Toxicology Letters[JOURNAL]
Sun
200 papers
Double-walled carbon nanotubes promote ASC speck formation and inflammasome activation in vascular endothelial cells.
Takizawa R, Ichihara G, Suzuki Y … +5 more , Izuoka K, Hayashi Y, Zong C, Ikegami A, Ichihara S
Toxicol Lett · 2026 May · PMID 41933809 · Publisher ↗
Carbon nanotubes (CNTs) are important industrial nanomaterials, yet their manufacture presents potential risks for respiratory exposure among workers. CNTs have a high aspect ratio, which raises concerns that they may ca...
Carbon nanotubes (CNTs) are important industrial nanomaterials, yet their manufacture presents potential risks for respiratory exposure among workers. CNTs have a high aspect ratio, which raises concerns that they may cause toxicity similar to that of asbestos. Asbestos is known to activate the NLR family pyrin domain containing 3: NLRP3, a key component of inflammasome. We hypothesized that CNTs promote atherosclerosis by enhancing inflammatory response triggered by inflammasome activation. Treatment of human umbilical vein endothelial cells (HUVECs) with two types of double-walled CNTs (DWCNT; NC2150 and NC2100) resulted in a significant increase in the levels of cytoplasmic agglutination of adapter apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) and the levels of phosphorylated ASC and interleukin (IL)-1β. In addition, DWCNT upregulated the expression of adhesion molecule ICAM-1. Consistent with these in vitro findings, apolipoprotein E-deficient (Apoe) mice exposed to high-dose DWCNT showed a significant increase in aortic plaque area, and upregulation of NLRP3 and IL-1β as well as that of adhesion molecule (ICAM-1) and chemokine (MCP-1) in the thoracic aorta. The results of our in vitro and in vivo studies suggested that exposure to high-dose DWCNT induced atherosclerogenesis by enhancing inflammasome-driven inflammatory responses with ASC speck formation.
Genotoxicity assessment of nylon and polyethylene microparticles in Caco‑2 cells.
Huovinen M, Järvelä E, Herrala M … +6 more , Järvenpää J, Özdemir H, Frenzel K, Hyyryläinen S, Lahtela-Kakkonen M, Rysä J
Toxicol Lett · 2026 May · PMID 41932662 · Publisher ↗
Microplastics (size 0.1µm - 5 mm) are ubiquitous in the environment, but their consequences on human health are still largely unknown. Nylon and polyethylene (PE) are widely used polymers in various applications, and alt...
Microplastics (size 0.1µm - 5 mm) are ubiquitous in the environment, but their consequences on human health are still largely unknown. Nylon and polyethylene (PE) are widely used polymers in various applications, and although human exposure to them has been detected, the potential health effects are understudied. The aim of our study was to determine whether nylon microparticles induce toxicity in human colorectal adenocarcinoma Caco-2 cells and analyze the genotoxic potential of nylon and PE microparticles in these cells. The cells were exposed to 0.01-0.5 mg/ml of nylon (polyamide6) for 48 h, after which cell viability and cytotoxicity were analyzed with MTT and lactate dehydrogenase (LDH) assays, respectively. Reactive oxygen species (ROS) production was measured with dichlorofluorescein diacetate assay, as well as cytoplasmic and mitochondrial production of superoxide were analyzed with dihydroethidium (DHE) and MitoSOX assays, respectively. In addition, genotoxicity of both nylon (0.005-0.1 mg/ml) and PE (0.25-1 mg/ml) were analyzed with alkaline comet assay and micronucleus assay. Nylon microparticles decreased the viability of Caco-2 cells dose-dependently, yet no cytotoxicity was observed with LDH assay. In addition, the nylon microparticles induced the production of ROS as well as mitochondrial and cytosolic superoxide dose-dependently in Caco-2 cells. However, genotoxicity was not observed with either of the polymers. In conclusion, our study shows that high concentrations of nylon microparticles decreased cell viability and increased oxidative stress response in intestinal cells, with mitochondria being one possible target of toxicity while genotoxic effects were absent. Furthermore, when compared to our previous studies, nylon microparticles were more toxic to Caco-2 cells than PE particles. This study brings important information about the toxicity of microplastic particles in human Caco-2 cells providing valuable data for risk assessment.
Deoxynivalenol-induced hepatic and renal injury via pyroptosis under heat stress conditions.
Zhang J, Rafique A, Liu J … +5 more , Saqlain M, Yang B, Zhang D, Niu R, Sun Z
Toxicol Lett · 2026 May · PMID 41932661 · Publisher ↗
Elevated temperatures impose physiological stress on mammals. Meanwhile, high heat and humidity boost mold growth in feed and bedding, potentially increasing deoxynivalenol (DON) contamination. Heat stress and DON both c...
