Toxicology Letters[JOURNAL]
Sun
200 papers
LEF1 regulated CTHRC1 Promotes Silica-Induced Pulmonary Fibrosis through CD44-Dependent Signaling.
Wang T, Sun W, Yang Q … +7 more , Jia X, Lian W, Meng F, Chen J, Xu S, Liu Y, Ni C
Toxicol Lett · 2026 Jul · PMID 42401354 · Publisher ↗
Silicosis is an incurable fibrotic lung disease caused by crystalline silica exposure. Aberrant activation of lung fibroblasts into pathological fibroblasts is a hallmark of silicosis. CTHRC1 has been considered a novel...
Silicosis is an incurable fibrotic lung disease caused by crystalline silica exposure. Aberrant activation of lung fibroblasts into pathological fibroblasts is a hallmark of silicosis. CTHRC1 has been considered a novel fibroblast activation biomarker. This study sought to explore CTHRC1's role in silicosis and determine the signaling pathways it modulates. A combination of transcriptomic analysis of clinical samples, LC-MS/MS, Co-IP, and cationic nanoliposome-based techniques was utilized. In vitro models of lung fibroblast activation induced by TGF-β1, PDGF or recombinant CTHRC1 (rCTHRC1), as well as in vivo models of pulmonary fibrosis induced by silica or bleomycin in mice were established. RNA sequencing, Western blot, RT-qPCR, AlphaFold2 analyses and rescue experiments using siCTHRC1, siCD44, CTHRC1 plasmids, and the PI3K activator 740 Y-P were performed to explore the underlying mechanisms. CTHRC1 is a significantly dysregulated gene implicated in myogenesis and ECM-related pathways. Mechanistically, lymphoid enhancer-binding factor 1 (LEF1) exerts its transcriptional regulator role by binding to the CTHRC1 promoter region in TGF-β1-activated fibroblasts. Further, CTHRC1 mediates its pro-fibroblast-to-myofibroblast transition function by directly binding to the CD44 receptor. AlphaFold2 analyses revealed the binding between CTHRC1 and CD44 is accomplished by three critical CD44 residues: Arg41, Asn172, and Trp650. Rescue experiments demonstrated that the CTHRC1-CD44 complex exerts its pro-fibrotic effects through AKT signaling. In vivo, liposomal Cthrc1 siRNA mitigated fibrogenesis in both silica- and bleomycin-induced mouse fibrosis models. Our results uncover a previously unrecognized role of the LEF1-CTHRC1-CD44 axis in silicosis and highlight the therapeutic target potential of CTHRC1 in fibrotic lung diseases.
hERG Channel Blockade and Additive Interactions of Magnolol and Honokiol from Magnolia Species.
Zhao W, Hao T, Lu H … +7 more , Jiang C, Xu J, Zhang Z, Stalin A, Zhang X, Pan L, Xu J
Toxicol Lett · 2026 Jul · PMID 42392381 · Publisher ↗
The Magnolia officinalis cortex (the dried bark known as "Houpo") is widely used in traditional Chinese medicine (TCM). In this study, we discovered some potential off-target effects of M. officinalis due to the blocking...
The Magnolia officinalis cortex (the dried bark known as "Houpo") is widely used in traditional Chinese medicine (TCM). In this study, we discovered some potential off-target effects of M. officinalis due to the blocking effects on hERG (human Ether-a-go-go-Related Gene) channels by magnolol and honokiol, two main active chemicals of M. officialis. This research investigated the modulatory effects of two neolignans and their cooperative effects on hERG channels using manual whole-cell patch-clamp techniques. Results showed that magnolol and honokiol blocked hERG currents with ICs of 5.2±0.3µM and 4.7±0.5µM. The blockade induced by two neolignans not only increased with increasing depolarizing strengths and durations but also significantly altered hERG activation and inactivation properties, which suggested a preferential binding to open or inactivated states. The reduced blockade by the less inactivating S631A mutation supported their inactivation preference. We also discovered an overall additive effect of two neolignans, which might increase potential cardiotoxic risks. To our knowledge, this is the first report of the additive effects of two chemicals from one herb on hERG channels and also the first discovery of neolignans acting as hERG blockers. In conclusion, magnolol and honokiol can block hERG channels in a similar way and an additive effect exists among them. The results add to the understanding of the cardiovascular risk profile of Magnolia herbs.
Evaluation of dose-dependent hematotoxic effects of celastrol on human blood cells in vitro.
Hemant G, Manikanta K, NaveenKumar SK … +6 more , Tejas C, Sumedini ML, Prashanth KS, Sunitha K, Kemparaju K, Girish KS
Toxicol Lett · 2026 Jul · PMID 42392380 · Publisher ↗
Over the past two decades, celastrol has gained significant scientific interest due to its ability to inhibit NF-κB, STAT3, and NLRP3 signaling pathways, resulting in antiinflammatory, antioxidant, and anticancer effects...
