Toxicology Letters[JOURNAL]
Sun
200 papers
Assessment of non-dietary human health risk based on concentration of multiresidue pesticides in soil of irrigated farmland around Lake Ziway, Ethiopia.
Demsie AF
Toxicol Lett · 2026 Mar · PMID 41679517 · Publisher ↗
Soil samples collected from irrigated farmlands around Lake Ziway were thoroughly analyzed for 35 different pesticides, yielding significant insights into contamination profiles and the non-dietary health risks associate...
Soil samples collected from irrigated farmlands around Lake Ziway were thoroughly analyzed for 35 different pesticides, yielding significant insights into contamination profiles and the non-dietary health risks associated with these substances in the region. The analysis utilized gas chromatography-mass spectrometry (GC-MS) techniques. To assess non-dietary health risks, the study employed metrics such as the hazard index (HI) and Incremental Lifetime Cancer Risk (ILCR), considering various exposure pathways, including ingestion, dermal contact, and inhalation for both children and adults. The results revealed a concerning level of pesticide contamination in the agricultural soils of the area. Propargite was identified as the most prevalent contaminant, with a concentration of 62.463 ± 21.963 µg/kg, followed by p,p'-DDE at 46.85 ± 10.052 µg/kg. Other pesticides were detected at significantly lower levels. Risk estimates based on HI values indicated a non-carcinogenic risk for children and adults at 1.08E-02 and 1.35E-03, respectively, suggesting that the non-carcinogenic risk remains within acceptable limits (HI <1). The ILCR for children across all exposure levels, as well as for adults in terms of ingestion was found to be range from 1.59E-08-3.38E-16, suggesting that there is no significant cancer risk to humans through these pathways. However, the ILCRs associated with dermal contact for adults indicate a potential cancer risk, with estimates ranging from 10 to 10. Furthermore, model estimates indicate that adults face a greater cancer risk of non-dietary pesticide exposure compared to children. These findings highlight the urgent need for enhanced monitoring programs that address both currently used and banned pesticides.
Corrigendum to "Busulfan plus cyclophosphamide induced spermatogenic dysfunction and recovery: A dynamic change perspective" [Toxicol. Lett. 417(2026) 111833].
Li T, Tang Z, Song Y … +8 more , Su M, Liu X, Li F, Wei X, Luo X, Zhou B, Wang Y, Zhang L
Toxicol Lett · 2026 Apr · PMID 41672838 · Publisher ↗
Abstract loading — click title to view on PubMed.
Toxicity and endocrine disrupting activity of monoanthraquinone dyes: Alizarin Blue Black B, Acid Blue 129 and Remazol Brilliant Blue R.
Rybczyńska-Tkaczyk K, Skóra B, Szychowski KA
Toxicol Lett · 2026 Mar · PMID 41672115 · Publisher ↗
The aim of this study was to determine the ecotoxicological and cytotoxic effects of monoanthraquinone dyes, i.e., Alizarin Blue Black B (ABBB), Acid Blue 129 (AB129), and Remazol Brilliant Blue R (RBBR), using Microbial...
The aim of this study was to determine the ecotoxicological and cytotoxic effects of monoanthraquinone dyes, i.e., Alizarin Blue Black B (ABBB), Acid Blue 129 (AB129), and Remazol Brilliant Blue R (RBBR), using Microbial Assay for Risk Assessment (MARA) and human hepatocellular carcinoma (HepG2) cells. Moreover, the study evaluated the (anti)estrogenic and (anti)androgenic properties of these dyes using Saccharomyces cerevisiae (YES/YAS assays) as a model organism. All dyes showed low (RBBR and ABBB) or slight toxicity (AB129), with average minimum toxic concentrations (MTC) of 151 and 184 mg/L, and 124 mg/L, respectively. Among the tested microorganisms, Brevundimonas diminuta was the most sensitive to all dyes. These dyes demonstrated estrogenic activity at concentrations ranging from 3 to 100 µM, acting as hERα receptor agonists. Both ABBB and RBBR were characterized by agonistic properties towards the hAR receptor at specific concentration (10-100 and 30-100 µM, respectively). ABBB increased mRNA expression of CYP1A1, CYP1A2 and CYP2B6 genes in HepG2 cells along with corresponding cytochrome activities (EROD, MROD and PROD assays). AB129 elevated CYP1A1 and CYP1A2 gene expression but increased only EROD activity. RBBR upregulated CYP1A2 and CYP2B6 gene expression, but did not affect the activity of any measured cytochrome assays.