Elevated temperatures impose physiological stress on mammals. Meanwhile, high heat and humidity boost mold growth in feed and bedding, potentially increasing deoxynivalenol (DON) contamination. Heat stress and DON both cause hepatorenal damage, yet their combined effects remain unclear. This study established two sequential mouse models to explore the synergistic impacts of heat stress and DON on hepatorenal injury and pyroptosis. In the heat stress gradient model, mice were subjected to 30°C, 36°C, or 42°C for 2 h per day over a 14-day period. Histopathological analysis demonstrated temperature-dependent hepatorenal damage: hepatic injury markers in liver tissue increased at 36°C and 42°C, whereas renal dysfunction indicators were elevated at 42°C. Tissue reactive oxygen species (ROS) levels rose in a temperature-dependent manner, with male mice exhibiting greater hepatic ROS accumulation than females, and significant renal ROS elevation was observed across all three heat stress temperatures (30°C, 36°C, and 42°C) in kidney tissues. Based on these observations, a combined exposure model was established with male mice divided into four groups: control, heat stress (42°C, 2 h/day), DON (2 mg/kg bw/day), and combined treatment. Heat stress upregulated HSP70 concentration in both liver and kidney, while DON disrupted hepatic and renal glutathione (GSH) homeostasis, each causing hepatorenal structural alterations. The combined group displayed the most severe histopathological and ultrastructural damage in both organs. Notably, hepatic mRNA levels of NLRP3, Caspase-1, and Gasdermin D (GSDMD) were significantly elevated in all treatment groups, whereas renal Caspase-1 and GSDMD mRNA were increased in the heat stress group, and all three genes were elevated in the DON and combined groups. At the protein level, hepatic NLRP3, Caspase-1, GSDMD-N, and ASC were most markedly elevated in the combined group, with synergistic upregulation of Caspase-1 and NLRP3 exceeding both single-stressor groups; a comparable pattern of synergistic NLRP3 protein elevation was also observed in the kidney. These molecular alterations were accompanied by elevated inflammatory cytokines (IL-1β, IL-18, TNF-α) in both hepatic and renal tissues and by aggravated structural damage in both organs in the combined treatment group. Collectively, these findings illustrate that heat stress and DON synergistically aggravate hepatic and renal injury, with pyroptosis pathway activation confirmed in both organs.
Chronic exposure to F-53B disrupts sperm quality and steroidogenic regulation in male rats.
Wang X, Wang A, Xu H … +7 more , Shan S, Li X, Zhang Y, Wang J, Jiang K, Tian H, Zhao Y
Toxicol Lett · 2026 May · PMID 41911982 · Publisher ↗
Chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESAs, trade name F-53B), an emerging substitute for perfluorooctane sulfonates (PFOS) used as mist suppressor in electroplating in China, has raised increasing attent...
Chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESAs, trade name F-53B), an emerging substitute for perfluorooctane sulfonates (PFOS) used as mist suppressor in electroplating in China, has raised increasing attention due to its environmental persistence, bioaccumulation, and potential health risks. F-53B exposure has been associated with multi-system toxicities, including hepatotoxicity, immunotoxicity, and developmental toxicity, etc. However, its chronic effects on mammalian reproductive system remain poorly understood. In this study, male Sprague-Dawley (SD) rats were exposed to F-53B via drinking water (0, 1, 10, 100, 1000 μg/L, corresponding to estimated doses of 0, 0.00008, 0.0008, 0.008 and 0.08 mg/kg/day) for 180 days to evaluate its reproductive toxicity. F-53B exposure led to reduced sperm counts, elevated sperm abnormality rates, along with histopathological damage in testicular and epididymal tissues. Hormonal disruptions were evident, including decreased testosterone and follicle-stimulating hormone (FSH) levels as well as increased gonadotropin-releasing hormone (GnRH), indicating hypothalamic-pituitary-testicular (HPT) axis disruption. Additionally, F-53B chronic exposure impaired testicular endocrine function in male SD rats, as reflected by dysregulated hormone receptor expression, reduced enzymatic activity, and inhibited testosterone biosynthesis.These findings demonstrate that chronic exposure to F-53B markedly disrupts sperm quality and steroidogenic regulation in male rats. Given the increasing environmental prevalence of F-53B and bioaccumulative nature of F-53B, the current study highlights a significant concern for its reproductive health risks in mammals and implies an urgent need for comprehensive toxicological evaluation of its widespread use.
The interaction between DNA methylation and single-nucleotide polymorphism in regulating the mRNA expression of CYP1A1, GSTP1 and GSTM1 in population.
Liu A, Shi Y, Li X … +5 more , Wu M, Zhao T, Wu Y, Xia N, Zhang H
Toxicol Lett · 2026 May · PMID 41903599 · Publisher ↗
While polycyclic aromatic hydrocarbon (PAH) exposure is widely known to influence the expression of metabolic enzyme genes, the roles of DNA methylation and single-nucleotide polymorphisms (SNPs) remain unclear. This stu...
