DOIUrl":"https://doi.org/10.1002/jat.4928","url":null,"abstract":"<p><p>Micro (nano)-plastics (MPs/NPs) are ubiquitously detected in human samples: stool, placenta, breastmilk, testes and semen, liver, lung, and blood, with their detailed toxicological profile still emerging. Numerous scientific studies are increasingly being conducted towards understanding possible deleterious effects of MPs/NPs on human, animal, plant, and environmental health. MPs/NPs rarely biodegrade, have small particle sizes, and are positively charged-features that make them dangerous to cells. They are capable of inducing oxidative stress, genotoxicity, immunological response, alteration in cellular membrane and cytoarchiture. The ability for MPs/NPs to induce DNA damage and genotoxicity may enhance genome instability, the hallmark of cancer and genetic disease syndrome. This review focused on determining the sensitivity of various biomarkers utilized to assess the DNA damage and genotoxicity potentials of MPs/NPs, the bioindicators used as models (invertebrates, vertebrates, cell lines/primary cells and plants), and the mechanisms of MPs/NPs-induced genotoxicity and DNA damage. The nature/type and size of the MP/NP polymers, concentration, and duration of exposure are determining factors considered in the DNA damage and genotoxicity assessment of MPs/NPs. Also, somatic and germ-line cells are susceptible to the genotoxic effects of MPs/NPs. Single and double DNA strand breaks assessed using the comet assay are the most used biomarker of DNA damage, while chromosome aberration is the least used. Others are sperm morphology assay, micronucleus assay, and toxicogenomics. The mechanisms of MPs/NPs-induced DNA damage include generation of free radicals and oxidative stress, induction of deleterious inflammatory cells, down-regulation of transcriptional genes related to apoptotic expressions, and increased DNA fragmentation in cells and tissues. Further studies are required to unequivocally confirm MPs/NPs as genotoxins, mutagens, and/or carcinogens.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091777","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":"Integrated Biomarker, Histopathological and Genotoxicity-Based Toxicological Evaluation of Polystyrene and Polyethylene Microplastics in Oreochromis mossambicus.","authors":"Ankit Anand Sinha, Krupa Jamdar, Aakanksha Prabhu, Avelyno D'Costa","doi":"10.1002/jat.4935","DOIUrl":"https://doi.org/10.1002/jat.4935","url":null,"abstract":"<p><p>Microplastic (MPs) pollution has emerged as a critical environmental stressor with growing implications for freshwater ecosystems. This study investigates the sub-lethal toxicological effects of polystyrene (PS-MPs) and polyethylene microplastics (PE-MPs) on Oreochromis mossambicus under controlled laboratory conditions. Acute toxicity tests established the 96-h LC<sub>50</sub> values, identifying PE-MPs as significantly more toxic than PS-MPs. Sub-lethal concentrations-15.33, 30.66, and 76.34 mg/L for PE-MPs and 50, 250, and 500 mg/L for PS-MPs-were selected based on the LC<sub>50</sub> values and applied in a 14-day semi-static exposure set-up. Tissue-specific MPs accumulation analysis revealed a dose-dependent retention of MPs in gill, gastrointestinal, and liver tissues. Biochemical assays indicated significant disruptions in oxidative stress markers and metabolic enzymes. Significant increases in catalase (CAT), superoxide dismutase (SOD), and thiobarbituric acid reactive substances (TBARS) levels were observed, along with alterations in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and essential macromolecules (proteins, carbohydrates), indicating oxidative and metabolic stress. Genotoxicity, assessed by the micronucleus assay, demonstrated a concentration-dependent increase in micronucleated erythrocytes, indicative of chromosomal damage. Histopathological evaluations of gill and intestinal tissues revealed MPs-induced structural alterations, supporting the observed altered biochemical and genotoxic responses. These findings offer mechanistic insights into the sub-lethal toxicity of MPs, highlighting their potential to induce oxidative imbalance, genotoxicity, and histoarchitectural damage in tilapia. The study underscores the urgent need for comprehensive risk assessments and mitigation strategies to address microplastic contamination in inland aquatic systems.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091710","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}
Hamid Ahmadpourmir, Seyedeh Faezeh Taghizadeh, Konstantinos Tsarouhas, Fatemeh Rakhshani, Vida Ebrahimi, Aristidis Tsatsakis, Christina Tsitsimpikou, Mahmoud Hashemzaei, Ramin Rezaee