Flocoumafen exposure induces skeletal developmental toxicity and neurotoxicity in zebrafish (Danio rerio).
Chen T, Fan F, Cheng A … +9 more , Xia Y, Chen H, Fang J, Chen Y, Li T, Wang A, Wang B, Yao W, Wu Y
Toxicol Lett · 2026 Mar · PMID 41643754 · Publisher ↗
Flocoumafen (FCF), a second-generation anticoagulant rodenticide (SGAR), has limited toxicological data regarding its effects on aquatic organisms. In this study, we exposed zebrafish embryos to FCF solutions at concentr...
Flocoumafen (FCF), a second-generation anticoagulant rodenticide (SGAR), has limited toxicological data regarding its effects on aquatic organisms. In this study, we exposed zebrafish embryos to FCF solutions at concentrations of 0.2, 0.4, and 0.8 mg/L until 120 h post-fertilization (hpf). The results revealed a decrease in survival rates. Notably, FCF exposure significantly reduced the frequency of spontaneous tail coils at 24 hpf, while shortened body length and induced spinal curvature at 120 hpf. Furthermore, zebrafish larvae exhibited craniofacial abnormalities and incomplete bone mineralization at 120 hpf following FCF exposure. In Tg(HuC:EGFP) transgenic strains, neuronal loss was observed. Additionally, FCF-exposed zebrafish larvae showed a marked reduction in locomotor ability, activity levels, and turning capacity. The qPCR and enzyme activity assays revealed significant changes in gene expression associated with the Notch signaling pathway, accompanied by increased levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA). Astaxanthin (ASTA) partially alleviated the toxicities induced by FCF. These findings suggest that FCF may induce skeletal and neurological toxicities by affecting oxidative stress, disrupting the normal expression of skeletal and nervous system-related genes in the Notch signaling pathway, and ultimately leading to behavioral abnormalities. Our findings may provide new insights into a comprehensive evaluation of FCF toxicology in aquatic organisms, and may assist the government in formulating and implementing regulatory policies regarding the application of FCF.
Association of urinary heavy metals with osteoporosis in US adults using interpretable machine learning.
Huang W, Liu D, Liu G … +1 more , Chen G
Toxicol Lett · 2026 Mar · PMID 41643231 · Publisher ↗
BACKGROUND: Exposure to heavy metals in the environment has always been the focus of public concern. More and more evidence suggests that heavy metal exposure may lead to bone degeneration and an increased risk of pathol...