While polycyclic aromatic hydrocarbon (PAH) exposure is widely known to influence the expression of metabolic enzyme genes, the roles of DNA methylation and single-nucleotide polymorphisms (SNPs) remain unclear. This study aimed to investigate the interplay between DNA methylation and SNPs on the mRNA expression of CYP1A1, GSTP1, and GSTM1. Participants were divided into the low- (n = 63) and high-exposure (n = 118) groups based on environmental monitoring data. Urinary 1-hydroxypyrene (1-OH-Pyr) concentration was measured using high-performance liquid chromatography (HPLC), mRNA expression, DNA methylation, and genotype of CYP1A1, GSTP1, and GSTM1 were assessed using real-time PCR, methylation-specific PCR (MSP), and Kompetitive Allele-Specific/Multiplex PCR (KASP), respectively. The individual and combined associations between 1-OH-Pyr levels, DNA methylation, SNPs, and mRNA expression were analyzed using multiple linear regression, analysis of covariance (ANCOVA), and generalized linear models (GLM). Compared to the low-exposure group, the high-exposure group exhibited significantly elevated 1-OH-Pyr levels, decreased mRNA expression of CYP1A1, GSTP1, and GSTM1, hypermethylation of CYP1A1 and GSTM1, and hypomethylation of GSTP1. The CYP1A1 rs1048943 wild type, the mutant type of GSTP1 rs1695 and GSTM1 (+/-)were negatively correlated with their respective mRNA expression. Furthermore, CYP1A1 hypermethylation and the rs1048943 mutant type showed a significant interaction effect on gene expression, jointly resulting in a marked decrease in mRNA levels. These results indicate that PAH exposure is associated with suppressed mRNA expression of CYP1A1, GSTP1, and GSTM1, which are influenced by DNA methylation and SNPs. Notably, the interaction between CYP1A1 hypermethylation and the rs1048943 mutant type is significantly negatively associated with CYP1A1 mRNA expression.
Monitoring air pollution effects on children (MAPEC) living near cement factories: The MAPEC_Gubbio Study.
Franceschini E, Rondini T, Acito M … +3 more , Fatigoni C, Villarini M, Moretti M
Toxicol Lett · 2026 May · PMID 41887377 · Publisher ↗
The present study examined the association between airborne pollutants and early biological effects in children, a group particularly vulnerable to immediate and long-term effects, underscoring the importance of early de...
The present study examined the association between airborne pollutants and early biological effects in children, a group particularly vulnerable to immediate and long-term effects, underscoring the importance of early detection. Researchers have performed the buccal micronucleucytome (BMCyt) assay focusing particularly on the assessment of two biomarkers of early genotoxic damage - micronuclei (MN) and nuclear buds - in exfoliated buccal mucosa cells of kids of 6-8 years from Gubbio (exposed area with two cement factories) and Città di Castello (control area). Overall, 164 children were enrolled, of whom 161 underwent cytome analysis. Air quality data were obtained from the publicly available database of the Regional Agency for Environmental Protection (ARPA Umbria). Information on indoor exposure, sociodemographic characteristics, diet, and health, were collected via questionnaires. Sampling was conducted in late spring and winter, seasons with differing pollutant concentrations. Analysis explored correlations between MN frequency and pollution levels. Results showed a significantly (p < 0.001) doubled MN frequency in exposed children during late spring, with a median of 2.0 (IQR 1.0-2.5), compared with 1.0 (IQR 0.5-1.5) of the control group, likely due to unmonitored summer-specific pollutants, despite measured pollutants being below legal limits. The findings indicate a residual genotoxic risk for children in exposed areas, underscoring the need to enhance air pollutant monitoring to better address potential genetic damage.
Is maternal smoking during pregnancy associated with childhood brain tumors? A systematic literature review.
Autio U, Sahlman H, Tiihonen M … +2 more , Laitinen H, Huovinen M
Toxicol Lett · 2026 May · PMID 41864483 · Publisher ↗
With a global prevalence of 1.7%, smoking during pregnancy commonly still occurs in many countries. Tobacco smoke contains several harmful and carcinogenic compounds which can cross the placental barrier and cause advers...
With a global prevalence of 1.7%, smoking during pregnancy commonly still occurs in many countries. Tobacco smoke contains several harmful and carcinogenic compounds which can cross the placental barrier and cause adverse effects on maternal and fetal health. Developing brains are particularly sensitive to the harmful effects of chemical exposures. The aim of this systematic literature review was to investigate the association between maternal smoking during pregnancy and childhood brain tumors in children aged 0-15 years. A systematic search was conducted using PubMed, Web of Science, CINAHL, and Scopus databases. Of the initial 192 articles, 18 were included in the final analysis, which comprised of three cohort studies and 15 case-control studies. Studies were evaluated for study quality using The National Health, Lung and Blood Institute Study Quality Assessment Tools website and the quality of the studies was mostly good. This systematic literature review found no consistent evidence of an association between maternal tobacco smoking during pregnancy and childhood brain tumors. Of the 18 studies, four reported an association between maternal smoking during pregnancy and childhood brain tumors (CBT), ependymoma, or astrocytoma. If there was an association between CBT and maternal tobacco smoking, it was seen more commonly in young children, ranging from 0 to 4 years. Further studies are needed to establish a more comprehensive understanding.