Over the past two decades, celastrol has gained significant scientific interest due to its ability to inhibit NF-κB, STAT3, and NLRP3 signaling pathways, resulting in antiinflammatory, antioxidant, and anticancer effects in various rodent disease models. Despite these findings, celastrol has not progressed beyond Phase I clinical evaluation due to its low bioavailability, limited stability, short half-life, and several off-target effects. Although studies have described the protective effects of celastrol on neutrophils, endothelial cells, and platelets, information regarding its cytotoxic effects on blood cells remains poorly understood. Since blood cells are the first cellular components exposed to the compound after intravenous or oral absorption, understanding its impact on these cells is essential. In this study, we examined the effects of celastrol on RBCs, platelets, neutrophils, and PBMCs. In RBCs, celastrol induced an elevated intracellular ROS and Ca²⁺ levels and loss of membrane integrity, leading to eryptosis and hemolysis. Inhibition of NOX activity mitigated these effects, indicating that celastrol-induced eryptosis and hemolysis is NOX-dependent manner. Celastrol also induced cell death in platelets, neutrophils, and PBMCs. At lower doses, celastrol exhibits protective role in RBCs and platelets. In contrast, higher concentrations exerted cytotoxic effects, suggesting concentration-dependent dual effect in its biological action. These findings underline the importance of establishing precise dosing regimens and optimized formulations to ensure safety in clinical translation.
Environmental pharmaceutical and antibiotic mixtures: An exposomics-guided framework for mechanistic toxicology.
Akhtar MS, Zaman W
Toxicol Lett · 2026 Jul · PMID 42392379 · Publisher ↗
Pharmaceuticals and antibiotics occur in the environment as complex, time-varying mixtures, but their toxicological interpretation remains limited by targeted chemical lists, parent-compound monitoring, and single-compou...
Pharmaceuticals and antibiotics occur in the environment as complex, time-varying mixtures, but their toxicological interpretation remains limited by targeted chemical lists, parent-compound monitoring, and single-compound testing. This narrative review synthesizes representative peer-reviewed evidence and integrates established exposomics, HRMS, EDA, AEP, and AOP concepts into a framework for mechanistic interpretation of environmental pharmaceutical and antibiotic mixtures. This integration connects target, suspect, and non-target HRMS screening with internal exposure verification, effect-directed analysis, aggregate exposure pathways, and AOP-informed mechanistic prioritization. The synthesis focuses on peer-reviewed studies that illustrate chemical screening, internal and tissue-resolved exposure, bioactivity anchoring, antibiotic transformation products, antimicrobial-resistance-relevant endpoints, and AEP/AOP-based mechanistic interpretation. Internal and tissue-resolved exposure data are emphasized as important for identifying biologically plausible drivers, particularly for neuroactive pharmaceuticals with conserved molecular targets and antibiotics that act through microbial, microbiome, immune, and resistance-selection pathways. Effect-directed analysis and mode-of-action-relevant bioassays provide a bridge between feature-rich exposome datasets and bioactivity-informed mechanistic interpretation. For antibiotics, inclusion of transformation products and antimicrobial resistance-related endpoints is significant because parent-only workflows can underestimate both chemical burden and biological relevance. AOP-network mapping offers a structured method for prioritizing key events, convergence points, and follow-up assays while separating confirmed evidence from tentative HRMS annotations. Finally, we summarize practical reporting and study-design considerations covering exposure verification, annotation confidence, QA/QC, bioactivity anchoring, omics interpretation, and qualitative evidence evaluation. This integrated approach can improve reproducibility, comparability, and decision relevance in the mechanistic toxicology of environmental pharmaceutical and antibiotic mixtures.
Size- and morphology-dependent cytotoxicity of metal-organic frameworks: Deciphering the structure-toxicity relationship.
Liu R, Li J, Yan X … +1 more , Lv Y
Toxicol Lett · 2026 Jun · PMID 42379481 · Publisher ↗
Metal-organic frameworks (MOFs), as an emerging nanomaterial, have been widely used in the field of biomedicine due to their excellent loading performance. However, the unclear synergistic biological toxicity associated...
Metal-organic frameworks (MOFs), as an emerging nanomaterial, have been widely used in the field of biomedicine due to their excellent loading performance. However, the unclear synergistic biological toxicity associated with variations in the morphology and particle size of nano-MOFs hinder their broader development. In this work, we prepared four kinds of nano-MOFs, which showed significant differences in cytotoxicity to human embryonic kidney 293 cells (HEK293) and human hepatocellular carcinomas (HepG2) due to their different particle sizes and morphologies. Uptake pathway analysis showed that the macropinocytosis pathway was more easily activated in HEK293 cells to engulf nano-sized particles, while clathrin-mediated endocytosis was more likely to encapsulate small-sized nanoparticles (NPs). In general, at low concentrations of NPs exposure, ZIF-67s had higher or similar cell damage than ZIF-8s, while at high concentrations, the overall toxicity of ZIF-8s was stronger than that of ZIF-67s; the larger size of ZIFs is more likely to lead to higher cell death rate; the cubic morphology ZIF-67s showed stronger biocompatibility to HEK293 cells than the dodecahedron. These findings establish a theoretical foundation for assessing the environmental health risks of MOFs and guaranteeing their safe application, providing valuable guidance for the subsequent design and development of biocompatible materials.
