Archives Of Toxicology[JOURNAL]
Sun
200 papers
Formation and persistence of estragole-derived DNA adducts in human liver cells and tissue.
Ackermann G, Abel-Beckmann M, Quarz C … +8 more , Halaczkiewicz M, Stegmüller S, Richling E, Manolikakes G, Christmann M, Küpper JH, Schrenk D, Fahrer J
Arch Toxicol · 2026 Jul · PMID 41915187 · Full text
Estragole (ES) is a phenylpropene naturally occurring in various herbs and spices, such as fennel and basil. Humans are exposed to ES via the diet or herbal medicinal products. Following its gastrointestinal resorption,...
Estragole (ES) is a phenylpropene naturally occurring in various herbs and spices, such as fennel and basil. Humans are exposed to ES via the diet or herbal medicinal products. Following its gastrointestinal resorption, hepatic bioactivation of ES by Cytochrome P450 monooxygenases (CYPs) and sulfotransferases (SULTs) can lead to DNA adduct formation and liver cancer in rodents. Up to now, no data is available on ES-dependent DNA adducts in human tissue, which would however be important for human risk assessment. Our work thus analyzed whether ES-derived DNA adducts are present in human liver samples. Furthermore, DNA adduct formation after repetitive ES exposure and upon incubation with an ES-containing bitter fennel infusion was studied in human liver cells. Using a sensitive UHPLC-MS/MS method, we detected E3'-N-dG adducts in a multitude of human liver samples. The adduct levels correlated positively with SULT1A1, but not CYP1A2 protein expression. Noteworthy, the E3'-N-dA adduct was not found in the analyzed human liver tissue. Further experiments revealed that E3'-N-dG adducts accumulate in metabolically competent human liver cells after repetitive short-term exposure to ES, whereas the E3'-N-dA adduct was not detected at all. Finally, we provided evidence that ES from a bitter fennel tea preparation induces E3'-N-dG adducts in human liver cells, however at lower levels than expected. Altogether, this study demonstrated the occurrence of ES-derived DNA adducts in human liver tissue at levels comparable to the structurally related methyleugenol. Notably, the found DNA adduct levels are well below those reported to cause mutagenicity and clastogenicity in human cells and rodent in vivo models.
In-silico toxicity study of tryptamine, psilocin, psilocybin, N,N-dimethyltryptamine, 5'-methoxy-N,N-dimethyltryptamine and O-acetylpsilocin.
Jurowski K, Kobylarz D, Noga M
Arch Toxicol · 2026 Mar · PMID 41915186 · Publisher ↗
Understanding the toxicity of serotonergic tryptamines is becoming increasingly important from both clinical and forensic perspectives, yet experimental data for these compounds remain extremely limited. Despite their gr...
Understanding the toxicity of serotonergic tryptamines is becoming increasingly important from both clinical and forensic perspectives, yet experimental data for these compounds remain extremely limited. Despite their growing medical relevance and widespread non-medical use, there is still no systematic evaluation of their toxicological risks. This study presents the first comprehensive in silico assessment of key toxicological endpoints for six tryptamines of clinical and forensic interest: tryptamine, psilocin, psilocybin (4-PO-DMT),N, N-dimethyltryptamine (DMT), 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT),and O-acetylpsilocin (4-AcO-DMT). A multi-model computational approach was applied using STopTox, admetSAR 3.0, ADMETlab 3.0, ACD/Labs Percepta, Toxtree, ProTox 3.0, OCHEM, TEST, and VEGA QSAR, following OECD principles for QSAR model validation. The study covered acute systemic toxicity (LD), organ-specific effects, cardiotoxicity (hERG inhibition), genotoxicity (Ames test), irritation potential, and estrogenic activity (ER-α binding). All compounds were classified as Cramer Class III (high toxicological concern). Predicted oral LD values were in the 100-500 mg/kg range, indicating moderate to high acute toxicity. Cardiovascular and gastrointestinal systems were consistently identified as primary targets (predicted effect ≥ 90%). DMT and 5-MeO-DMT showed the highest predicted hERG inhibition (20 < IC < 45 µM), suggesting possible cardiotoxic potential, while psilocybin demonstrated lower risk (IC ≈ 760 µM). Most tryptamines were predicted to be non-mutagenic and non-endocrine active (LogRBA < - 3).
CYP2C19 as a key enzyme in the metabolism of cantharidin in Huh-7 cells and mice.
Zhang J, Lyu F, Tian T … +8 more , Ma J, Liu Y, Wu Y, Song K, Zhou X, Wang QK, Yao Y, Liu L
Arch Toxicol · 2026 Jul · PMID 41915185 · Publisher ↗
Cantharidin (CTD), a traditional Chinese medicinal with a long history of use, exhibits broad-spectrum antitumor properties. However, its clinical application is severely limited by its inherent toxicity. Cytochrome P450...