{"title":"Early-Life Dietary Exposure to Perfluorooctanoic Acid (PFOA) Through Milk Consumption: A Systematic Review.","authors":"Hamid Ahmadpourmir, Seyedeh Faezeh Taghizadeh, Konstantinos Tsarouhas, Fatemeh Rakhshani, Vida Ebrahimi, Aristidis Tsatsakis, Christina Tsitsimpikou, Mahmoud Hashemzaei, Ramin Rezaee","doi":"10.1002/jat.4932","DOIUrl":"https://doi.org/10.1002/jat.4932","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA) has raised public concern due to its widespread presence/use and toxic health effects including hepatotoxicity, neurotoxicity, and developmental toxicity. Because dietary intake is a major route of PFOA exposure, and milk is a primary source of nutrition in early life, the present systematic review discusses PFOA occurrence in milk samples and the employed determination methods. In the present article, 69 studies (published 2007-2024) reporting PFOA levels in infant formula, commercial milk, and human breast milk were included. The highest concentration of PFOA in infant formula and commercial milk was reported from Spain (2490 ng/kg) and the highest level of PFOA in breast milk from Belgium (3.5 ng/mL). The most commonly used approaches for extraction and analysis of PFOA were solid-phase extraction and LC-MS/MS, respectively. The evidence indicates the need for constant monitoring of PFOA levels in milk samples to safeguard vulnerable populations, especially neonates, infants, and children.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080772","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}
Caroline V L Moreira, John Ogbu, Kadja L C Monteiro, Thiago M de Aquino, Edeildo F da Silva-Júnior, Alberto S S Filho, Hamilton B Napolitano, Christianah A Elusiyan, Renê O do Couto, Elson A Costa, James O Fajemiroye
{"title":"Bifenthrin Under Scrutiny: Revisiting Toxicological Evidence Amid Regulatory Gaps.","authors":"Caroline V L Moreira, John Ogbu, Kadja L C Monteiro, Thiago M de Aquino, Edeildo F da Silva-Júnior, Alberto S S Filho, Hamilton B Napolitano, Christianah A Elusiyan, Renê O do Couto, Elson A Costa, James O Fajemiroye","doi":"10.1002/jat.4929","DOIUrl":"https://doi.org/10.1002/jat.4929","url":null,"abstract":"<p><p>Despite growing health concerns, bifenthrin (BF) remains widely used for controlling agricultural and residential pests. However, different perspectives on its toxicological profile and regulatory framework warrant a revisit and update on BF regulation towards a robust risk-safety assessment. Out of 4102 search outputs, only 62 studies on BF disposition and biological effects met screening and eligibility criteria. Our findings demonstrate oral, dermal, and inhalation toxicity of BF. Studies suggest potential effects, including immunotoxic, endocrine, and reproductive effects, but lack multi-level substantiation and modeling approaches amidst risk biases. Emerging evidence of anxiogenic, depression-like, and Parkinsonian-like effects, which implicate monoaminergic, metabolic, and enzymatic pathways, supports the involvement of several molecular culprits beyond voltage-gated channel disruption. Toxicity concerns raised by the Food and Agriculture Organization-World Health Organization (FAO/WHO), the United States Environmental Protection Agency (USEPA), and the European Food Safety Authority (EFSA) inform the establishment of reference doses of 0.01, 0.03, and 0.031 mg/kg per day, respectively. While the USEPA considers the current toxicological and safety benchmarks adequate for approved uses, it identified potential acute risks of concern to pollinators and terrestrial invertebrates, leading to precautionary labeling measures. In contrast, the EFSA has questioned the reliability of toxicological data and recommended lowering maximum residue levels. Regulatory disparities are traceable to variations in the study designs and risk assessments. While emerging data on behavioral and neurochemical changes may warrant a regulatory reevaluation of BF's toxicological data, integrating predictive models and other new approach methodologies, using high-quality designs, may address current regulatory gaps and inconsistencies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080803","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}
Xiao-Han Yang, Sheng-Long Cao, Jia-Xuan Xu, Gang Zhang, Yi-Jun Zhang, Qu-Nan Wang
{"title":"Di(2-Ethylhexyl) Phthalate Exposure Alters Hepatic Lipid Metabolism in Male SAMP8 Aged Mice.","authors":"Xiao-Han Yang, Sheng-Long Cao, Jia-Xuan Xu, Gang Zhang, Yi-Jun Zhang, Qu-Nan Wang","doi":"10.1002/jat.4927","DOIUrl":"https://doi.org/10.1002/jat.4927","url":null,"abstract":"<p><p>As a widespread environmental pollutant, di(2-ethylhexyl) phthalate (DEHP) mainly leaches from plastic products into food and is ultimately absorbed by living organisms. DEHP and its metabolites pose potential threats to human and animal health, particularly through metabolic disorders. While existing studies have explored DEHP's impact on lipid metabolism, investigations in aged mice remain scarce. This study aimed to investigate the effects of DEHP exposure on hepatic lipid metabolism and gut microbiota in mice. Male senescence-accelerated (SAMP8) were orally exposed to DEHP (0, 0.2, and 200 mg/kg/day) for 5 weeks. Results showed that DEHP exposure significantly interfered with hepatic lipid profiles, leading to elevated liver triglyceride (TG) levels. Furthermore, DEHP exposure influenced the alpha and beta diversity of the gut microbiota. An increase in the Firmicutes/Bacteroidota ratio suggests that DEHP exposure causes changes in the composition of the gut microbiota. The association between hepatic lipidomics and gut microbiota showed a positive correlation between specific genera like Alloprevotella and various hepatic lipids. Finally, we further clarified the molecular mechanism of increased hepatic TG, identifying elevated fatty acid synthase FASN as a key factor. In summary, these results suggest that DEHP exposure disrupts lipid metabolism in the liver, possibly mediated by gut microbiota dysbiosis.