Steroidogenesis suppression in H295R cells by 1,3-disubstituted ureas: A potential off-target effect of some sEH inhibitors.
Hsu YC, Lynch AD, Morisseau C … +1 more , Hammock B
Toxicol Lett · 2026 Jun · PMID 42365935 · Publisher ↗
The soluble epoxide hydrolase (sEH) is widely studied for its therapeutic potential in inflammation, cardiovascular disease, and pain through stabilization of endogenous epoxyeicosatrienoic acid (EET). Here, we evaluated...
The soluble epoxide hydrolase (sEH) is widely studied for its therapeutic potential in inflammation, cardiovascular disease, and pain through stabilization of endogenous epoxyeicosatrienoic acid (EET). Here, we evaluated the impact of several urea-type sEH inhibitors on steroid hormone synthesis; another pathway in which sEH may be involved. Steroidogenesis assays employing the adrenocortical carcinoma cell line H295R demonstrated that TPPU and several other urea-type sEH inhibitors induce dose-dependent suppression of multiple steroid hormones without cytotoxicity, whereas the amide-based GSK2256294A had no effect on steroid production or cell survival. Substrate-to-product ratio analysis suggested selective modulation of CYP17, CYP21, and 17β-hydroxysteroid dehydrogenase activities, with only partial transcriptional changes in select steroidogenic genes. Exogenous 11,12-epoxyeicosatrienoic acid (EET) did not reproduce these effects, and TPPU maintained suppression under dbcAMP stimulation, indicating an off-target mechanism downstream of cAMP signaling. Collectively, these findings reveal that urea-based sEH inhibitors suppress adrenal steroidogenesis via scaffold-dependent, off-target mechanisms independent of sEH. In addition, it suggests that sEH is not involved directly in steroid metabolism.
Signaling pathways in tobacco smoking-induced cervical carcinogenesis: Beyond HPV-mediated activation.
Hu Y, Liu X, Zhang Z … +3 more , Zhou J, Zhou T, Wang H
Toxicol Lett · 2026 Jun · PMID 42364717 · Publisher ↗
Tobacco smoking is a well-established cofactor for human papillomavirus (HPV) in the development of cervical cancer (CC), but it also contributes to a subset of HPV-negative carcinomas. While the epidemiological link is...
Tobacco smoking is a well-established cofactor for human papillomavirus (HPV) in the development of cervical cancer (CC), but it also contributes to a subset of HPV-negative carcinomas. While the epidemiological link is clear, the molecular signaling pathways through which smoking promotes CC, particularly in the absence of HPV, have not been comprehensively reviewed. This article summarizes current evidence on smoking-triggered signaling mechanisms in both HPV-negative and HPV-positive CC. Our analysis, based on a systematic evaluation of experimental studies, reveals distinct pathways in each context. In HPV‑negative and functionally HPV‑negative cervical cells, smoking activates EGF and VEFG pathways and induces oxidative DNA damage, leading to p53 mutation. In HPV-positive cells, several signaling pathways are activated, encompassing the dysregulated expression of oncogenes governed by the PI3K/AKT axis, such as NF-κB, MMP-2, and p53. Additionally, pathways including Rps27a/Mdm2/p53, AKT/mTOR/4EBP1/eIF4E, EGFR/PI3K/AKT/c-Jun, and α-enolase-mediated glycolysis are also involved, alongside the activation of Ras‑Raf‑Mek1/2‑Erk1/2 signaling pathway. The collective findings indicate that HPV-mediated activation is not a prerequisite for smoking-induced carcinogenic signaling in the cervix. This synthesis underscores the potential for developing targeted interventions against these pathways to prevent or treat smoking-related CC, irrespective of HPV status. However, several questions remain regarding the interplay of smoking with other risk factors, the nuances between HPV-positive and negative contexts, and the need for in vivo validation of these primarily in vitro findings.
Neurobehavioral, cholinergic and histopathological alterations induced by copper oxide nanoparticles in male mice.
Ammar R, Slimen SB, Mhadhbi A … +4 more , de Sevilla DF, Boudawara O, Chtourou Y, Fetoui H
Toxicol Lett · 2026 Jun · PMID 42331115 · Publisher ↗
Copper is an essential element involved in metabolic processes in both plants and animals. However, in its nanoparticle form, copper is widely used in industrial and biomedical applications, raising concerns about its po...
