Toxicology Reports最新文献

{"title":"Comparative analysis of teratogen-induced malformations and gene expression across zebrafish strains in early development","authors":"Chitose Taya ,&nbsp;Kota Ujibe ,&nbsp;Shinnosuke Shimodaira ,&nbsp;Aoto Sakamoto ,&nbsp;Seiji Wada ,&nbsp;Makoto Kashima ,&nbsp;Hiromi Hirata","doi":"10.1016/j.toxrep.2025.102117","DOIUrl":"10.1016/j.toxrep.2025.102117","url":null,"abstract":"<div><div>Zebrafish embryos are widely used in developmental toxicity testing. However, the extent to which genetic background influences susceptibility to teratogenic compounds remains incompletely understood. We here evaluated inter-strain variability in both phenotypic and transcriptomic responses to six model teratogens using five commonly utilized zebrafish strains, AB, TU, RW, WIK, and PET. All test compounds, valproic acid, hydroxyurea, methotrexate, acitretin, topiramate, and ibuprofen, elicited concentration-dependent developmental toxicity characterized by malformations at moderate doses and lethality at higher concentrations. Despite distinct toxicodynamic profiles, the incidence and severity of phenotypic outcomes were highly consistent across strains. Transcriptomic analysis was performed following exposure to valproic acid, hydroxyurea, and warfarin, revealing strong, dose-dependent gene expression changes that were largely conserved among strains. Principal component analysis demonstrated that chemical concentration, rather than strain, was the dominant driver of transcriptional variation. Minor strain-specific differences were observed at baseline or low-dose levels but did not alter the overall direction or magnitude of response. These findings demonstrate that zebrafish embryos from diverse genetic backgrounds exhibit broadly conserved developmental and molecular responses to teratogens. The minimal inter-strain variability supports the use of any wild-type strain, transgenic line, or even outbred population in developmental toxicity testing without compromising sensitivity or reproducibility. Our study reinforces the suitability of zebrafish as a robust vertebrate model in regulatory toxicology.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102117"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastics and child health: A scoping review of prenatal and early-life exposure routes and potential health risks","authors":"Sakuntala Nadarasan ,&nbsp;Zhi Xin Phuna ,&nbsp;Rahela Zaman ,&nbsp;Chung Keat Tan ,&nbsp;Normina Ahmad Bustami ,&nbsp;Yu Bin Ho ,&nbsp;Stephanie Julia Kosasih ,&nbsp;Eugenie Sin Sing Tan","doi":"10.1016/j.toxrep.2025.102143","DOIUrl":"10.1016/j.toxrep.2025.102143","url":null,"abstract":"<div><div>Microplastics (MPs) is defined as plastic particles less than 5 mm. MPs have become a major environmental pollutant and it is originating from the breakdown of larger plastic waste. This article aims to explore MPs exposure to human health, particularly its potential effects during early developmental years. Studies reveal that MPs exposure begins via intra-uterine route, where MPs were detected in the placenta, amniotic fluid, umbilical cord, fetal membranes, and umbilical vein blood. As infants developed, the MPs exposure continued via breast milk, milk storage bags, formula, feeding bottles, and even from pacifiers. During early childhood, exposure routes can be from 3 different routes, including dermal contact (clothing, childcare products), ingestion (bottled milk, school dust, playground sand, sugar, salt), and inhalation (toy blocks, play mats, indoor air). The review also highlights the potential health risks to vital organs and systems from prenatal as well as postnatal MPs exposure in <em>in vivo</em> studies. These includes the optical, neurological, cardiovascular, pulmonary, hepatic, urinary, digestive, skeletal, lymphatic and reproductive systems. Given their small size and potential toxicity, MPs may disrupt these important developmental processes, leading to long-term health consequences. This article explores the route of MPs exposure with the potential severity and health impacts of those exposure, especially for fetuses, infants, and children. By doing so, it aims to identify any missing knowledge in this area. This research will serve as a foundation for designing future studies that identify health risks in generations exposed to MPs from a very young age.