Surface-water estradiol-benzo[a]pyrene mixtures: Transcriptomics in a PC12 neuronal differentiation model nominate an E2F1-PTPRO axis as a candidate mechanistic biomarker.
Sun C, Wang P, Xia Y … +8 more , An M, Liu S, Wu C, Zhang W, Li W, Zhou Y, Hao J, Xu L
Toxicol Lett · 2026 May · PMID 41833663 · Publisher ↗
BACKGROUND: Mixtures of estradiol (E2) and benzo[a]pyrene (BaP) occur in surface waters. Seasonal sampling at Longxing Village (Jilin, China) showed total PAHs 1.07-3.14 mg L⁻¹ (BaP 3.0 ×10⁻²-1.3 ×10⁻¹ mg L⁻¹) and estrog...
BACKGROUND: Mixtures of estradiol (E2) and benzo[a]pyrene (BaP) occur in surface waters. Seasonal sampling at Longxing Village (Jilin, China) showed total PAHs 1.07-3.14 mg L⁻¹ (BaP 3.0 ×10⁻²-1.3 ×10⁻¹ mg L⁻¹) and estrogenic compounds 42.4-81.8 ng L⁻¹ .We investigated mechanistic indicators and testable hypotheses capturing their joint neurotoxic effects. METHODS: A PC12 neuronal-differentiation model was exposed to BaP, E2 and NGF. Phenotypic assays (proliferation/viability, ROS, neurite outgrowth) were integrated with time-series transcriptomics (GO/KEGG), qPCR, and molecular docking of E2/BaP to protein tyrosine phosphatase receptor type O (PTPRO). SIGNIFICANT FINDINGS: BaP accelerated proliferation and increased ROS, accompanied by transcriptomic enrichment of chemokine/GPCR-PI3K-Akt survival and anti-apoptotic signaling. Under BaP background, NGF-containing conditions were associated with a shift toward TrkA-MAPK-linked programs and up-regulation of neuronal differentiation/axonogenesis genes, consistent with the observed neurite outgrowth. Docking suggested plausible binding poses of E2 and BaP within a ligandable pocket on PTPRO and associated residue-level interaction features. Consistently, NGF up-regulated PTPRO, BaP attenuated this induction, and E2 + NGF partially restored expression, consistent with an E2F1-PTPRO-linked module. Overall, NGF partially offset BaP-associated toxicity, and PTPRO was nominated as a mechanistic candidate node associated with exposure to axonal growth. Together, these results provide mechanistic plausibility and prioritize E2F1/PTPRO- and ROS-linked pathways as mixture-associated indicators for follow-up validation in water-quality-relevant contexts.
An in vitro model of bleomycin-induced epithelial injury using stem cell-derived alveolar type 2 epithelial cells.
Han Y, Kim HR, Kim JW … +4 more , Shin TH, Kim HS, Chung KH, Park YJ
Toxicol Lett · 2026 May · PMID 41806949 · Publisher ↗
Human alveoli constitute most of the lung parenchyma and play a pivotal role in respiratory diseases. Traditional alveolar type 2 epithelial cells, such as A549 and H441, have been widely used to study pulmonary toxicity...
Human alveoli constitute most of the lung parenchyma and play a pivotal role in respiratory diseases. Traditional alveolar type 2 epithelial cells, such as A549 and H441, have been widely used to study pulmonary toxicity mechanisms. However, these cells have inherent limitations, including insufficient barrier function, lack of functional surfactant protein expression, and failure to recapitulate the physiological features of human alveolar epithelial cells. Here, we established differentiated AEC2s (diff-AEC2s) from human embryonic stem cells and validated their stage-specific differentiation. We confirmed key AEC2-like features in vitro, including lamellar body-like organelles, higher TEER values, and increased AEC2 marker expression relative to A549 and H-6053 cells under ALI culture. The diff-AEC2s were treated with bleomycin to evaluate their potential for modeling disease-related epithelial injury. Transcriptomic analysis with benchmark dose showed epithelial stress related to DNA damage and cell cycle arrest quantitatively. Bleomycin also induced the dose-dependent alterations of alveolar epithelial and damage-related markers, including LGALS3, KRT8, CTGF, and senescent phenotypes. This study presents a human stem cell-derived alveolar epithelial platform to quantify early epithelial stress and injury-associated responses in vitro.
Tripchlorolide-induced reversible impairment of male fertility and the involvement of PI3K/Akt/mTOR signaling.
Zhou L, Chen L, Zheng C … +5 more , Wu J, Zhong M, Huang Z, Xin Z, Chen Z
Toxicol Lett · 2026 May · PMID 41780610 · Publisher ↗
Tripchlorolide, a low-toxicity derivative of the natural product triptolide, exhibits significant therapeutic potential for inflammatory and autoimmune diseases; however, its profile of male reproductive toxicity remains...