Cantharidin (CTD), a traditional Chinese medicinal with a long history of use, exhibits broad-spectrum antitumor properties. However, its clinical application is severely limited by its inherent toxicity. Cytochrome P450 (CYP) enzymes are major phase I drug-metabolizing enzymes in clinical settings. To date, however, no enzymes responsible for the metabolism of CTD have been reported yet. In this study, specific CYP450 isoforms involved in CTD metabolism were identified and validated. We first performed in vitro experiments using Huh-7 cells to screen for enzymes capable of metabolizing CTD. Subsequent in vivo studies were conducted by tail vein injection of adeno-associated virus (AAV8-CYP2C19) to achieve CYP2C19 overexpression in mice. Mice were then administered CTD (1.5 mg/kg) by gavage, and survival was monitored. Cardiac injury was evaluated using Hematoxylin-Eosin (HE) staining and Masson staining, while cardiac function was assessed by echocardiography. Myocardial apoptosis was examined by TUNEL staining and Western blotting. The expression levels of genes encoding related enzymes were measured by Real-Time quantitative PCR. GC-MS was employed to quantify CTD concentrations in cell culture medium, mouse blood, and mouse liver tissues. Additionally, single-nucleotide polymorphism (SNP) analysis was performed on human samples. Our in vitro results identified CYP2C19 as a key enzyme involved in CTD metabolism. Consistent with this, AAV8-CYP2C19‑mediated overexpression in mice significantly accelerated CTD metabolism. CTD administration induced cardiac dysfunction, particularly within 6 h of gavage, as evidenced by a rapid decline in cardiac output. Histological analysis revealed myocardial damage characterized by inflammatory cell infiltration and collagen fiber deposition. TUNEL staining and Western blotting further confirmed increased cardiomyocyte apoptosis following CTD exposure. GC-MS analysis demonstrated reduced CTD concentrations in the blood and liver of AAV8‑CYP2C19‑treated mice, which corresponded to alleviated myocardial injury in the AAV8-CYP2C19 + CTD group. In human samples, liver samples from patients who died of CTD-induced toxicity were found to carry the CYP2C19*2 SNP, a variant associated with the slow-metabolizer phenotype. Collectively, our findings demonstrate, for the first time, that CTD is metabolized by CYP2C19. These results suggest that genetic testing for CYP2C19 polymorphisms could be performed prior to CTD-based cancer therapy, thereby facilitating precision medicine approaches that minimize toxicity and improve therapeutic efficacy.
The toxicity of psychedelic LSD derivatives: 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), 1-valeryl-LSD (1V-LSD) and 1-cyclopropylmethanoyl-LSD (1cP-LSD)-prediction of toxicological parameters relevant to clinical and forensic toxicology using multi-in silico approach.
Jurowski K, Krośniak A, Kobylarz D … +1 more , Fijałkowska O
Arch Toxicol · 2026 Jul · PMID 41915184 · Full text
Lysergamide analogs such as ALD-52, 1P-LSD, 1B-LSD, 1 V-LSD, and 1cP-LSD have emerged as new psychoactive substances (NPS) with hallucinogenic potential, yet their toxicological profiles remain largely unexplored. In thi...
Lysergamide analogs such as ALD-52, 1P-LSD, 1B-LSD, 1 V-LSD, and 1cP-LSD have emerged as new psychoactive substances (NPS) with hallucinogenic potential, yet their toxicological profiles remain largely unexplored. In this study, a comprehensive in silico assessment was conducted using multiple platforms (e.g., ADMETlab 3.0, Percepta, STopTox, ProTox 3.0, VEGA, TEST 5.1.2) to predict critical toxicological parameters relevant to clinical and forensic toxicology. Acute toxicity was predicted for all compounds, with LD values in rats ranging from 49 to 85 mg/kg (Percepta) and oral/inhalation exposure identified as the most concerning routes. Organ-specific toxicity highlighted elevated pulmonary risk for 1 V-LSD (92%) and 1cP-LSD (81%), and highest predicted hematotoxicity for 1P-LSD (76%) and 1B-LSD (75%). Genotoxicity alerts were consistently identified for ALD-52 and 1cP-LSD (up to 90% predicted probability, Percepta), while OCHEM classified all compounds as non-mutagenic. Cardiotoxicity assessment revealed the strongest hERG channel inhibition for 1 V-LSD (IC = 1.4 µM, Percepta), suggesting elevated proarrhythmic potential. Dermal and ocular irritation risks were uniformly low across platforms. The results support that structural modifications at the N-1-acyl position influence toxicity patterns, particularly affecting cardiopulmonary and genotoxic endpoints. These findings underscore the utility of in silico methods for early risk assessment and prioritization of lysergamide-based NPS for further toxicological evaluation.
Exposure to second-generation flame retardants and risk of metabolic diseases: a systematic review and meta-analysis.
Shi L, Du W, Peng XY … +9 more , Miao J, Li W, Ur-Rehman A, Ge MW, Shen LT, Feng R, Zhong K, Mu ZR, Chen HL
Arch Toxicol · 2026 Jun · PMID 41874589 · Publisher ↗
As replacements for legacy flame retardants, second-generation organophosphorus flame retardants (OPFRs) exhibit high environmental mobility and persistence, resulting in ubiquitous human exposure. The metabolic impacts...