BACKGROUND: Exposure to heavy metals in the environment has always been the focus of public concern. More and more evidence suggests that heavy metal exposure may lead to bone degeneration and an increased risk of pathological fractures. In this study, we analyzed the data of NHANES (National Health and Nutrition Survey) and applied nine machine learning models to check the relationship between heavy metal exposure and osteoporosis. METHODS: The data originates from NHANES conducted during the periods of 2003-2004,2005-2006,2007-2008,2009-2010,2013-2014 and 2017-2018 and is utilized for the development of machine learning models. The Spearman Correlation analysis was employed to identify the relationships among all independent variables, while the Boruta algorithm was utilized for feature selection. The chosen data was equilibrated with SMOTE and partitioned into training and testing sets in a 7:3 ratio. Support Vector Machine, Gradient Boosting Machine, Neural Network, Random Forest, XGBoost, K-Nearest Neighbors, AdaBoost, LightGBM, and CatBoost were employed to construct machine learning models. The optimum model was chosen for further research based on area under the curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score. The Shapley additive explanation (SHAP) method was employed to elucidate the contribution of variables to the machine learning model. RESULTS: The XGBoost model among nine machine learning models demonstrated the best and most balanced performance in evaluating the correlation between heavy metal exposure and osteoporosis (AUC value of 0.834), significantly outperforming the other eight models. It achieved an accuracy of 0.822, sensitivity of 0.709, specificity of 0.830. Age was identified as the primary influencing factor in this machine learning model (mean |SHAP| = 0.30). Based on SHAP feature importance, the metals were ranked (descending) as Tl, Pb, Cd, Ba, Mo, Sb, Cs, Co and Tu, with Tl showing the strongest contribution to osteoporosis prediction.SHAP dependency plots and waterfall plots further illustrate the decision-making mechanism of the model. CONCLUSIONS: In this study, the XGBoost model showed better performance than the other eight models. Among the nine types of urine metals, thallium (Tl) is the most important variable in the prediction of osteoporosis in machine learning models. Among all independent variables, age and gender are considered the most important components of the model. Subsequent research should develop more sophisticated algorithms to authenticate these findings and adjust relevant parameters to improve the model's precision.
Triclosan's interference with endocrine signalling: A mechanistic investigation.
Sharma D, Shah TK, Sinha R
Toxicol Lett · 2026 Mar · PMID 41638407 · Publisher ↗
The triclosan (TCS) has been widely used as an antimicrobial and antibacterial agent in personal care products, medical, acrylic, veterinary, and household items. Owing to its capacity to interfere with hormone-regulated...
The triclosan (TCS) has been widely used as an antimicrobial and antibacterial agent in personal care products, medical, acrylic, veterinary, and household items. Owing to its capacity to interfere with hormone-regulated pathways, it has been evidenced as a potential endocrine-disrupting chemical. This review summarizes the existing data on the mechanistic basis of TCS-induced endocrine disruption, emphasizing its impacts on steroidogenesis, receptor-based signalling, thyroid hormone regulation, crosstalk with metabolic hormones, and transformation product hazards. Consolidating molecular and cellular studies, this review highlights TCS-altered major endocrine functions and identifies areas of concern requiring further investigation for risk assessment and regulatory decisions.
Heavy metal exposure and cancer risk: Findings from a Mendelian randomization study.
Qin S, Xie L, Lan J … +3 more , Yang Y, Diao W, Ning Y
Toxicol Lett · 2026 Mar · PMID 41638406 · Publisher ↗
BACKGROUND: Epidemiological evidence has established associations between heavy metal exposure and increased risks of various cancers. However, causality remains difficult to establish in conventional observational studi...
BACKGROUND: Epidemiological evidence has established associations between heavy metal exposure and increased risks of various cancers. However, causality remains difficult to establish in conventional observational studies due to residual confounding and reverse causation. Mendelian randomization (MR) could overcome these limitations by using genetic variants as instrumental variables to strengthen causal inference. This study employs a two-sample MR approach to investigate the potential causal effects of serum heavy metal concentrations on multiple cancer types. METHODS: Genetic instruments for heavy metal exposure were obtained from genome-wide association study (GWAS) data. The primary causal estimates were derived using the inverse variance weighted (IVW) method, with robustness assessed and pleiotropy addressed through supplementary analyses, including weighted median, MR-Egger regression, and MR-PRESSO. All analyses accounted for multiple testing via Bonferroni correction. RESULTS: Mendelian randomization analysis revealed that genetically predicted serum nickel conferred an elevated risk of cervical cancer (OR = 1.473, 95 % CI: 1.102-1.969, P = 0.009), while serum manganese exhibited a protective effect against acute lymphoblastic leukemia (OR = 0.399, 95 % CI:0.173-0.922, P = 0.032). Additionally, serum lead was associated with an increased risk of biliary tract cancer (OR = 1.315, 95 % CI: 1.04-1.661, P = 0.022), and serum copper was causally linked to higher overall cancer incidence (OR = 1.052, 95 % CI: 1.004-1.102, P = 0.032). CONCLUSION: This study provides solid evidence for causal effects of heavy metal exposure on cancer development. The findings compel further investigation into the biological mechanisms involved and highlight the urgency of developing targeted public health interventions to mitigate these risks.