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102143"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute cutaneous adverse effects of methotrexate: A case report highlighting therapeutic challenges","authors":"Saarthak Miglani,&nbsp;Tanshi Daljit,&nbsp;Anurita Srivastava,&nbsp;Arun Kumar Rathi","doi":"10.1016/j.toxrep.2025.102108","DOIUrl":"10.1016/j.toxrep.2025.102108","url":null,"abstract":"<div><div>Methotrexate (MTX) is a commonly used antimetabolite for managing various autoimmune disorders and cancers. While it is generally well-tolerated at low doses, certain factors may predispose patients to significant toxicity. Here we present a case of 49-year-old male with advanced buccal mucosa squamous cell carcinoma who developed acute severe cutaneous toxicity following low dose of intravenous MTX therapy. After receiving two weekly doses, the patient experienced grade 4 oral mucositis and multiple erythematous plaques. This case highlights the importance of early recognition and prompt management of MTX toxicity, even at low doses, particularly in patients with risk factors such as prior antibiotic use and low serum albumin levels.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102108"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival following intentional overdose of veterinary insulin: A case report","authors":"Elsa Sandeno ,&nbsp;Sergey Karachenets ,&nbsp;Kourtney Zehlke ,&nbsp;Raza Khan ,&nbsp;Michael Kalinoski ,&nbsp;Pravin Meshram ,&nbsp;James V. Harmon Jr.","doi":"10.1016/j.toxrep.2025.102114","DOIUrl":"10.1016/j.toxrep.2025.102114","url":null,"abstract":"<div><div>A 40-year-old man presented to the emergency department within 6 h of a massive overdose of 500 units of long-acting feline glargine insulin intravenously and an estimated 50 mg of clozapine. Upon initial assessment, his Glasgow Coma Scale (GCS) was 15 and his blood sugar level was 45 mg/dL. The patient was successfully managed with dextrose infusions and close monitoring of blood sugar and electrolytes. To date, no cases have been documented in the literature describing an overdose of insulin formulation intended for veterinary use. Cases of overdose with animal-prescribed human insulin analogs can be managed similarly to previously reported cases of human insulin overdose.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102114"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotoxicity evaluation of kaurenoic acid","authors":"Lonneke C. Wilms ,&nbsp;Jennifer L.G. van de Ligt ,&nbsp;Christine M. Crincoli ,&nbsp;Alex K. Eapen","doi":"10.1016/j.toxrep.2025.102144","DOIUrl":"10.1016/j.toxrep.2025.102144","url":null,"abstract":"<div><div>Genotoxicity evaluations are essential components of the safety assessment for compounds intended for ingestion. Kaurenoic acid, a naturally occurring diterpene, is found in various plant species that are under investigation for potential therapeutic and sweetening properties. <em>Salmonella typhimurium</em> strains TA1535, TA1537, TA98 and TA100 and <em>Escherichia coli</em> strain WP2uvrA were treated with kaurenoic acid using the Ames plate incorporation and pre-incubation methods. Up to eight dose levels were tested, with and without metabolic activation using 10 % rat liver S9 mix with standard co-factors. Kaurenoic acid did not induce an increase in revertant colony frequency at any dose level under either condition indicating a lack of mutagenic activity. Additionally, genotoxic potential was evaluated in human peripheral blood lymphocytes via the in vitro micronucleus assay. Duplicate cultures were treated with kaurenoic acid at four dose levels with exposure conditions including a 4-hour exposure with or without 2 % S9 and a 24-hour exposure without S9. While kaurenoic acid exhibited marked toxicity, it did not produce any statistically significant increase in micronucleated binucleate cells. The assay included a dose that induced approximately 55 ± 5 % cytostasis, consistent with current OECD guidelines. Under the conditions of these studies, kaurenoic acid demonstrated no evidence of mutagenicity, clastogenicity, or aneugenicity. When considered with existing literature, the current findings support the conclusion that kaurenoic acid does not pose a genotoxic risk.