Tripchlorolide, a low-toxicity derivative of the natural product triptolide, exhibits significant therapeutic potential for inflammatory and autoimmune diseases; however, its profile of male reproductive toxicity remains a major concern for clinical translation. To address this, we first established its median lethal dose at 33.13 mg/kg in mice to guide safe exposure levels. We then systematically evaluated its reproductive toxicity in male rats following 8-week intraperitoneal administration (2.5, 5, and 10 μg/kg/day). Our results demonstrated a clear dose-dependent toxicity, characterized by significant reductions in testicular and epididymal coefficients, impaired sperm count and motility, disrupted testosterone, follicle-stimulating hormone, and luteinizing hormone levels, and evident histopathological damage in the testes and epididymides. Encouragingly, these adverse effects showed signs of reversal after a 4-week recovery period, suggesting that the impairment is reversible. Through an integrated approach combining network pharmacology prediction and molecular docking, we identified the inhibition of the PI3K/Akt/mTOR signaling pathway as the pivotal molecular event. This mechanism was conclusively validated by our in vivo rescue experiment, where co-administration of the Akt activator SC79 markedly attenuated the tripchlorolide-induced reproductive impairments. Our study provides a comprehensive toxicological profile, defining the dose-response, reversibility, and mechanistic basis of tripchlorolide's male reproductive toxicity, thereby offering critical insights for its risk assessment and potential repurposing.
Advances in aluminum oxide nanoparticles-induced neurotoxicity: CNS translocation, phenotypic outcomes, and mechanistic insights.
Yu L, Rana MN, Quan C … +4 more , Zhou Z, Chen Z, Gao X, Gao X
Toxicol Lett · 2026 May · PMID 41765294 · Publisher ↗
Aluminum oxide nanoparticles (AlO NPs) exhibit remarkable physicochemical properties, making them essential for many applications such as high-temperature refractory materials, catalysis, biomedical uses, and environment...
Aluminum oxide nanoparticles (AlO NPs) exhibit remarkable physicochemical properties, making them essential for many applications such as high-temperature refractory materials, catalysis, biomedical uses, and environmental remediation. The extensive use of AlO NPs increases the risk of human exposure through various routes. Owing to their small size, AlO NPs can cross biological barriers and accumulate within the central nervous system (CNS), where they could impair cognitive function and promote neuropathological changes. This review provides a critical, mechanism-oriented synthesis of current evidence on AlO NPs-induced neurotoxicity. We first summarize the principal CNS entry routes, emphasizing size-dependent translocation and the influence of crystalline phase. We then evaluate experimental data on neurobehavioral, neurodevelopmental, and electrophysiological outcomes. Particular attention is given to oxidative stress, mitochondrial dysfunction, neuroinflammation, abnormal protein expression, autophagy, and programmed cell death as key mechanistic pathways. Collectively, data support AlO NPs as plausible neurotoxic hazards, particularly under conditions favoring CNS exposure (small particle size and prolonged or developmental exposure windows). However, interpretation is constrained by incomplete nanoparticle characterization, limited use of realistic exposure scenarios, and insufficient distinction between nanoparticle-specific and dissolved Al³ ⁺-mediated effects. On this basis, we propose three priority research directions: phase- and size-dependent neurotoxicity, speciation-informed toxicokinetics, and cell-type-resolved mechanisms linking microglial and astrocytic responses to neuronal injury and neurodegenerative risk. Addressing these gaps will advance mechanistically grounded risk assessment of AlO NPs-related CNS dysfunction.
Artificial intelligence revolution in toxicology: Clinical precision, global equity, and the 2030 roadmap.
Domingo JL
Toxicol Lett · 2026 Apr · PMID 41762830 · Publisher ↗
Artificial intelligence (AI) is transforming toxicology by enabling faster, more accurate, and more equitable approaches to diagnosis, treatment, research, and education. This review synthesizes recent advances in AI app...
Artificial intelligence (AI) is transforming toxicology by enabling faster, more accurate, and more equitable approaches to diagnosis, treatment, research, and education. This review synthesizes recent advances in AI applications across clinical toxicology, predictive modeling, pharmacovigilance, and training, highlighting innovations such as deep learning for diagnostic stratification, reinforcement learning for personalized antidote dosing, and generative AI for virtual patient simulations. While these technologies demonstrate substantial promise, their clinical and regulatory adoption remains constrained by algorithmic bias, limited model interpretability, validation challenges specific to feature importance accuracy, and persistent global digital inequities. Critical limitations include the distinction between target prediction accuracy and feature importance accuracy in supervised models, where high predictive performance does not guarantee mechanistic reliability. Moreover, the potential for AI-generated misinformation and the need for continuous human oversight in clinical contexts warrant careful consideration. To guide responsible integration, the "ToxAI Pact" is proposed, a 2030 roadmap emphasizing harmonized validation standards, robust feature importance validation protocols, watermarking of generative outputs, and infrastructure investment for low-resource settings. By embedding fairness, explainability, and robust governance, AI can evolve from experimental tools into foundational infrastructure for safer, more inclusive toxicology worldwide.
Thallium: An overview of its distribution in the environment and its cellular and molecular toxicity.