Bisphenol S and F disrupt cerebellar functions and neuronal health: The role of estrogen receptor and BMP2 signaling.
Das U, Shukla N, Ojha D … +3 more , Sagar G, Roy SK, Bandyopadhyay S
Toxicol Lett · 2026 Mar · PMID 41621464 · Publisher ↗
Bisphenol S (BPS) and bisphenol F (BPF) have gained attention as endocrine disruptors that affect brain functions, with their specific impact on the cerebellum being less thoroughly explored. Estrogen receptors (ERs) are...
Bisphenol S (BPS) and bisphenol F (BPF) have gained attention as endocrine disruptors that affect brain functions, with their specific impact on the cerebellum being less thoroughly explored. Estrogen receptors (ERs) are crucial in maintaining neuronal health in the cerebellum, which participates in motor coordination. Additionally, bone morphogenetic proteins (BMPs) participate in various neuronal processes and are influenced by ER signaling. This study investigated how environmentally relevant doses of BPS and BPF (0.4-40 μg/kg) affect cerebellar functions in adult female rats, with a particular emphasis on ER and BMP signaling. Our assessments of motor coordination, conducted using rota-rod and grip strength tests, indicated that exposure to BPS/BPF significantly compromised balance and muscle strength. Investigation of cerebellar tissue revealed decreased levels of estrogen receptors ERα and ERβ, along with reduced BMP2 at both mRNA and protein levels. BMP2 signaling was also diminished, marked by lower BMPR2 and downstream components like p-Smad. Notably, ER agonists PPT and DPN restored BMP2 levels, while BMP2 administration enhanced ERα and ERβ levels, highlighting a reciprocal relationship between these signaling pathways. Moreover, treatments with PPT, DPN, and BMP2 led to improvements in neuronal survival, NeuN levels, and overall motor coordination performance. In conclusion, BPS and BPF disrupt cerebellar functions and neuronal health by interfering with the interplay between ER and BMP2 signaling, suggesting that targeting these pathways may help mitigate the adverse effects of these chemicals.
Association between perfluoroalkyl and polyfluoroalkyl substances exposure and reproductive longevity for female in the United States: A population-based study.
Ning A, Shao F, Yang Q … +5 more , Ren Y, Zhou S, Lin J, Chu M, Zhang Y
Toxicol Lett · 2026 Mar · PMID 41620147 · Publisher ↗
Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women'...
Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women's healthy ageing. However, few studies have comprehensively evaluated the correlation between serum PFAS concentrations and female reproductive age, including menarche, reproductive longevity, and menopause. The purpose of this research is to investigate the correlation between serum PFAS levels and female reproductive age using linear regression models based on the National Health and Nutrition Examination Survey (NHANES) database. A total of 4743 participants were included in this analysis, and the results showed that age at menopause was inversely associated with perfluorooctanoic acid (PFOA) (β = -0.77, 95 % CI = -1.36, -0.18, P = 0.01), perfluorohexane sulfonic acid (PFHxS) (β = -1.07, 95 % CI = -1.53, -0.60, P < 0.001) and perfluorooctane sulfonic acid (PFOS) (β = -0.84, 95 % CI = -1.30, -0.38, P < 0.001). Moreover, the results showed that PFOS (β = -0.89, 95 % CI = -1.36, -0.42, P < 0.001), PFHxS (β = -1.08, 95 % CI = -1.55, -0.60, P < 0.001), and PFOA (β = -0.68, 95 % CI = -1.28, -0.08, P = 0.03) exposure were inversely related to reproductive longevity in women, exhibiting a strong dose-response trend. Evidence from the study indicates that exposure to PFAS may raise the risk of shortened reproductive longevity in women.
Rosuvastatin exposure during adulthood increases ovarian follicular atresia and reduces reproductive performance in female mice.