As replacements for legacy flame retardants, second-generation organophosphorus flame retardants (OPFRs) exhibit high environmental mobility and persistence, resulting in ubiquitous human exposure. The metabolic impacts of OPFR exposure remain controversial despite extensive epidemiological investigation. Comprehensive searches were performed in four databases up to Nov 2025. Following independent selection and quality grading by two reviewers, meta-analysis was conducted using R (version 4.4.3). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models, depending on the I² statistic. The robustness of findings was verified via subgroup, sensitivity, and publication bias analyses, while restricted cubic spline regression characterized dose-response relationships. OPFR exposure was significantly associated with an elevated risk of metabolic diseases (OR = 1.11, 95% CI: 1.09–1.14, p < 0.0001). Stronger associations for chlorinated (OR = 1.36, 95% CI: 1.22–1.52) and aryl-OPFRs (OR = 1.39, 95% CI: 1.12–1.72). Significant positive associations in both Chinese (OR = 1.37, 95% CI: 1.19–1.57) and US populations (OR = 1.14, 95% CI: 1.07–1.21). Blood biomarkers yielded higher risk estimates (OR = 1.67, 95% CI: 1.62–2.26) than urine (OR = 1.25, 95% CI: 1.15–1.35). OPFRs were linked to diabetes (OR = 1.39, 95% CI: 1.16–1.68), obesity (OR = 1.35, 95% CI: 1.16–1.57), metabolic liver disease (OR = 1.56, 95% CI: 1.18–2.07), metabolic syndrome (OR = 1.58, 95% CI: 1.32–1.89), and dyslipidemia (OR = 1.18, 95% CI: 1.02–1.37). This study reveals a significant positive association between OPFR exposure and metabolic disease risk, with distinct dose-response patterns identified across various OPFR congeners. This highlights OPFRs as critical environmental risk factors and underscores the public health risks they pose.
Next-generation broad-spectrum reactivators for effective countermeasure against organophosphorus poisoning.
Zdarova Karasova J, Hrabinova M, Dlabkova A … +20 more , Hepnarova V, Zivna N, Schmidt M, Sheshko V, Torruellas C, Opravil J, Prchal L, Vanova N, Fibigar J, Vecera Z, Kucera T, Chladek J, Horn G, Worek F, Marek J, Pejchal J, Jun D, Soukup O, Korabecny J, Gorecki L
Arch Toxicol · 2026 Jun · PMID 41838063 · Full text
Sustained effort has been dedicated to the development of novel cholinesterase reactivators-the only causal antidotes-to counter organophosphorus (OP) intoxication. As more lethal nerve agents-such as A-agents-continue t...
Sustained effort has been dedicated to the development of novel cholinesterase reactivators-the only causal antidotes-to counter organophosphorus (OP) intoxication. As more lethal nerve agents-such as A-agents-continue to emerge, the existing arsenal of causal antidotes remains unchanged. Approved oxime reactivators-2-PAM, HI-6, and LüH-6-are restricted by their limited efficacy spectrum, poor blood-brain barrier permeability, and suboptimal pharmacokinetics. The objective of this study is to design, synthesize, and characterize a new class of asymmetric monoquaternary bisoxime reactivators with broad-spectrum reactivation potential, favorable pharmacokinetics, and dual mechanisms of action-cholinesterase reactivation and direct OP compound degradation. In vitro and in vivo experiments identified LG-1795 as the lead candidate with the broadest OP spectrum. The averaged second-order reactivation constant (k) across five hAChE-OP and two hBChE-OP complexes was 16.8 mM min, surpassing clinical standards. Notably, LG-1795 reactivated both AChE and BChE, a dual activity not previously reported for reactivators. In vivo, LG-1795 restored both cholinesterase enzymes and demonstrated prophylactic efficacy against GB, VX, and PXE following intramuscular administration, preventing symptoms in sarin-poisoned animals. These findings represent a significant advance in antidotal therapy, providing the first evidence that asymmetric monoquaternary bisoximes deliver broad-spectrum efficacy against nerve agents and pesticides while simultaneously targeting both OP-inhibited cholinesterases. The translational potential of LG-1795 supports its further preclinical development as a next-generation countermeasure for both clinical and regulatory use in chemical defense.
Long noncoding RNAs at the crossroads of smoking, oxidative stress, inflammation, and lung disease.
Blumenfeld H, Besaratinia A, Tommasi S
Arch Toxicol · 2026 May · PMID 41838062 · Publisher ↗
Cigarette smoking is a well-recognized risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer, but the underlying molecular mechanisms remain the subject of intense investigation. A large body of ev...
Cigarette smoking is a well-recognized risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer, but the underlying molecular mechanisms remain the subject of intense investigation. A large body of evidence has shown the role of long noncoding RNAs (lncRNAs) in the pathogenesis of smoke-related diseases. LncRNAs are > 200 nt-long functional transcripts with limited protein-coding potential, which are emerging as critical regulators of gene expression in a variety of biological processes. Exposure to cigarette smoke (CS) is known to cause widespread dysregulation of lncRNAs in lung tissues and immune cells, thus leading to disruption of cell homeostasis, and induction of oxidative stress and chronic inflammation. This review article discusses the interplay of lncRNAs, smoking, oxidative stress, immune response, and lung disease. First, we provide an overview of the functions and modes of action of lncRNAs in the regulation of gene expression at the epigenetic, transcriptional, and post-transcriptional levels. We then examine the different mechanisms by which tobacco-induced dysregulation of lncRNAs contributes to oxidative stress, chronic inflammation, and disease pathogenesis, while focusing on COPD and lung cancer. Finally, we highlight the importance of extending lncRNA research to new and emerging tobacco products and discuss the promises and pitfalls of lncRNAs as predictive biomarkers and prognostic targets. Understanding the intricate roles of lncRNAs in the pathogenesis of COPD and lung cancer can provide new avenues for advancing diagnostic tools and therapeutic strategies in the fight against these devastating smoke-associated diseases.