Moura AV, Pedroza LAL, da Silva JDS … +3 more , Martins AC, Aschner M, Gubert P
Toxicol Lett · 2026 Apr · PMID 41759642 · Publisher ↗
Thallium (Tl), a rare but highly toxic trace metal, poses significant environmental and health risks due to its increasing industrial applications and potential for contamination. This narrative review focuses on Tl's pr...
Thallium (Tl), a rare but highly toxic trace metal, poses significant environmental and health risks due to its increasing industrial applications and potential for contamination. This narrative review focuses on Tl's presence in soil and its subsequent uptake by food crops, emphasizing the critical entry pathway into the food chain and the associated human health implications. Tl contamination in soil primarily arises from mining activities, industrial processes, and atmospheric deposition. The metal's high solubility in water facilitates its mobility and bioavailability, leading to accumulation in agricultural soils. Plants, particularly leafy vegetables, can readily absorb Tl from contaminated soil through their roots, translocating it to edible parts. The transfer of Tl from soil to food crops raises concerns about human exposure through dietary intake. Consuming Tl-contaminated vegetables, especially those grown in polluted areas, can lead to chronic toxicity. Moreover, we discuss the diagnosis of Tl intoxication, treatment and for risk assessment. Future studies focused on elucidating the mechanisms of Tl toxicity and its environmental contamination will contribute to novel information for adequate risk assessment and the implementation of effective safety policies.
Hepatobiliary clearance of a long and thick carbon nanotube following pulmonary exposure in mice.
Sundberg M, Berthing T, Danielsen PH … +2 more , Tveden-Nyborg P, Vogel U
Toxicol Lett · 2026 Apr · PMID 41759641 · Publisher ↗
Long and thick carbon nanotubes (CNTs), such as Mitsui-7, can translocate from the lungs to secondary organs, including the liver, following pulmonary exposure. Although Mitsui-7 CNT is biopersistent, previous studies ha...
Long and thick carbon nanotubes (CNTs), such as Mitsui-7, can translocate from the lungs to secondary organs, including the liver, following pulmonary exposure. Although Mitsui-7 CNT is biopersistent, previous studies have suggested clearance from the liver. The mechanisms underlying this process remain poorly understood. Fiber-shaped nanomaterials interact differently with hepatic cell types, including hepatocytes, compared with spherical nanoparticles. Based on these observations, this study aimed to investigate whether long and thick CNTs can be eliminated from the liver via the hepatobiliary system. In this study, female C57BL/6 J mice (n = 6 per group) were exposed by a single intratracheal instillation to 54 μg Mitsui-7 or vehicle (2% mouse serum). Twenty-eight days after exposure, the animals were euthanized, and tissue samples (lung, kidney, spleen, urinary bladder, liver, gallbladder, bile, and hepatic lymph nodes) were collected. Samples were formalin-fixed, paraffin-embedded, and sectioned. Sections were stained with hematoxylin and eosin, and the presence of CNTs within tissue sections was assessed using enhanced darkfield microscopy. CNTs were detected in the liver, gallbladder, and bile, indicating that long, thick CNTs were excreted from liver via the biliary route, suggesting hepatobiliary clearance. CNTs were also observed in hepatic lymph nodes, suggesting possible hepatic clearance; however, the hepatic lymph nodes do not contribute to systemic elimination. No CNTs were detected in the urinary bladder, indicating that long and thick CNTs were not cleared by glomerular filtration. These results indicate that the hepatobiliary system serves as a route for systemic elimination of long and thick CNTs.
Exposure to welding fumes and health effects: A systematic evaluation based on human biomonitoring analyses.
Khoshakhlagh AH, Ghobakhloo S, Vogel UB … +1 more , Gruszecka-Kosowska A
Toxicol Lett · 2026 Apr · PMID 41759640 · Publisher ↗
BACKGROUND: Occupational exposure to heavy metals (HMs) through inhalation of welding emissions presents a serious health hazard to welders. This systematic review aimed to evaluate the concentrations of HMs in biologica...
BACKGROUND: Occupational exposure to heavy metals (HMs) through inhalation of welding emissions presents a serious health hazard to welders. This systematic review aimed to evaluate the concentrations of HMs in biological matrices (blood, urine, serum, and plasma) of welders, and to examine the associations between exposure to welding emissions, oxidative stress markers, and respiratory health outcomes. METHODS: A comprehensive literature search was conducted using Web of Science, Scopus, PubMed, Medline, and Embase up to September 16, 2025, based on the PECO (Population, Exposure, Comparator, and Outcomes) framework. A total of 76 studies met the inclusion criteria. RESULTS: The majority of studies reported significantly higher HM levels in welders compared to control groups. A strong association was observed between metal concentrations in welding emissions and corresponding levels in biological matrices, although the strength of this relationship was occasionally diminished due to confounding variables. More than half of the included studies demonstrated elevated oxidative stress markers such as MDA and 8-OHdG in welders. However, fewer than half of the studies reported significant differences in pulmonary function parameters, with forced vital capacity (FVC) being the most frequently affected. CONCLUSION: These findings underscore the importance of implementing protective strategies, including routine human biomonitoring and engineering controls, to mitigate HM exposure, reduce oxidative stress, and prevent related health outcomes among welders.