Oltramari AR, Da Silva AS, Cabrera MM … +3 more , Nardi GM, Mena Barreto Silva FR, Leite GAA
Toxicol Lett · 2026 Mar · PMID 41617063 · Publisher ↗
Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, rec...
Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.
Tributyl phosphate disrupts hepatic lipid metabolism via cGAS-STING signal pathway mediated inflammation.
Yang L, Ge Z, Ding X … +6 more , Shi J, Zhang J, Wang T, Jiang H, Zhang X, Zhou L
Toxicol Lett · 2026 Mar · PMID 41617062 · Publisher ↗
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid m...
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.
Maternal dibutyl benzene-1,2-dicarboxylate exposure accelerates bone marrow mesenchymal stem cells senescence to induce skeletal retardation in male offspring mice.
Zhang Y, Wang K, Lu J … +4 more , Wang R, Pan C, Ma T, Ma F
Toxicol Lett · 2026 Mar · PMID 41617061 · Publisher ↗
Dibutyl benzene-1,2-dicarboxylate (DBP), a ubiquitous plasticizer, readily crosses the placenta, posing a risk to male offspring development. Previous studies have found that maternal DBP exposure leads to multiple organ...
Dibutyl benzene-1,2-dicarboxylate (DBP), a ubiquitous plasticizer, readily crosses the placenta, posing a risk to male offspring development. Previous studies have found that maternal DBP exposure leads to multiple organ development disorders in male offspring, but the effect on skeletal development in male offspring mice is unclear. In this study, pregnant mice were orally administered corn oil from day 12 of pregnancy or given different doses of DBP by gavage. Our results showed that prenatal DBP exposure induced dose-dependent deterioration in the male offspring's femoral bone microarchitecture, as revealed by micro-CT. In vitro, we found that the primary metabolite MBP disrupted the osteogenic-adipogenic balance in bone marrow mesenchymal stem cells (BMSCs) by suppressing osteogenic differentiation while promoting adipogenic differentiation. Mechanistically, MBP treatment induced a premature senescent phenotype in BMSCs, as evidenced by heightened senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of senescence markers (γH2AX, p16, p21), and increased secretion of senescence-associated inflammatory factors. Critically, treatment with rapamycin prevented MBP-induced senescence and restored the osteogenic-adipogenic balance in BMSCs. This study identifies BMSCs senescence as a pivotal mechanism underlying DBP-induced skeletal retardation, providing novel insights into the environmental bone toxicity of phthalate exposure.
Enantioselective CYP inhibition by diclofop, the active metabolite of diclofop-methyl: Mechanism and relevance for human exposure.
Barbetta MFS, Baviera GS, Oka-Duarte L … +2 more , Perovani IS, de Oliveira ARM
Toxicol Lett · 2026 Mar · PMID 41617060 · Publisher ↗
Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evalua...
Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (-)-DF was more active against CYP2C19 and CYP3A4/5. IC and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a K value of 2.13 µmol L. Finally, R factor estimations indicated that in vivo inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide-drug interactions and human toxicity.
Mechanisms and management of crizotinib-induced toxicity in non-small cell lung cancer.
Liu X, Tao X, Cheng M … +7 more , Yan H, Xu Z, Yang B, He Q, Luo P, Yan F, Du J
Toxicol Lett · 2026 Mar · PMID 41617059 · Publisher ↗
Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicitie...
Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicities. This review synthesizes evidence regarding crizotinib-induced adverse effects-such as hepatotoxicity, cardiotoxicity, and interstitial lung disease-along with associated clinical management strategies. Through a systematic examination of the molecular mechanisms and multifactorial determinants of toxicity, this work aims to enhance understanding of the limitations associated with crizotinib's clinical applicability. Although most toxicities are manageable through dose adjustments, prophylactic monitoring, and adjunct therapies, unresolved mechanistic questions and rare, severe adverse events underscore the need for further research. By integrating molecular insights with practical approaches, this review underscores the essential balance between therapeutic efficacy and toxicity risks, thereby informing personalized treatment decisions and facilitating the development of safer targeted therapies. The synthesis of current knowledge is intended to optimize the clinical application of crizotinib and to foster innovative strategies for toxicity management within the evolving paradigms of NSCLC treatment.