Copper is an essential element involved in metabolic processes in both plants and animals. However, in its nanoparticle form, copper is widely used in industrial and biomedical applications, raising concerns about its potential health risks. This study aimed to evaluate the impact of CuO-NPs on cognitive and memory functions in mice, with a particular focus on the cholinergic system and oxidative stress pathways. Adult male mice were exposed to CuO-NPs at different doses (0, 5, and 10 mg/kg bw) via intraperitoneal administration over a period of 21 days. Behavioral assessments, including the open field test (OF), novel object recognition test (NORT), and Morris water maze (MWM), revealed significant impairments in spatial learning, short-term memory, and recognition ability in the group treated with 10 mg/kg CuO-NPs. In contrast, no alterations in memory or anxiety-like behaviors were observed at the low dose (5 mg/kg) compared to controls. Biochemical analyses of brain tissues showed increased lipid peroxidation and altered antioxidant and cholinesterase activities, while qRT-PCR analysis revealed significant downregulation of cholinergic-related genes in mice exposed to the high dose (10 mg/kg) compared with controls. Additionally, histopathological examination confirmed pronounced neuronal damage, particularly in the hippocampus and cortex, indicating severe neuropathological lesions at the highest dose. Importantly, no significant toxic effects were observed at the 5 mg/kg dose. These findings suggest that CuO-NPs are relatively safe at lower doses; however, higher exposure may impair cognitive and memory functions by disrupting cholinergic neurotransmission and inducing oxidative stress, emphasizing the need for caution in their widespread application.
Toxicology and biodistribution of plant-derived extracellular vesicles for drug delivery: Quality control, safety mechanisms, and translational testing priorities.
Naseem MT, Zaman W
Toxicol Lett · 2026 Jun · PMID 42302635 · Publisher ↗
Plant-derived extracellular vesicles and plant-derived exosome-like nanoparticles are increasingly investigated as natural nanocarriers for drug delivery and as bioactive materials with intrinsic therapeutic potential. H...
Plant-derived extracellular vesicles and plant-derived exosome-like nanoparticles are increasingly investigated as natural nanocarriers for drug delivery and as bioactive materials with intrinsic therapeutic potential. However, their translational development is limited by unresolved questions surrounding safety, biodistribution, product identity, and batch consistency. In this review, we synthesize current knowledge on the toxicology and biodistribution of plant-derived extracellular vesicle products, with emphasis on route-dependent exposure, barrier interactions, immune recognition, hemocompatibility, microbiome effects, and off-target organ accumulation. We argue that an edible plant origin should not be considered a surrogate for safety, particularly when products are administered at high doses, repeatedly, or through non-oral routes. We further identify quality control as a central determinant of both efficacy and safety, because plant source, growth conditions, harvest timing, isolation workflow, storage, and co-isolated contaminants can substantially alter vesicle composition and biological activity. To address these challenges, we propose a translational framework that integrates chemistry, manufacturing, and control principles with route-specific nonclinical toxicology testing and mechanism-linked potency assays. The framework highlights minimum expectations for identity, purity, potency, stability, and contaminant testing, including microbial burden, endotoxin-like activity, pesticide residues, and heavy metals. We also outline research priorities needed for regulatory-grade development, including harmonized nomenclature, reference materials, orthogonal characterization strategies, and mechanistic studies that distinguish vesicle-intrinsic effects from cargo- or impurity-driven toxicity. Collectively, this review positions toxicology and product quality as the key organizing principles for the safe and reproducible development of plant-derived extracellular vesicles in drug delivery.
Effects of combustible cigarettes and heated tobacco products on immunomodulatory and hepatoprotective properties of mesenchymal stem cells in acute liver failure.
Pavlovic D, Papic D, Kastratovic N … +2 more , Jurisic V, Volarevic V
Toxicol Lett · 2026 Jun · PMID 42297058 · Publisher ↗
Numerous experimental and clinical studies have indicated that mesenchymal stem cells (MSCs) and their secretome can modulate progression of acute liver failure (ALF). Our earlier research has demonstrated that exposure...
Numerous experimental and clinical studies have indicated that mesenchymal stem cells (MSCs) and their secretome can modulate progression of acute liver failure (ALF). Our earlier research has demonstrated that exposure to cigarette smoke significantly diminished these capabilities, rendering MSCs incapable of mitigating hepatic inflammation induced by immune cells. It remains uncertain whether heated tobacco products (HTPs), which produce fewer hazardous chemicals than combustible cigarettes, would similarly impact MSC function. In this study, we cultured murine Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) in Aqe (aqueous extracts) generated from combustible cigarettes (CC) or HTPs assessed their therapeutic efficiency in α-GalCer (alpha-galactosylceramide)-induced fulminant hepatitis in C57BL/6 mice. We also co-cultured human PDL-MSCs (Periodontal Ligament-derived Mesenchymal Stem Cells) with activated CD4⁺ T lymphocytes and NKT cells in a transwell system to validate these findings in a human setting. Consistent with our earlier work, cigarette smoke-exposed MSCs failed to attenuate hepatocyte damage and did not suppress the expansion of inflammatory and hepatotoxic immune cells in injured livers. By contrast, HTPs-exposed MSCs retained a certain amount of their immunosuppressive and hepatoprotective capacity- serum transaminase levels were lower, liver necrosis was less extensive, and fewer pro-inflammatory NK, NKT, Th1, Th17, and CD8⁺ T cells infiltrated the liver parenchyma. The human in vitro experiments yielded comparable results, indicating that HTPs impair MSCs' function to a lesser extent than cigarette smoke.
Nonclinical safety evaluation strategies for mRNA/LNPs platform agents: Evidence from comprehensive animal toxicity studies.
Ahn JH, Lee NY, Bae HJ … +15 more , Kim J, Kwak J, Kwon E, Roh G, Bae SH, Lee SY, Hwang IK, Lee J, Park HJ, Kwon SP, Bang EK, Kim JE, Keum G, Nam JH, Kang BC
Toxicol Lett · 2026 Jun · PMID 42289207 · Publisher ↗
Antigen-encoded messenger RNA (mRNA) formulated with lipid nanoparticles (LNPs) represent a rapidly expanding platform technology, extending beyond prophylactic infectious disease vaccines into therapeutic applications....
Antigen-encoded messenger RNA (mRNA) formulated with lipid nanoparticles (LNPs) represent a rapidly expanding platform technology, extending beyond prophylactic infectious disease vaccines into therapeutic applications. Despite their increasing clinical use, harmonized and modality-specific guidance for nonclinical safety evaluation of mRNA/LNP platform agents remains limited, creating regulatory uncertainty during investigational new drug (IND)-enabling development. In this study, we systematically evaluated key variables influencing nonclinical safety profiles of mRNA/LNP agents from a regulatory toxicology perspective. Using comprehensive animal (mice and cynomolgus macaques) toxicity studies, we examined the impact of dose level (25∼100 μg/head), LNP composition, mRNA platform type (modified, unmodified, self-amplifying, and circular mRNA), antigen encoding, and animal species selection on toxicological outcomes. Dose-dependent toxicity profiling in mice revealed parameter-specific responses across hematological, biochemical, and organ weight parameters, underscoring the regulatory relevance of rational dose selection. Comparative analyses demonstrated that LNP composition alone can drive distinct toxicity phenotypes, while mRNA/LNPs platform further modulated specific toxicological parameters such as AST, reticulocyte and cardiac troponin I levels. Importantly, different mRNA platforms resulted in distinct toxicological patterns, particularly with respect to platelet counts and cardiac troponin I levels. Repeated-dose studies in non-human primates identified reversible toxicological changes, while revealing species-specific minor differences in selected blood chemistry and organ weight parameters not observed in rodents. Collectively, these findings highlight that nonclinical safety profiles of mRNA/LNP agents are shaped by multiple interdependent platform variables. This study provides regulatory-relevant experimental evidence to inform evidence-based nonclinical study design and interpretation, supporting development of mRNA vaccines and therapeutics.
Bromacil attenuates benzo[a]pyrene cytotoxicity and mutagenesis through the AhR and Nrf2 pathways.
Koike M, Takemoto S, Komatsu S … +4 more , Karube R, Kanamaru S, Shiozawa M, Shiizaki K
Toxicol Lett · 2026 Jun · PMID 42285379 · Publisher ↗
The aryl hydrocarbon receptor (AhR) is known to respond to various chemicals as a sensor for environmental chemicals that induce drug-metabolizing enzymes; however, reports on its activation by pesticides and herbicides...
The aryl hydrocarbon receptor (AhR) is known to respond to various chemicals as a sensor for environmental chemicals that induce drug-metabolizing enzymes; however, reports on its activation by pesticides and herbicides remain limited. We evaluated compounds from commonly used pesticides and herbicides that modulate AhR using a yeast reporter gene assay. Notably, bromacil (Brm), which is a uracil herbicide, exhibited ligand-like activity with mouse AhR in a yeast-based assay used for first screening., functioning as an antagonist and inducing AhR nuclear translocation in human cells, while exhibiting no cytotoxicity or mutagenicity. Although AhR modulators may be nontoxic, they could alter the mutagenicity of procarcinogens, which are metabolically activated by inducing the expressions of drug-metabolizing enzymes. Co-exposure to Brm and benzo[a]pyrene (BaP) reduced BaP-induced cytotoxicity and mutagenicity. Moreover, Brm induced Nrf2 activation and upregulated its target gene mRNA levels in an AhR-dependent manner, which may contribute to the observed attenuation of BaP-induced cytotoxicity and mutagenicity. These findings indicated that Brm is a novel AhR antagonist that modifies AhR-mediated chemical toxicity through AhR inhibition and Nrf2 activation.
MC-LR detoxication in human and rats: inter-organ and inter-species differences.
Malandrucco V, Santori N, Dorne JCM … +2 more , Buratti FM, Testai E
Toxicol Lett · 2026 Jun · PMID 42259476 · Publisher ↗
The transition from animal-based chemical risk assessment to Next-Generation Risk Assessment requires the integration of human-relevant New Approach Methodologies and mechanistic kinetic data to support physiologically b...
The transition from animal-based chemical risk assessment to Next-Generation Risk Assessment requires the integration of human-relevant New Approach Methodologies and mechanistic kinetic data to support physiologically based kinetic (PBK) modelling for quantitative in vitro-to-in vivo extrapolation. This study investigated isoform-specific and extrahepatic glutathione (GSH) conjugation of Microcystin-LR (MC-LR), a widespread cyanobacterial toxin of emerging concern in food and feed safety. MC-LR detoxification occurs via spontaneous GSH conjugation or catalysed by glutathione-S-transferases (GSTs). A panel of recombinant human GSTs and pooled human and rat intestinal and kidney cytosols was incubated with 1-60 µM MC-LR to characterise kinetic parameters and intrinsic clearance (Cli). The tested GST isoforms catalysed MC-LR conjugation with efficiencies spanning a 15-fold range, with P1 and T1 showing the highest activity. Isoforms exhibited distinct kinetic behaviours, including positive cooperativity, influencing their relative contribution across substrate concentrations. Human intestinal and renal cytosols showed GST-mediated metabolic efficiencies comparable to hepatic data, attributable to the high expression of GSTP1 and T1. However, when scaling to whole-organ Cli, the hepatic enzymatic conjugation exceeded extrahepatic one. In rats, intestine and kidney detoxification capacity was low with respect to the hepatic one, the latter resulting 3.3-fold more efficient than the human GST-mediated reaction. Although the spontaneous conjugation in vitro accounted for 70-80% of total conjugate formation, when the reaction rate scaled to the total hepatic cytosolic volume, its relative contribution was lower than the GST-mediated one. In addition the enzymatic reaction became dominant even in vitro under GSH depletion, at low MC-LR concentrations, typical of long term exposure. These findings underscore the relevance of GST isoform distribution, polymorphism, and GSH availability in driving inter-organ, interspecies, and inter-individual variability in MC-LR detoxification. Overall, this study fills critical data gaps on MC-LR kinetics and provides quantitative parameters to inform PBK model development.
Comparing the performance of solution-based decontaminants following exposure to toxic industrial chemicals on human skin.
Gaskin S, Ranaweera R, Thredgold L … +2 more , Dixit N, Redmore N
Toxicol Lett · 2026 Jun · PMID 42248220 · Publisher ↗
The extensive use of industrial chemicals increases the likelihood of accidental or deliberate environmental release, potentially occurring in occupational, public, or military settings, with skin contact being an import...
The extensive use of industrial chemicals increases the likelihood of accidental or deliberate environmental release, potentially occurring in occupational, public, or military settings, with skin contact being an important route of exposure. The effectiveness of subsequent skin decontamination depends on the physicochemical properties and absorption profiles of the chemicals involved, as well as the decontamination method applied. This study assessed three solution-based decontamination approaches, hard water, 2% soapy water, and Dahlgren Decon Skin Soap against three representative compounds: chloroacetone, chloroacetonitrile, and crotonaldehyde. For all chemicals tested, statistically significant differences (p < 0.05) were more commonly observed between decontaminated and untreated samples than among the decontamination treatments themselves. These findings indicate that decontamination reliably reduces dermal permeation, even though the specific formulations did not consistently produce distinguishable differences in efficacy. These results support the practical value of prompt decontamination, highlighting that readily accessible solutions can meaningfully mitigate dermal exposure risks in real‑world chemical release scenarios.
Permethrin in companion animals: mechanistic neurotoxicity, dermal pharmacokinetics, and secondary exposure pathways.
Britti D, Castagna F, Bava R
Toxicol Lett · 2026 Jun · PMID 42242635 · Publisher ↗
Permethrin remains one of the most widely used pyrethroids in companion animal ectoparasite control, yet its toxicological profile reflects a complex interplay between mechanism of action, dermal delivery, formulation be...
Permethrin remains one of the most widely used pyrethroids in companion animal ectoparasite control, yet its toxicological profile reflects a complex interplay between mechanism of action, dermal delivery, formulation behaviour and secondary exposure. Its primary activity is mediated through state-dependent modification of voltage-gated sodium channels, resulting in delayed channel deactivation/inactivation, repetitive firing and excitatory neurotoxicity. While this mechanism underpins insecticidal and repellent efficacy, it also explains adverse effects in non-target species. Following topical application, permethrin preferentially partitions into the lipid-rich stratum corneum and hair coat, forming a persistent cutaneous reservoir. This reservoir supports sustained ectoparasiticidal activity while limiting systemic absorption under labelled conditions, but it also maintains surface residues that may be transferred through contact, grooming, bathing or water exposure. Comparative toxicology reveals a marked divergence between relative canine tolerance and pronounced feline susceptibility. This difference should not be reduced to impaired glucuronidation alone, but rather interpreted as a dose-formulation-species interaction involving high-concentration canine products, low feline body weight, grooming-mediated oral uptake and metabolic constraints. Secondary exposure is discussed using a cautious, evidence-weighted framework. Companion animal topical products are biologically plausible contributors to domestic and environmental residues, but permethrin-specific source apportionment remains limited. This review integrates mechanistic toxicology, dermal pharmacokinetics and comparative susceptibility to provide a formulation-centred framework for interpreting non-target risk associated with veterinary permethrin use.
Acetyl-CoA synthetase 2 nuclear translocation impediment contributes to nickel induced histone hypoacetylation and neurite outgrowth impairment.
Zhou C, Zhang J, Zhang W … +10 more , Xu Y, Mei X, Deng P, Ma Q, Chen C, Zhang L, Pi H, Zhou Z, Yu Z, He M
Toxicol Lett · 2026 Jun · PMID 42184874 · Publisher ↗
Histone hypoacetylation is a well-documented phenomenon associated with nickel (Ni) induced toxic effects, including neurotoxicity. However, the mechanism for histone hypoacetylation in Ni exposure remains ambiguous. Rec...
Histone hypoacetylation is a well-documented phenomenon associated with nickel (Ni) induced toxic effects, including neurotoxicity. However, the mechanism for histone hypoacetylation in Ni exposure remains ambiguous. Recently, acetyl-CoA availability, especially in the nuclear compartment, for histone acetylation dynamics, is emphasized. In the present study, histone hypoacetylation was evaluated in Ni neurotoxicity cell models, where Ni exposure caused neurite outgrowth impairment. The effects of Ni on histone deacetylases (HDACs) and histone acetyltransferases (HATs), combining with the results of energy metabolites analysis, revealed that the distortion on acetyl-CoA availability was involved in Ni-induced histone hypoacetylation. The function of three nuclear acetyl-CoA synthetases was evaluated, while acetyl-CoA synthetase 2 (ACSS2) nuclear translocation impediment was found in Ni exposure. Promoting ACSS2 nuclear translocation restored Ni-induced H3K9 hypoacetylation and neurites outgrowth impairment. These results indicated that Ni inhibited ACSS2 nuclear translocation to compromise the acetyl-CoA supply for histone acetylation. The impact of Ni on ACSS2 nuclear translocation may provide a new sight into the histone acetylation regulation, suggesting Ni-associated health adverse effects.
A full thickness in vitro model of human skin for the penetration of highly toxic VX and the evaluation of different decontaminants.
Horn G, Schwab A, Worek F … +3 more , Wille T, Steinritz D, Amend N
Toxicol Lett · 2026 Jun · PMID 42173174 · Publisher ↗
The dermal exposure to persistent nerve agents such as VX may lead to skin penetration and uptake in the circulatory system. So far, the efficacy of decontamination lotions to remove VX from the skin has been investigate...
The dermal exposure to persistent nerve agents such as VX may lead to skin penetration and uptake in the circulatory system. So far, the efficacy of decontamination lotions to remove VX from the skin has been investigated in vitro using methods for transdermal drug delivery systems such as the vertical diffusion cell, which suffer from several disadvantages. We assessed a full thickness model of human skin placed in inserts of 6-well plates to investigate the efficacy of decontaminants to remove VX. Six different decontamination lotions (reactive skin decontamination lotion (RSDL), the potassium salt of the acetohydroxamic acid (AHAK), sodium hypochlorite (NaOCl) 2% and 10%, soapy water 2% and tap water) were evaluated by calculating the amount of VX that penetrated over 300 min. In addition, the impact of the initiation of decontamination (5 min versus 30 min) was investigated. Early decontamination of VX with AHAK was very effective resulting in a complete decontamination. RSDL and NaOCl 2% showed a substantial decontamination efficacy and the penetrated amount of VX was reduced by 88% (RSDL) and 84% (NaOCl 2%). In contrast, the decontamination efficacy of soapy water and tap water was significantly lower. The delayed decontamination was less effective but still the amount of penetrated VX was significantly reduced. In conclusion, the results underline that the full thickness model of human skin is a suitable tool for investigating the decontamination efficacy of various decontaminants. In addition, the model benefits from low technical requirements.
Mitigating algorithmic bias in AI-powered toxicology: Frameworks for explainable and equitable predictions in human health and environmental safety.
Ajisafe OM, Ogebule LA, Egbon E … +3 more , Olawuyi OF, Olasilola OR, Olawade DB
Toxicol Lett · 2026 Jun · PMID 42167618 · Publisher ↗
The rapid integration of artificial intelligence (AI) and machine learning into predictive toxicology has transformed chemical hazard identification, toxicity endpoint forecasting, and risk assessment for pharmaceuticals...
The rapid integration of artificial intelligence (AI) and machine learning into predictive toxicology has transformed chemical hazard identification, toxicity endpoint forecasting, and risk assessment for pharmaceuticals, environmental pollutants, and consumer products. While these tools promise faster, more ethical alternatives to traditional testing, they introduce significant risks of algorithmic bias arising from imbalanced datasets, historical data limitations, under-represented chemical classes or populations, and model design choices. Such biases can lead to inaccurate predictions, disproportionate errors in vulnerable subgroups (e.g., demographic or geographic disparities in human health outcomes), and unreliable environmental safety evaluations. This review synthesises sources of bias in AI-powered toxicology models, including data selection, feature engineering, and black-box opacity. It examines detection methods (e.g., fairness metrics, disparity audits) and mitigation frameworks, encompassing data-centric approaches (diverse inclusion, debiasing techniques, synthetic data generation), algorithmic interventions (adversarial training, regularisation), and holistic strategies aligned with emerging principles such as trustworthiness, reproducibility, explainability, applicability, and transparency. Special emphasis is placed on explainable AI (XAI) methods, such as SHAP, LIME, attention mechanisms, and Grad-CAM visualisations, that enhance interpretability, reveal mechanistic insights, and facilitate bias identification in toxicity predictions. Applications to human health (e.g., reducing inequities in adverse drug reaction forecasting) and environmental safety (e.g., equitable chemical prioritisation and ecosystem risk modelling) are highlighted, alongside regulatory considerations for acceptance of bias-resilient, transparent models. Challenges persist, including data heterogeneity, validation gaps, and ethical oversight needs. Future directions call for standardised bias auditing protocols, interdisciplinary collaboration, and policy frameworks to ensure AI-driven toxicology delivers fair, reliable, and human-relevant outcomes for safer public and environmental health.
Plasma protein binding, metabolic stability, oral bioavailability and disposition kinetics of bisphenol AP in rats.
Sharma A, Yahavi C, Bhateria M … +1 more , Pratap Singh S
Toxicol Lett · 2026 Jun · PMID 42167617 · Publisher ↗
Bisphenol A (BPA) is a recognised endocrine disruptor resulting in regulatory restrictions and a search for safer alternatives. Bisphenol AP (BPAP), introduced as a BPA substitute, has shown endocrine-disrupting potentia...
Bisphenol A (BPA) is a recognised endocrine disruptor resulting in regulatory restrictions and a search for safer alternatives. Bisphenol AP (BPAP), introduced as a BPA substitute, has shown endocrine-disrupting potential and is linked to genotoxicity and recurrent miscarriages. Toxicokinetic evaluation is essential for health risk assessment, yet data on BPAP are lacking. This study characterizes the in vitro and in vivo TK profile of BPAP to facilitate its comparative risk assessment with BPA. A sensitive LC-MS/MS method was developed and validated for quantifying BPAP in rat plasma. In vitro assessments revealed high plasma protein binding in rat and human plasma and indicated metabolism through glucuronidation. Predicted hepatic clearance using the well-stirred model suggested BPAP as a high and intermediate extraction chemical in rats and humans, respectively. In vivo studies showed rapid oral absorption and high clearance (4.24 L/h/kg) after intravenous dosing. BPAP exhibited 18% oral bioavailability. BPAP excretion studies showed feces as major elimination route, with negligible urinary excretion. These findings provide insights into BPAP's disposition profile and highlight that BPAP may not be a safer replacement analogue. This study emphasize the need for further toxicity studies and risk evaluation before considering BPAP a safer BPA alternative.
HECTD1 promotes pulmonary fibrosis by targeting EMT and subsequent fibroblasts activation.
Zhou Z, Geng T, Hu Y … +6 more , Sun C, Xiao N, Lu S, Zhang C, Gao Y, Chao J
Toxicol Lett · 2026 Jun · PMID 42167616 · Publisher ↗
Epithelial-mesenchymal transition (EMT) is characterized by enhanced fibroblast activation and excessive extracellular matrix deposition, ultimately leading to fibrosis. However, its specific role in silicosis and the un...
Epithelial-mesenchymal transition (EMT) is characterized by enhanced fibroblast activation and excessive extracellular matrix deposition, ultimately leading to fibrosis. However, its specific role in silicosis and the underlying mechanisms remain poorly understood. In this study, we investigated the EMT process using a murine model of silicosis and epithelial cell lines (MLE12, A549, and BEAS-2B) exposed to SiO. Notably, HECTD1 (HECT domain E3 ubiquitin protein ligase 1) was found to be significantly upregulated in epithelial cells during silicosis progression. HECTD1 induced EMT by upregulating mesenchymal markers (α-SMA, Vimentin, and Collagen I) and downregulating the epithelial marker E-cadherin, thereby promoting cell migration and proliferation and ultimately contributing to pulmonary fibrosis. Furthermore, HECTD1 facilitated fibroblast activation through promoting the release of inflammatory cytokines from epithelial cells, thereby exacerbating silicosis. Collectively, our findings establish a link between HECTD1-induced EMT and pulmonary fibrosis, providing new insights into HECTD1 as a potential target for the development of novel therapeutic strategies for silicosis.
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