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102144"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145361061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of GABAergic receptors in acute, subacute, and withdrawal syndrome on pain and seizure thresholds in mice: A connection to mitochondrial function and oxidative stress in the brain","authors":"Roghayeh Jahani ,&nbsp;Paria Pourbahram ,&nbsp;Mohammad Seyedabadi ,&nbsp;Fatemeh Nasiri ,&nbsp;Hamidreza Mohammadi","doi":"10.1016/j.toxrep.2025.102158","DOIUrl":"10.1016/j.toxrep.2025.102158","url":null,"abstract":"<div><div>One of the most serious neurological disorders is epilepsy. This study aimed to investigate the effects of baclofen, a GABA receptor agonist, on pain and seizure thresholds, as well as on oxidative damage in brain mitochondrial membranes of mice. Sixty male mice were divided into 10 groups. Control, baclofen (1, 5, and 10 mg/kg) with short-term exposure (1 day), long-term exposure (7 days), and withdrawal syndrome (eight days). The withdrawal syndrome was evaluated one day after the last dose of the drug. Hotplate and tail-flick tests were performed to assess pain threshold, and the rotarod was used to assess motor coordination. The seizure threshold and oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), protein carbonyl (PC), glutathione (GSH), and the MTT assay, were investigated. The results showed that baclofen (10 mg/kg) in short-term and all doses (1, 5, and 10 mg/kg) in long-term increased the seizure threshold. Evaluation of motor function and coordination in mice revealed decreased motor activity. The effect of baclofen on oxidative damage showed that, in long-term exposure, it improved mitochondrial ROS, malondialdehyde, and GSH levels. Protein carbonyl and MTT tests did not show a significant difference. A GABAB receptor agonist causes a dose- and time-dependent increase in the seizure threshold. Baclofen could reduce oxidative damage by decreasing ROS levels and malondialdehyde formation, and increasing GSH content.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102158"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of the main signaling pathways involved in the combined therapy of hepatocellular carcinoma using Sorafenib and NK cells in xenograft mice model","authors":"Faezeh Hosseinzadeh ,&nbsp;Tahereh Komeili movahhed ,&nbsp;Masoumeh Dolati ,&nbsp;Amir Hossein Kheirkhah ,&nbsp;Nima Beheshtizadeh ,&nbsp;Javad Verdi","doi":"10.1016/j.toxrep.2025.102131","DOIUrl":"10.1016/j.toxrep.2025.102131","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Sorafenib is the only FDA approved drug for HCC patients, affecting patient survival by just a few months with significant toxicities in approximately half of HCC patients and the poor prognosis of these patients. Thus, the combination therapy with Sorafenib and Natural killer (NK) cells has been suggested, due to NK cells' distinct effectiveness against HCC. This research examined the main signaling pathways in HCC progression affected by Sorafenib or NK cells in combination or individual treatment. The xenograft model of HCC was created by implanting human HepG2 cells subcutaneously into the flank of 12 nude mice and then divided into four groups: Control, Sorafenib, NK cells, and Sorafenib plus NK cells. Four weeks post tumor implantation, the mice were euthanized, and the levels of liver and kidney enzymes were analysed for safety purposes. Quantitative real-time PCR analysis was used to measure the expression of key effector genes related to Sorafenib and NK cell functions with focused on the signaling pathways involved in the development of HCC. The levels of Aspartate aminotransferase (AST), Alanine transaminase (ALT), Blood urea nitrogen (BUN), and creatinine (Cr) in all groups remained in normal ranges. The expression levels of certain proliferative, anti-apoptotic factors were reduced in groups treated with either Sorafenib or NK cells only, but in combinational treated group showed no significant differences compared to control group. Also, the NK cell effector function related genes were upregulated in NK cell treated group, but inhibited in co administration of both NK cell and Sorafenib. Therefore, combining Sorafenib and NK cells at the prescribed dosage led to a decrease in the anti-cancer efficiency of both and may not be a successful option for HCC treatment.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102131"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pervasive food contaminant ochratoxin‐A induces energy crisis: Mitochondrial dysfunction in human primary proximal tubule cells","authors":"Anish Mahadeo ,&nbsp;Theo K. Bammler ,&nbsp;James MacDonald ,&nbsp;Angela R. Zheng ,&nbsp;Catherine K. Yeung ,&nbsp;Jonathan Himmelfarb ,&nbsp;Edward J. Kelly","doi":"10.1016/j.toxrep.2025.102169","DOIUrl":"10.1016/j.toxrep.2025.102169","url":null,"abstract":"<div><div>Ochratoxin-A (OTA) is a ubiquitous mycotoxin contaminant in food products and a known nephrotoxin that is not currently regulated in the United States. OTA is hypothesized to be a potential environmental agent causing chronic kidney disease of unknown etiology (CKDu), however the mechanism of OTA toxicity in the human