Integrated transcriptomic and variant analysis reveals molecular mechanisms of pyrethroid resistance in a genetically homogenized Cas9 strain of Aedes aegypti.
Brown D, Houck R, Liu N
Arch Toxicol · 2026 Jun · PMID 41838061 · Full text
Insecticide resistance, a central problem in insecticide toxicology, in Aedes aegypti continues to undermine vector control efforts worldwide. Although transcriptomic studies have identified numerous resistance-associate...
Insecticide resistance, a central problem in insecticide toxicology, in Aedes aegypti continues to undermine vector control efforts worldwide. Although transcriptomic studies have identified numerous resistance-associated genes, differences in genetic background between resistant and susceptible strains often obscure which changes are directly linked to resistance. To reduce background variability, we generated a genetically homogenized pyrethroid-resistant Cas9 strain (PRCas9) by repeatedly backcrossing a susceptible Cas9 strain (exu-Cas9 line) with a highly permethrin-resistant Puerto Rico (PR) strain. PRCas9 retained extreme resistance comparable to the parental PR strain (> 18,000-fold resistance ratio) and was further analyzed alongside the PR and Cas9 strains using RNA-seq. Using this controlled genetic background, transcriptomic profiling identified > 70 differentially expressed genes between resistant and susceptible mosquitoes, revealing reproducible resistance-associated detoxification in insecticide toxicology signatures dominated by cytochrome P450s and carboxylesterases. qRT-PCR validated elevated expression of key detoxification candidates. Variant and promoter sequencing further revealed unique SNPs in detoxification genes, including CYP9J23, CYP9J28, and venom carboxylesterase-6, as well as distinct variants in NOX4-art, a NADPH oxidase involved in reactive oxygen species (ROS) production. Gene ontology analysis supported enrichment of detoxification-related molecular functions. Increased NOX4-art expression, together with these regulatory variants, suggests a potential role for ROS-linked regulatory pathways in coordinating detoxification gene activation. This study demonstrates the value of a genetically homogenized resistant Cas9 background for dissecting resistance mechanisms while identifying candidate genes and regulatory elements contributing to pyrethroid resistance. PRCas9 provides a powerful platform for future CRISPR-based functional analyses in insect toxicology aimed at improving vector control strategies.
Critical appraisal of animal studies assessing risk of heated tobacco products: a systematic review.
Liu X, Tayyarah R, Liu S
Arch Toxicol · 2026 Jun · PMID 41838060 · Publisher ↗
Heated tobacco products (HTPs) are promoted as reduced-risk alternatives to conventional cigarettes due to their heating-based aerosol generation, yet inconsistencies in animal study outcomes-such as divergent findings i...
Heated tobacco products (HTPs) are promoted as reduced-risk alternatives to conventional cigarettes due to their heating-based aerosol generation, yet inconsistencies in animal study outcomes-such as divergent findings in respiratory versus cardiovascular toxicity-and variability in experimental designs (e.g., exposure modes and dose markers) complicate regulatory assessments. This systematic review addressed this gap by conducting a SYRCLE-compliant evaluation of 48 animal studies identified through a comprehensive search of PubMed, Medline, Scopus, Web of Science, and Google Scholar through July 2024. Results indicated that 28 studies supported reduced toxicological effects of HTPs compared to cigarettes (e.g., mitigated lung histopathology and inflammation), while 20 studies highlighted persistent safety concerns, including adverse effects relative to the air control (e.g., alveolar apoptosis and testicular damage). Although switching to HTPs reduced cigarette-related toxicity, inherent risks and methodological limitations preclude definitive safety claims. Consequently, high-quality, independent studies expanding to multi-organ endpoints and diverse models are urgently needed to inform evidence-based regulation.
Cadmium causes osteoporosis by osteogenic differentiation inhibition via miR-155/SMAD5 pathway: evidence from in vivo and in vitro studies.
Mo L, Mo L, Hu Y … +7 more , Wan S, Zhou M, Zhu W, Yang G, Wei Q, Song J, Yang X
Arch Toxicol · 2026 Jun · PMID 41838059 · Publisher ↗
Cadmium (Cd) exposure causes osteoporosis by primarily inhibiting osteogenic differentiation. However, the specific epigenetic mechanisms, particularly the role of miRNAs, remain to be elucidated. Here, our study reveals...