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075043","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":"Assessing Acute and Subacute Toxicity and Phytochemical Screening of the Methanolic Extract of Foeniculum vulgare in Wistar Rats.","authors":"Bougrine Soukaina, Abouyaala Oumaima, Elgui Radia, El Brouzi Mohamed Yassine, El-Khiraoui Fatima Ezzahra, Elmotia Khadija, Mesfioui Abdelhalem, Ouahidi Moulay Laarbi","doi":"10.1002/jat.4907","DOIUrl":"https://doi.org/10.1002/jat.4907","url":null,"abstract":"<p><p>Foeniculum vulgare, commonly known as fennel, has a long history of use in traditional medicine, particularly for treating problems related to the digestive, endocrine, reproductive, and respiratory systems. The major constituents found in fennel seed extracts are trans-anethole (68.6%-75.0%), fenchone (8.40%-14.7%), and methyl chavicol (5.09%-9.10%). However, before introducing this plant into the human environment, it is essential to understand its toxicological properties. In this study, we investigated the acute and sub-acute toxicity of methanolic extracts of F. vulgare. A phytochemical screening was performed to identify the major chemical constituents of the plant. For the acute toxicity study, female Wistar rats received a single dose of the methanolic extract of F. vulgare at doses of 1000, 2000, 3000, and 5000 mg/kg for 14 days. In the sub-acute toxicity study, the methanolic extract of F. vulgare was administered orally daily at doses of 125, 250, and 500 mg/kg for 28 days. Hematological, biochemical, and histological changes were evaluated. Phytochemical tests were also performed. The phytochemical analysis showed that the methanolic extract of F. vulgare is rich in flavonoids, catechic, gallic tannins, and total polyphenols. Toxicological tests showed no animal deaths, suggesting that the LD<sub>50</sub> was greater than 5000 mg/kg. In the sub-acute oral toxicity study, no significant differences were observed in body weight, food consumption, or water intake. Additionally, there were no significant changes in hematological and biochemical parameters or differences in the macroscopic and microscopic examination of organs. Therefore, this study concludes that the methanolic extract of F. vulgare, at the doses tested, is considered non-toxic under the conditions evaluated.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075015","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":"Cytogenotoxicity and Hematological Alterations Induced by the Environmentally Relevant Concentration of Low-Density Polyethylene Microplastics and Nickel Oxide Nanoparticles in Cirrhinus mrigala (Ham.).","authors":"Simran Sharma, Megha Andotra, Arvinder Kaur","doi":"10.1002/jat.4924","DOIUrl":"https://doi.org/10.1002/jat.4924","url":null,"abstract":"<p><p>The omnipresence of microplastics and metal nanoparticles in aquatic ecosystems has become an escalating threat to the health of fish and consumers. Keeping this in mind, this study envisaged the assessment of hematological alterations and cytogenotoxicity in Cirrhinus mrigala during an exposure and a recovery period (60 days each) due to environmentally relevant concentration (50 μg/L) of 150-250 μm (M1) and < 150 μm (M2) low-density polyethylene microplastics and predicted no-effect concentration (2.95 mg/L: 1/100 96 h LC<sub>50</sub>) of nickel oxide nanoparticles (N) and their combination (M1N and M2N). Cell viability, frequency of nucleo-cellular abnormalities, hemoglobin content, hematocrit, MCHC, and count of RBCs, WBCs, and platelets decreased (p < 0.001), but tail length, % tail DNA, tail moment, and olive tail moment increased (p < 0.001) over control throughout the experiment. The MPs and NPs showed synergism, and the order of toxicity was M2N > M1N > M2 > M1 > N. Necrotic cell frequency was higher than apoptotic cells. In comparison to M2 and N, M2N showed lower frequency of viable cells (49.1 and 56.11%, respectively), but a higher frequency of nucleo-cellular abnormalities (98 and 238.66%, respectively) and DNA damage (tail moment: 267 and 577.94%, respectively). Hb, RBC count, and Hct of M2N were 2.6, 2.2, and 1.3 times less than N. More increase in monocytes and neutrophils indicates an extreme inflammatory impact of co-existing MPs and NPs. Therefore, there is a dire need to regulate levels of MPs and NPs in aquatic ecosystems to maintain the health and well-being of organisms, especially fish.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053679","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}