Excessive fluoride induces renal cell apoptosis and subsequent renal dysfunction.
Zhang Y, Xu Z, Xie P … +4 more , Xiao Y, Dong S, Chen C, Chen Q
Toxicol Lett · 2026 Apr · PMID 41747946 · Publisher ↗
This study investigated the mechanisms of renal injury and dysfunction induced by chronic excessive fluoride exposure. Sixty female Sprague-Dawley rats were administered sodium fluoride (NaF) at 0, 50, 100, or 150 mg/L i...
This study investigated the mechanisms of renal injury and dysfunction induced by chronic excessive fluoride exposure. Sixty female Sprague-Dawley rats were administered sodium fluoride (NaF) at 0, 50, 100, or 150 mg/L in drinking water for 2, 4, or 6 months. NaF exposure was confirmed by elevated urinary fluoride levels. Renal function was assessed by the increase in serum creatinine, and structural damage was evaluated by histopathology. The expression of key apoptosis-related markers (Bax, Bcl-2, Caspase-3) was analyzed using qRT-PCR, immunohistochemistry, and Western blotting. Fluoride exposure caused a dose- and time-dependent increase in serum creatinine, indicating impaired glomerular filtration. Histopathological analysis confirmed significant tubular degeneration. Notably, functional impairment occurred despite no pathological change in kidney yet, suggesting that functional deficits preceded overt morphological alterations. Mechanistically, fluoride exposure induced a clear pro-apoptotic molecular shift with increased Bax and decreased Bcl-2 expression, culminating in the activation of Caspase-3. The histopathological findings were consistent with a mixed pattern of cell death. However, the integrated molecular evidence demonstrated that the activation of the intrinsic (mitochondrial) apoptotic pathway was a key mechanism contributing to the excessive fluoride-induced nephrotoxicity. In summary, a central molecular pathway involved in fluoride-induced renal injury was demonstrated, providing a foundation for assessing excessive fluoride toxicological impact.
Histone H3K4 monomethyltransferase SETD7 promoted osteogenic differentiation of bone marrow mesenchymal stem cells exposed to Hydroquinone via autophagy.
Shen Y, Niu Y, Xu T … +9 more , Luo Z, Song D, Luo C, Liu Y, Cui Q, Chen D, Zhao X, Luo H, Gao Y
Toxicol Lett · 2026 Apr · PMID 41740875 · Publisher ↗
Hydroquinone (HQ), a major metabolite of benzene, is a recognized risk factor for acute myeloid leukemia (AML). However, the mechanisms underlying HQ-associated leukaemogenesis remain incompletely understood. Increasing...
Hydroquinone (HQ), a major metabolite of benzene, is a recognized risk factor for acute myeloid leukemia (AML). However, the mechanisms underlying HQ-associated leukaemogenesis remain incompletely understood. Increasing evidence suggests that defective osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), contributes to HQ-induced hematopoietic dysfunction and leukemic progression. SET domain-containing 7 (SETD7) has been found to regulate the proliferation and differentiation of BMSCs, while autophagy is known to play a crucial role in promoting osteogenic differentiation. Therefore, this study aimed to investigate the regulatory roles of SETD7 and autophagy in the osteogenic differentiation of HQ-exposed BMSCs. The results demonstrated that HQ exposure was associated with decreased histone 3 lysine 4 monomethylation (H3K4me1) and SETD7 protein levels, autophagy, and osteogenic differentiation capacity in BMSCs. Activation of autophagy by rapamycin (Rapa) effectively rescued the BMSCs osteogenic differentiation reduced by HQ. Moreover, overexpression of SETD7 restored both autophagic activity and osteogenic differentiation capacity suppressed by HQ. Notably, co-treatment with the autophagy inhibitor 3-methyladenine (3-MA) abrogated the pro-osteogenic effects induced by SETD7 overexpression in HQ-exposed BMSCs. Collectively, these findings indicated that SETD7 promoted osteogenic differentiation in HQ-exposed BMSCs via autophagy-dependent mechanism. This study provides mechanistic insight into how HQ may disrupt the bone marrow microenvironment, highlights the role of SETD7 in maintaining osteogenic differentiation and autophagy in HQ-exposed BMSCs, and contributes to a better understanding of the epigenetic and cellular pathways involved in HQ-induced hematotoxicity.
Identification of xenobiotics interfering with 5α-reductase (SRD5A2) activity.
Kędzierski J, van Diest RE, Allard JA … +3 more , Erharter AM, Odermatt A, Smieško M
Toxicol Lett · 2026 Apr · PMID 41722875 · Publisher ↗
5α-Dihydroxytestosterone (DHT) is essential for male sexual development, and its synthesis from testosterone is mediated by the steroid 5α-reductase (SRD5A) isoenzymes, SRD5A1 and SRD5A2. SRD5A2 is the predominant isofor...