kidney remains elusive. This study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that exposure to OTA (10 μM) induces over 7000 differentially expressed genes, including key regulators of mitochondrial fission and fusion. This was confirmed at the cellular level by confocal microscopy, where a breakdown of the mitochondrial network was observed at 100 nM OTA. Crucially, low exposure (10 nM – 1 μM) was found to significantly inhibit basal mitochondrial oxidative phosphorylation as well as glycolysis through measurements of oxygen consumption rate and extracellular acidification, indicating reduced cellular energetics and mitochondrial toxicity. We demonstrate that OTA induces mitochondrial dysfunction and reduced ATP production in PTECs characteristic of renal disease progression. These findings provide insight into early proximal tubule damage induced by OTA which has been linked to pathophysiological changes involved in chronic kidney disease.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102169"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Massive caffeine overdose with extremely high blood caffeine concentration and prolonged toxidrome","authors":"Yuka Okazaki ,&nbsp;Suguru Hitomi ,&nbsp;Shigemasa Taguchi ,&nbsp;Ryoko Kyan ,&nbsp;Tomohiro Yoshizawa ,&nbsp;Yoshito Kamijo ,&nbsp;Tomoki Hanazawa ,&nbsp;Kazuya Kiyota","doi":"10.1016/j.toxrep.2025.102177","DOIUrl":"10.1016/j.toxrep.2025.102177","url":null,"abstract":"<div><div>The easy availability of caffeine has led to an increased risk of ingesting toxic levels in recent years. Although several studies reported severe and fatal cases of massive caffeine poisoning, few cases of caffeine overdose with a protracted toxidrome have been described. We present the case of a 37-year-old man with a massive caffeine overdose. He presented with altered consciousness and non-sustained ventricular tachycardia and was intubated and placed on continuous venovenous hemodiafiltration. The patient was extubated but had to be reintubated on day 4 because of altered consciousness, tachypnea, and tachycardia. His renal and hepatic dysfunction worsened, requiring three sessions of hemodialysis. The patient was eventually extubated on day 8, without worsening of symptoms. The present case illustrates high caffeine concentration as a cause of prolonged toxidrome with hepatic and renal damage.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102177"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Caenorhabditis elegans worm Development and Activity Test (wDAT) can be used to differentiate between reversible and irreversible developmental effects","authors":"Piper Reid Hunt,&nbsp;Nicholas Olejnik,&nbsp;Jeffrey Yourick,&nbsp;Robert L. Sprando","doi":"10.1016/j.toxrep.2025.102124","DOIUrl":"10.1016/j.toxrep.2025.102124","url":null,"abstract":"<div><div>Developmental delay and spontaneous locomotor activity changes, as well as the reversibility of these adverse effects are apical endpoints used in chemical safety evaluations. These endpoints were assessed at sublethal concentrations in <em>C. elegans</em> using 5-fluorouracil (5FU), hydroxyurea (HU), or ribavirin (RV), teratogens that are associated with reduced fetal growth in mammals. <em>C. elegans</em> develop from egg to egg-laying adult in about three days. Synchronized cohorts were exposed either continuously, or for 24 h (early-only) from first-feeding after hatching. Developmental delays were dose-responsive for all three chemicals in both exposure schemes. For 5FU and HU, developmental delays and hypoactivity levels were similar in continuous and early-only exposure groups, consistent with irreversible developmental effects. The observed hypoactivity in developing <em>C. elegans</em> may be related to reported 5FU-induced muscle impairment and HU-induced post-exposure effects on locomotion parameters in mammals. In contrast to 5FU- and HU-induced hypoactivity, RV was associated with a non-significant trend to slight hyperactivity in both exposure schemes. Continuous RV exposures induced delays to sequential developmental milestones that increased with exposure duration. RV-induced delays were significantly reduced but not eliminated in early-only exposure cohorts, consistent with cumulative RV effects on developmental progress. These findings suggest that <em>C. elegans</em> may be a useful model for detecting chemicals with irreversible, reversible, and/or cumulative effects on organismal development.</div></div>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"15 ","pages":"Article 102124"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}