Cadmium (Cd) exposure causes osteoporosis by primarily inhibiting osteogenic differentiation. However, the specific epigenetic mechanisms, particularly the role of miRNAs, remain to be elucidated. Here, our study reveals the critical function of the miR-155/SMAD5 axis in this pathological process. In vivo, female Sprague–Dawley rats were randomly assigned to four groups and treated for 16 weeks: control, 25, 50, and 100 mg/L cadmium chloride (CdCl2). In vitro, primary bone marrow mesenchymal stem cells (BMSCs) from rats were treated with 0, 25, 50, 100 mg/L CdCl2, and 0, 0.46, 0.92 mg/L CdCl2 for primary human BMSCs (hBMSCs). We demonstrated that Cd exposure induced a dose-dependent trabecular bone damage and reduced serum bone formation markers in rats. Cd suppressed osteogenic differentiation in both BMSCs and hBMSCs, as evidenced by inhibited calcium nodules formation and downregulation of the bone formation markers (Runx2, ALP, and Osterix). Mechanistically, we discovered that miR-155 expression was significantly upregulated, accompanied by the downregulation of its target, Smad5, both in vivo and in vitro. Notably, the miR-155 inhibitor effectively rescued Cd-induced impairments by restoring SMAD5 expression, enhancing ALP activity, and promoting calcium nodule formation. In conclusion, our findings revealed a novel mechanism by which Cd inhibited osteogenic differentiation via the miR-155/SMAD5 pathway, providing new insights into epigenetic regulation of Cd-induced osteoporosis and potential therapeutic targets for controlling Cd-related bone damage.
Hepatotoxicity of chlorinated organophosphate flame retardants (Cl-OPFRs): a comprehensive review.
Wang X, Li R, Liu W … +3 more , Song M, Zeng T, Zhang C
Arch Toxicol · 2026 Jun · PMID 41838058 · Publisher ↗
As the primary alternatives to brominated flame retardants, chlorinated organophosphorus flame retardants (Cl-OPFRs) have seen surging production and usage. Consequently, they are now widely distributed and persistent in...
As the primary alternatives to brominated flame retardants, chlorinated organophosphorus flame retardants (Cl-OPFRs) have seen surging production and usage. Consequently, they are now widely distributed and persistent in indoor dust, air, water, and food. These pollutants accumulate in human samples and pose significant hazards to living organisms, with increasing evidence identifying the liver as the main target organ. This paper systematically summarises current progress regarding the absorption and metabolic fate of Cl-OPFRs and reviews their hepatic effects. We propose that Cl-OPFRs induce liver damage through multiple pathways: oxidative stress, inflammatory responses, lipid metabolism disruption, mitochondrial dysfunction, gut-liver axis disruption, cell cycle arrest, and apoptosis. Importantly, these mechanisms function synergistically rather than in isolation. Core drivers, particularly oxidative stress and mitochondrial dysfunction, engage in complex interactions that form positive feedback loops, collectively amplifying liver injury. Despite these advances, current research is constrained by the discrepancy between high-dose experimental models and real-world exposures, as well as limited metabolite data. Future research should prioritise environmentally relevant chronic models and investigate non-apoptotic cell death (e.g., ferroptosis), sex-specific vulnerabilities, and metabolite toxicity. In conclusion, this review provides an outlook for future research and offers scientific evidence to support the rational application of Cl-OPFRs and the mitigation of their environmental health risks.
Simple, robust and near optimal designs for the estimation of log-logistic dose response functions.
Holland-Letz T, Kopp-Schneider A
Arch Toxicol · 2026 Jun · PMID 41807795 · Full text
Experimental designs in dose response experiments often use simple setups where the dose levels are increased by a fixed factor on the log scale. More efficient or even formally optimal experimental designs exist for thi...
Experimental designs in dose response experiments often use simple setups where the dose levels are increased by a fixed factor on the log scale. More efficient or even formally optimal experimental designs exist for this context, but these are often unpopular among applied scientists as they usually depend on the true value of some of the parameters and also frequently propose using only a small number of distinct dose levels. On the other hand, more generally optimal designs such as quasi-bayesian designs are often quite complicated, and still require specifying an a-priori distribution of parameters. In this paper we propose a single graphical representation which shows the performance of any given experimental design under a wide range of possible parameters. Using this representation, we propose four different possible designs which are both simple and still provide reasonable efficiency under many parameter constellations, without needing anything but the most coarse prior knowledge about these parameters. Specifically, our recommended design proposes 10 different dose levels in total, 8 main doses spaced equally around the most likely ED50 value, exactly one natural log step apart, and one more set of observations each under control, and under the maximum technically feasible dose. The available observations should be distributed among these dose levels so that each of the main dose levels is assigned roughly [Formula: see text] of the observations, while control and maxdose are assigned roughly [Formula: see text] of the observations, rounding when necessary.
Prediction of human exposure and first-pass metabolism of the fungicide trifloxystrobin using an in vitro intestinal pancreatin and Caco-2/HT29-MTX model.
Hallscheidt E, Bothe K, Hahn M … +3 more , Hartmann K, Thevis M, Lamshoeft M
Arch Toxicol · 2026 Jun · PMID 41807794 · Full text
Conducting toxicological risk assessment of agrochemicals for human health and safety lacks human data and is predominantly based on experimental data obtained from in vivo animal studies. In alignment with the 3R approa...