5α-Dihydroxytestosterone (DHT) is essential for male sexual development, and its synthesis from testosterone is mediated by the steroid 5α-reductase (SRD5A) isoenzymes, SRD5A1 and SRD5A2. SRD5A2 is the predominant isoform expressed in reproductive organs. Disruption of SRD5A2 activity can significantly lower the available DHT concentration in human reproductive organs and cause complications during development. Hence, unintentional inhibition of this enzyme should be avoided. This study aimed to establish an in silico/in vitro approach to identify potential inhibitors of SRD5A2 through virtual screening. Therefore, we generated an ensemble of minimized SRD5A2 receptor conformational states using molecular dynamics simulations, and applied consensus docking with a validation set to select the most representative structure. Next, compounds from various databases were docked to the selected protein structure and their binding poses were evaluated through an automated protocol. The selected potential inhibitors were then tested in an enzyme activity assay, revealing that the androgen receptor modulator MK-0773 is a moderate SRD5A2 inhibitor with an IC value of 1.70 ±0.54μM. Quantum-mechanical calculations suggested, however, that MK-0773 does not act as a covalent inhibitor, as observed for the structurally similar known inhibitor finasteride. These findings improve our understanding of the SRD5A2-ligand interactions. Lastly, our in silico/in vitro approach can be used to identify new SRD5A2 inhibitors.
Dissolution of man-made vitreous fibres (MMVF) using the USP-4: Part I. Fluid choice for closed-loop configuration tests.
Okhrimenko DV, Hiéronimus L, Hoffman JW … +12 more , Kessler H, Dan Edson, Jacquemin M, Hérault Q, Drnovšek N, Kovačič U, Aixart J, Mascaraque N, Rickabaugh K, Wiggins B, Madl AK, Solvang M
Toxicol Lett · 2026 Apr · PMID 41722874 · Publisher ↗
In this research, we extended our examination of the US pharmacopeia apparatus 4 (USP-4) application for the development of an in vitro acellular dissolution protocol for man-made vitreous fibres (MMVF). The aim of this...
In this research, we extended our examination of the US pharmacopeia apparatus 4 (USP-4) application for the development of an in vitro acellular dissolution protocol for man-made vitreous fibres (MMVF). The aim of this study was to achieve robust differentiation in solubility of glass and stone wool fibres using a USP-4 closed-loop configuration. For this, synthetic lung fluids representing extra-cellular conditions of the lungs (pH 7.4) and the environment in the phagolysosome (pH 4.5) were evaluated and tested in closed-loop dissolution experiments with multiple fibres across several labs. Our results showed that it was possible to differentiate between high- and low-solubility fibres using all candidate fluids. However, we found that it was crucial to limit the pH variability and to adapt the levels of organics in the fluid, as they impacted the dissolution of the fibres. Our findings indicated good inter-lab variability of an in vitro acellular biosolubility testing with the USP-4. For further development of the USP-4 closed loop configuration protocol, we propose focusing on phosphate-based buffers for pH 7.4 and acetate buffers or PSF + 10 mg/L citrate for pH 4.5.
Recovery from chronic PFAS exposure can reverse chemotherapy resistance and mitochondrial alterations in ovarian cancer cells.
Rickard BP, Sapienza-Lundie LA, Chappell VA … +2 more , Fenton SE, Rizvi I
Toxicol Lett · 2026 Mar · PMID 41722873 · Full text
Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of global concern that have been associated with a variety of adverse health outcomes, including diminished chemotherapy response. Previous studie...
Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of global concern that have been associated with a variety of adverse health outcomes, including diminished chemotherapy response. Previous studies in moderately chemosensitive ovarian cancer cells (OVCAR-3) have shown that the induction of chemoresistance from PFAS exposure is duration-dependent, with longer, more human-relevant exposure durations leading to worse outcomes. Mitochondrial content was also altered following chronic PFAS exposure, suggesting mitochondria as contributors to PFAS-induced chemoresistance. Here, chemotherapy response following chronic PFAS exposure in a chemoresistant human ovarian cancer cell line, OVCAR-8, was evaluated. Compared to OVCAR-3 cells, chemotherapy response was unaffected by chronic PFAS exposure in OVCAR-8 cells. As individuals gain awareness of sources of PFAS exposure, and associated harmful effects, actions can be taken to limit exposure using water filtration systems and/or safer alternatives to PFAS-containing consumer goods. Thus, we also explored the ability of PFAS-sensitive OVCAR-3 cells to recover from chronic exposure. Following 6 passages of chronic PFAS exposure, cells were "outgrown" in the absence of PFAS for 7 additional passages and proliferation, chemotherapy response, and mitochondria-related alterations were assessed. Compared to chronically-exposed cells, outgrown cells displayed heightened sensitivity to chemotherapy along with decreased superoxide production and mitochondrial content. Proliferation remained significantly elevated compared to controls, suggesting that not all PFAS-induced effects are abrogated by a recovery period. Together, these findings suggest that ovarian cancer cells differ in their PFAS sensitivities and that mitochondria-related alterations resulting from chronic PFAS exposure can be reversed following a "recovery period", potentially resensitizing cancer cells to chemotherapy.
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