Transcript-protein discrepancy of glutamatergic receptor subunits in human iPSC-derived neurons: Implications for neurotoxicity testing.
Serafini MM, Midali M, Grumelli G … +4 more , Cutarelli A, Marinovich M, Conti L, Viviani B
Toxicol Lett · 2026 Mar · PMID 41592671 · Publisher ↗
The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show...
The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show limitations in recapitulating certain neurodevelopmental processes. Currently, rodent primary cultures remain the gold standard for studying complex processes such as synaptogenesis. A key mechanism in glutamatergic synapse maturation is the GluN2B/GluN2A switch, which promotes the recruitment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, increasing the structural and functional complexity of the synaptic spines. This study characterizes the development of the glutamatergic machinery in hiPSC-derived neurons, focusing on the expression and maturation of N-methyl-D-aspartate (NMDA) and AMPA receptors. The increase of neuronal markers and the reduction of progenitor markers confirmed the differentiation efficiency. However, discrepancies emerged between transcriptional and protein profiles of key receptor subunits. GluN2A mRNA levels increased over time, while protein levels remained similar to those of neural progenitor cells (NPCs). Conversely, the GluN3A transcript increased at 30 and 60 days in vitro (DIV), while protein abundance decreased. Similar transcript-protein mismatches were observed for some AMPA receptor subunits. These results suggest that this model does not reach full glutamatergic maturity within the tested timeframe. Therefore, optimizing differentiation conditions (such as extending culture duration or adding maturation cues) may be necessary to better reproduce receptor dynamics. Finally, this study highlights the need to integrate protein-level analyses with transcriptional data to improve the reliability of hiPSC-derived neuronal models for neurotoxicity and NMDA receptor-mediated excitotoxicity studies.
Busulfan plus cyclophosphamide induced spermatogenic dysfunction and recovery: A dynamic change perspective.
Li T, Tang Z, Song Y … +8 more , Su M, Liu X, Li F, Wei X, Luo X, Zhou B, Wang Y, Zhang L
Toxicol Lett · 2026 Mar · PMID 41587595 · Publisher ↗
Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreve...
Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreversible infertility. Existing mouse models mostly use busulfan alone, which does not fully mimic clinical treatment. Here, we applied a BuCy treatment regimen in mice and performed a longitudinal characterization of testicular injury and recovery. BuCy treatment caused marked testicular atrophy in mice, severely disrupted seminiferous tubule architecture, and dramatically reduced sperm count and motility, with partial recovery at later time points. ScRNA-seq revealed a stepwise decline in germ cell populations, with spermatogonia disappearing earlier than spermatogonial stem cells (SSCs). In addition, we observed the highest number of differentially expressed genes (DEGs) at day 28. Functional enrichment highlighted disruptions in spermatogenesis, RNA metabolism, and chromatin regulation. This study systematically characterized the long-term, multi-time-point dynamics of BuCy-induced testicular damage and recovery in mice, with single-cell transcriptomic profiling providing complementary observations at the cellular level.
MicroRNA-based discrimination of hepatotoxic and non-hepatotoxic drugs using a humanized liver mouse model.
Okada N, Enomoto H, Goto R … +2 more , Tachiki H, Kitahara T
Toxicol Lett · 2026 Feb · PMID 41577211 · Publisher ↗
Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and repres...