Conducting toxicological risk assessment of agrochemicals for human health and safety lacks human data and is predominantly based on experimental data obtained from in vivo animal studies. In alignment with the 3R approach (reduce, refine, replace animal testing) and in support of advancing next generation risk assessment of pesticides for human safety, there is a growing demand of implementing new approach methodologies. Therefore, the fungicide trifloxystrobin was investigated concerning human exposure and intestinal first-pass metabolism for the first time using intestinal new approach methodologies. Simulated intestinal fluid containing pancreatin, along with an optimized static in vitro human gut-model (Caco-2/HT29-MTX cell barriers), were established to study the radiolabeled fungicide. A single dose of 10 µM was applied to the in vitro systems, resembling an estimated exposure to humans upon oral uptake from food and feed crops. Trifloxystrobin underwent mainly phase I metabolism to its carboxylic acid metabolite, before entering the systemic circulation consistent with findings from in vivo studies with rodents. The results agree with published in vivo and in vitro data and indicate that the carboxylic acid metabolite is a primary metabolite formed before hepatic phase II conjugation. Moreover, minimal passage through the in vitro gut barriers, facilitated by extensive metabolism indicated low oral bioavailability in humans. The presented in vitro methodologies provide valuable insights into the interplay between human intestinal metabolism and oral bioavailability, exemplified by the active ingredient trifloxystrobin. Moreover, the opportunity of transferring the models to more complex microphysiological technologies such as organ-on-a-chip systems, represents an additional value of these models regarding future studies on oral absorption, metabolism, and organ interactions in vitro.
In vitro and in vivo metabolism of the synthetic cannabinoid FUB-144: comprehensive phase I and II profiling using UHPLC-HRMS.
Kim DE, Park J, Park YT … +5 more , Farzand S, Lee H, Kim J, Jung BH, Lee H
Arch Toxicol · 2026 Jun · PMID 41807793 · Publisher ↗
Synthetic cannabinoids (SCs), including FUB-144, are emerging psychoactive substances; however, a lack of metabolic information limits toxicological risk assessments. Owing to ethical constraints in obtaining human biolo...
Synthetic cannabinoids (SCs), including FUB-144, are emerging psychoactive substances; however, a lack of metabolic information limits toxicological risk assessments. Owing to ethical constraints in obtaining human biological samples, in vitro studies using human liver microsomes (HLMs) and animal experiments are essential to elucidate metabolic pathways. In this study, we investigated SC metabolism using HLM cultures treated with 30 µM FUB-144 and a mouse model orally administered 20 mg/kg FUB-144. Metabolites were analyzed by UHPLC-HRMS. In total, 12 phase I and 2 phase II metabolites were identified (referred to as M1–M14). Phase I metabolism was dominated by hydroxylation, primarily at the indole nucleus and tetramethyl cyclopropyl moiety, followed by secondary reactions, such as dehydrogenation and further oxidation. Phase II metabolism produced two glucuronide conjugates (M4 and M10), generated by conjugation at oxidized sites. The in vitro findings were largely consistent with in vivo data, as most metabolites observed in microsomal assays were confirmed in mouse serum and urine samples. Among these, M8—formed through sequential hydroxylation and oxidation—was sustained at relatively high concentrations for up to 24 h, suggesting its diagnostic value. A time-course analysis revealed a rapid decline of the parent compound in serum, paralleled by a pronounced rise in metabolites, indicating the fast metabolic turnover of FUB-144. Taken together, this study provides a comprehensive description of phase I and II metabolic pathways and establishes a critical foundation for toxicological and forensic monitoring of FUB-144.
Oxidative stress-mediated DNA fragmentation involved in STING-dependent apoptosis in human keratinocytes by 5-amino-2-methylphenol under ambient UVB exposure.
Kamar MD, Bala M, Dwivedi A … +1 more , Ray RS
Arch Toxicol · 2026 Jun · PMID 41807792 · Publisher ↗
Permanent hair dyes are widely used cosmetic products, but they can pose health risks due to their potential to cause DNA damage, inflammation, and allergic reactions. 5-Amino-2-methylphenol (5AMP), a widely used coupler...
Permanent hair dyes are widely used cosmetic products, but they can pose health risks due to their potential to cause DNA damage, inflammation, and allergic reactions. 5-Amino-2-methylphenol (5AMP), a widely used coupler with documented skin sensitization, absorbs UVB, but its photochemical behaviour is insufficiently characterized and remains unassessed in regulatory phototoxicity reports. Preliminary data showed that 5AMP undergoes UVB-induced photodegradation, forming a new photoproduct confirmed by LC-MS/MS. Still, its potential to induce phototoxicity upon simultaneous skin contact and UV exposure remained unknown. We therefore investigated its phototoxicity and underlying mechanisms. In this study, we examined the phototoxic potential of 5AMP at two concentrations (5 and 10 µg/ml) in human keratinocytes under environmentally relevant UVB dose (0.018-2.16 J/cm). Photosensitized 5AMP generated superoxide anion radicals via a type-I photodynamic mechanism, resulting in increased intracellular and mitochondrial ROS. Oxidative stress induced by photosensitized 5AMP disrupted mitochondrial membrane potential and induced DNA damage, culminating in apoptosis. Pretreatment with NAC/SOD mitigated photosensitized 5AMP-induced apoptosis. Further investigation into the molecular mechanisms revealed that the upregulation of cGAS, STING, and downstream gene expression triggered IFNβ production. Treatment with H151, an inhibitor of STING, significantly reduces IFNβ expression and cell death, confirming its key role in the phototoxicity mechanism. Therefore, we conclude that oxidative stress and subsequent cGAS-STING activation play a key role in photosensitized 5AMP-induced apoptosis. These insights into the mechanisms uncovered a critical gap in the safety assessment of photolabile hair dye ingredients under environmental UVB/sunlight exposure and underscore the need for safer alternatives.
Single-cell transcriptomics reveals a differential response of human bronchial epithelial cell-types to cadmium chloride.
Abou Choucha F, Lopes Goncalves R, Hermet T … +13 more , Mille J, Guardini L, Benkhedher M, Lacoux C, Gautier-Isola M, Mograbi B, Roux J, Cottrez F, Mari B, Groux H, Pasquier C, Rezzonico R, Vassaux G
Arch Toxicol · 2026 Jun · PMID 41807791 · Publisher ↗
Exposure of cells or tissues to chemical compounds can be analyzed through transcriptomic signatures, which can be used to classify chemical agents. This information can also enrich Adverse Outcome Pathways (AOP). Transc...
Exposure of cells or tissues to chemical compounds can be analyzed through transcriptomic signatures, which can be used to classify chemical agents. This information can also enrich Adverse Outcome Pathways (AOP). Transcriptional signatures have generally been obtained using "bulk" analysis, by which the global gene expression pattern of an entire tissue is determined. Although this approach has been useful in toxicology, some information is lost, especially when tissues containing multiple cell types are considered. With the advent of single-cell transcriptomics (scRNA-seq), it is now possible to obtain higher resolution, cell type-specific responses in complex tissues. The aim of the present study was to evaluate the added value of scRNA-seq in analysis of the acute response of human bronchial epithelial cells grown at the air/liquid interface (ALI) to a known toxic compound, CdCl with well described transcriptional signatures of exposure. Fully differentiated mucocilliary epithelia obtained from three independent donors were exposed to 10 µM CdCl and scRNA-seq analysis was performed on a total of 18,255 cells to obtain cell type-specific signatures. Our results show that the contribution of each cell type to the overall transcriptomic bulk response varies. For example, the classical heavy metal detoxification response was only detected in multiciliated and secreting cells, while absent in basal cells. The data demonstrate that scRNA-seq provides high-resolution transcriptional signatures with unexpected features. This added information is likely to have implications for the refinement of AOPs and could serve as a basis for a new generation of tests in predictive toxicology.
Dietary folate supplementation modifies effects of arsenic exposure on DNA methylation profiles in sperm of mice expressing the human AS3MT.
Shang B, Douillet C, Hartwell H … +9 more , Miller M, Cable P, Shi Q, Zou F, Krupenko SA, Ideraabdullah FY, de Villena FP, Fry RC, Stýblo M
Arch Toxicol · 2026 Jun · PMID 41807790 · Publisher ↗
Folate is an essential nutrient that supports the formation of S-adenosyl methionine (SAM) in the pathway of one carbon metabolism. Dietary folate intake has been shown to affect the SAM-dependent methylation of diverse...
Folate is an essential nutrient that supports the formation of S-adenosyl methionine (SAM) in the pathway of one carbon metabolism. Dietary folate intake has been shown to affect the SAM-dependent methylation of diverse substrates, including DNA and inorganic arsenic (iAs). The methylation of iAs by arsenic methyltransferase (AS3MT) plays a key role iAs detoxification in both humans and mice. Our recent studies using wild-type C57BL/6N mice showed that preconception exposure to iAs resulted in heritable changes in DNA methylation in paternal sperm and differential expression of genes in tissues of the offspring that developed a diabetic phenotype. The goal of the present study was to determine if dietary folate can modify the iAs-induced differential methylation of DNA in sperm of male C57BL/6 mice expressing the human AS3MT and exhibiting a human-like pattern of iAs metabolism. Mice were fed folate deficient (FD, 0 mg folic acid/kg) or folate supplemented (FS, 10 mg folic acid/kg) diet for 6 weeks, followed by exposure to 0 (controls) or 400 ppb iAs (arsenite) in drinking water for 5 weeks while on the same types of diet. Reduced Representation Bisulfite Sequencing was used to identify CpG sites and genes that were differentially methylated in response to iAs exposure, followed by analysis of pathways enriched for these genes. Genes and pathways associated with cell morphology and function, and neural structure and function were the top pathways enriched by iAs exposure in both FD and FS mice. Notably, pathways associated with diabetes, regulation of insulin secretion and signaling were enriched for differentially methylated genes only in the sperm of iAs-exposed FS mice. These results suggest that folate intake modifies the effects of iAs exposure on DNA methylation in sperm of the humanized mice, providing strong rationale for studies that will examine the role of folate in modulation of adverse effects of preconception exposure to iAs.
Weathered plastic particles negatively affect mouse primary neurons and glial cells.
Shin HS, So YH, Lee DH … +6 more , Chang Y, Kim MJ, Joung D, Youn B, Lee EH, Jung EM
Arch Toxicol · 2026 Jun · PMID 41807789 · Publisher ↗
The global increase in plastics production has raised significant concerns regarding plastic waste in marine and terrestrial ecosystems and potential human health risks. Environmental weathering processes such as physica...
The global increase in plastics production has raised significant concerns regarding plastic waste in marine and terrestrial ecosystems and potential human health risks. Environmental weathering processes such as physical abrasion and ultraviolet (UV) irradiation cause plastic waste to fragment into tiny particles termed weathered nano- and microplastics (W-NMPs). Despite their potential human health hazards, W-NMPs are underinvestigated in terms of their effects, particularly on the central nervous system. We comparatively evaluated the effects of W-NMPs and plain NMPs (P-NMPs) synthesized for specific purposes on brain-derived cells in vitro. W-NMPs triggered apoptosis more robustly than P-NMPs in both primary neural progenitors and isolated oligodendrocyte progenitors, and significantly reduced cell proliferation in primary neural progenitors. We found that W-NMPs induced a more potent inflammatory response in isolated primary microglia than P-NMPs. In the neuron-glia co-culture model, W-NMPs also caused morphological changes in astrocytes. Finally, P-NMPs induced microglial cytotoxicity, but W-NMPs triggered a more vigorous inflammatory response in microglia than P-NMPs in the co-culture model. Our findings provide novel insights into the hazards of W-NMPs exposure to brain health.
Characterization of anti-fentanyl antibodies as antagonists of ultra-toxic, clinically relevant or endogenous opioids.
Endt F, Steinritz D, Amend N … +2 more , Gudermann T, Breit A
Arch Toxicol · 2026 Jun · PMID 41807788 · Full text
The ultra-potent synthetic opioid carfentanil acts lethally by potently activating µ opioid receptors (µOR). Treatment based on competitive antagonists is of limited use due to the ultra-high affinity of the carfentanil/...
The ultra-potent synthetic opioid carfentanil acts lethally by potently activating µ opioid receptors (µOR). Treatment based on competitive antagonists is of limited use due to the ultra-high affinity of the carfentanil/µOR complex. Thus, preventing formation of this complex by car neutralizing antibodies might be a promising alternative strategy. We tested nine antibodies raised against fentanyl (ab-fen) in receptor-ligand binding and receptor activation assays using µOR expressing HEK293 cells in the presence of fen or car. When high antibody concentrations (500 nM) were pre-incubated with opioids, seven ab-fen significantly inhibited fen binding to the µOR completely and four car binding up to 90 %. None of the tested antibodies affected remifentanil, morphine or endomorphine-1. Concentration-response curves revealed IC50-values of ab-fen between 25 and 74 nM against fentanyl and between 121 and 900 nM against carfentanil. Hill-slopes against fen were way above one (2.7–6.0), indicating extremely high positive cooperativity of ab-fen, which was not observed against carfentanil. Furthermore, low antibody concentrations (1.0 nM) enhanced fentanyl- and to a lesser extent carfentanil-induced µOR activation, indicating bi-functional actions of ab-fen. Moreover, when lethal carfentanil concentrations were first added to cells, ab-fen also disrupted the µOR/carfentanil complex with carfentanil still being present. Overall, ab-fen maybe able to stop and reverse carfentanil intoxications in vivo and their effects on opioid efficacy at low ab-fen concentrations suggest that they might be used in a new way to improve opioid-based pain therapy. Our findings might pave the way for future antibody development and refinement.
Neurodevelopmental effects of methylmercury (MeHg): a review of epidemiological points of departure (PoDs), toxicological reference values (TRVs), and key uncertainties in human health risk assessment.
Blechinger SR, Singh K, Afghan A … +1 more , Smith CA
Arch Toxicol · 2026 Jun · PMID 41807787 · Full text
The adverse neurological effects of methylmercury are well characterized in animal models and humans. Neurodevelopmental effects in infants and children following prenatal exposure to methylmercury have been the critical...
The adverse neurological effects of methylmercury are well characterized in animal models and humans. Neurodevelopmental effects in infants and children following prenatal exposure to methylmercury have been the critical endpoint used for many years in risk assessment for the derivation of toxicological reference values. Most risk assessments of methylmercury have continued to rely on the same epidemiological birth-cohorts from New Zealand, the Faroe Islands, and the Seychelles, in which neurodevelopmental effects of methylmercury were examined during the 1980s and 1990s. New epidemiological studies have since emerged, prompting several organizations to reassess whether current reference values remain protective. As these evaluations proceed, clarity on the basis for derivation of the existing values will be critical particularly if different toxicological reference values are recommended. This review summarizes the history, pivotal data, and methodologies used by different regulatory bodies and expert committees (US EPA, ATSDR, Health Canada, JECFA, and EFSA) to derive toxicological reference values for neurodevelopmental effects of prenatal methylmercury exposure. Although methodologies differed in the choice of points of departure, uncertainty factors, and dosimetry conversions, there is good agreement between the toxicological reference values derived by these organizations. Nonetheless, there remain important uncertainties and data gaps particularly related to how observational epidemiology data were used in derivation of the toxicological reference values. Discussion of these uncertainties should help inform future work on methylmercury and have broader implications for other chemical risk assessments relying on similar types of observational data.
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