Drug-induced liver injury (DILI) is one of the most common adverse drug effects and a major cause of drug development failure. However, preclinically identifying drugs that cause liver injury remains difficult and represents a major challenge in drug development. MicroRNAs (miRNAs) have been proposed as biomarkers for the early detection of DILI owing to the dynamic changes in their expression in response to hepatotoxic insults. Therefore, identifying human-specific miRNAs that change early in response to diverse hepatotoxicants may enable a practical screening approach for drug development. Here, we evaluated whether hepatic miRNA responses can distinguish hepatotoxic from non-hepatotoxic drugs using a highly humanized liver chimeric mouse model (PXB-mouse). We administered eight hepatotoxic compounds (hTOX) and three non-hepatotoxic compounds (non-hTOX) to PXB-mice and performed a comprehensive analysis of the changes in hepatic RNA expression. PXB-mice exposed to hTOX exhibited an increased expression of liver mRNAs which were related to early activation of transcriptional pathways induced by liver damage. Among the miRNAs that exhibited expression changes exclusively in the hTOX-treated group but not in the non-hTOX group compared to the controls, we identified miR-4306 and miR-1237 as potential candidates of human-specific miRNAs whose expression was changed only after hTOX treatment. Although further validation studies are warranted, our findings suggest that detection of miR-4306 and miR-1237 in PXB-mice may help discriminate hepatotoxic from non-hepatotoxic drug exposure.
Corrigendum to "Mechanisms, pathological features, and intervention strategies for nitrogen mustard-induced skin toxicity" [Toxicol. Lett. 416 (2026) 111815].
Zhu B, Mao G, Meng Q … +10 more , Li A, Jin C, Wang Y, Wang X, Xue W, Hou F, Yang J, Xu Q, Xue C, Wu M
Toxicol Lett · 2026 Feb · PMID 41571539 · Publisher ↗
Abstract loading — click title to view on PubMed.
Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats.
Li G, Du X, Wang X … +3 more , Han X, Peng M, Nan C
Toxicol Lett · 2026 Mar · PMID 41571214 · Publisher ↗
OBJECTIVE: This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure. METHODS: Forty-e...
OBJECTIVE: This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure. METHODS: Forty-eight healthy Sprague-Dawley rats (200 ± 20 g), equally stratified by sex, were randomized into four groups: a control group (0 g/m³) and low- (25.344 g/m³), medium- (50.688 g/m³), and high-dose (101.376 g/m³) methanol exposure groups. Rats were exposed via inhalation for 2 h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM). RESULTS: Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis. CONCLUSION: Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.
The novel PFOS substitute OBS induces visual developmental toxicity in zebrafish embryos via ferroptosis.
Liu X, Wu X, Xia M … +6 more , Fan Y, Zhao Y, Han J, Chen R, Peng Y, Qu M
Toxicol Lett · 2026 Feb · PMID 41539631 · Publisher ↗
Sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a widely used substitute for perfluorooctanesulfonic acid, may threaten ocular development, but its mechanisms remain unclear. In this study, zebrafish embryos were ex...
Sodium p-perfluorous nonenoxybenzenesulfonate (OBS), a widely used substitute for perfluorooctanesulfonic acid, may threaten ocular development, but its mechanisms remain unclear. In this study, zebrafish embryos were exposed to OBS (0, 0.01, 0.1, 1 mg/L) for 120 h. OBS exposure resulted in pronounced ocular developmental abnormalities, including lens deformation, reduced retinal layer thickness, and a significant decrease in eye size. Mechanistic analyses revealed that OBS induced oxidative stress and ferroptosis-associated alterations: the number of early apoptotic cells increased in a dose-dependent manner, accompanied by marked downregulation of key eye development genes (lhx4, pax6, rx1, and vsx1). Additionally, elevated Fe and malondialdehyde levels, abnormally increased superoxide dismutase activity, and reduced catalase activity and glutathione content were observed. Expression levels of ferroptosis-related genes (gpx4, slc7a11, fth, and tfr) were also significantly altered. Notably, treatment with the ferroptosis-specific inhibitor Ferrostatin-1 (Fer-1) effectively alleviated OBS-induced ocular damage, further supporting ferroptosis as a central regulatory mechanism. Collectively, this study provides the first evidence that ferroptosis plays a pivotal role in OBS-induced ocular developmental defects in zebrafish embryos, offering insights into PFOS alternatives' risks and therapeutic targets.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe