Archives Of Toxicology[JOURNAL]
Sun
200 papers
Pesticide bioavailability, bioaccumulation, and bioconcentration in zebrafish: a critical review with emphasis on methodological inadequacies.
Pamanji R, Sivan G
Arch Toxicol · 2026 Apr · PMID 42047700 · Publisher ↗
Zebrafish (Danio rerio) have become the pre-eminent vertebrate model in aquatic ecotoxicology, yet the evidence base on pesticide bioavailability, bioaccumulation, and bioconcentration in this species is characterised by...
Zebrafish (Danio rerio) have become the pre-eminent vertebrate model in aquatic ecotoxicology, yet the evidence base on pesticide bioavailability, bioaccumulation, and bioconcentration in this species is characterised by profound methodological fragmentation that limits the derivation of reliable risk estimates. This review critically appraises the primary literature across five major pesticide classes, namely organophosphates, pyrethroids, organochlorines, triazole and succinate dehydrogenase inhibitor (SDHI) fungicides, and herbicides, and argues that the field's central limitation is not a deficit of primary studies but rather a systematic failure to implement methodological standards capable of generating internally consistent, cross-comparable toxicokinetic data. Bioconcentration factors (BCFs) in zebrafish span four orders of magnitude, from less than 2 for glyphosate to over 1300 for chlorfenapyr, with log Kow as the primary predictor; yet BCF values derived from embryo stages cannot be extrapolated to adults given the profound life-stage dependency of CYP450 metabolic capacity. A recurring pattern of nominal-concentration reporting, pure active-ingredient testing, single life-stage design, and single-compound exposure has generated a body of evidence that diverges systematically from real-world pesticide exposure conditions. Quantitative analysis of methodological bias reveals that biotransformation alone can reduce internal concentrations by 5- to 90-fold; sediment partitioning can confine pyrethroid bioavailability in the water column to as little as 0.07% of total added mass; and formulation adjuvants can redirect pesticide distribution entirely between water and sediment compartments. A cross-study quality assessment of the ten primary studies forming the evidence core of this review shows that the majority score 7 or below on a 10-point methodological adequacy scale, with no study simultaneously verifying concentrations, capturing tissue-specific BCFs, tracking metabolites, and incorporating realistic mixture or formulation conditions. This review provides the first integrated, methodologically-focused, quantitative synthesis of these issues in zebrafish, identifies five priority knowledge gaps, and proposes a minimum standards framework for future zebrafish pesticide bioaccumulation studies.
Quantifying milk yield-dependent aflatoxin B1-to-M1 transfer in dairy cows: a Bayesian consensus toxicokinetic model.
Moenning JL, Numata J
Arch Toxicol · 2026 Apr · PMID 42047699 · Publisher ↗
Aflatoxin B1 (AFB1) is a hepatocarcinogenic mycotoxin found in animal feed contaminated by mold from the genus Aspergillus. It can be transferred into food of animal origin, such as the milk of dairy cows, as the metabol...
Aflatoxin B1 (AFB1) is a hepatocarcinogenic mycotoxin found in animal feed contaminated by mold from the genus Aspergillus. It can be transferred into food of animal origin, such as the milk of dairy cows, as the metabolite aflatoxin M1 (AFM1), which has 10% of the potency of AFB1. A multitude of studies has been conducted over the last decades to quantify the transfer of AFB1 as AFM1 in milk. The transfer rates derived from these studies vary considerably, with one variability source being the different milk yields of the experimental animals. A simple deterministic model was developed in the past to predict the influence of milk yield on the transfer rate in a steady-state setting. Although that previous model could predict transfer, it lacked dynamic predictions and did not quantify uncertainty, as is necessary for risk analysis. In this work, we synthesized transfer data from 19 published controlled dairy cow feeding studies (AFB1 doses: 6.6-2800 µg/d up to a 20,000 µg single dose ; milk yields: 6.4-46.4 L/d) using a hierarchical Bayesian approach with a reparametrized two-compartment toxicokinetic model designed to overcome parameter correlations, capture between-study heterogeneity and quantify prediction uncertainty. The model communicates prediction uncertainty using milk yield-dependent credible intervals (CI) for concentration profiles in milk across studies. It predicts a median transfer rate of 0.41% (95% CI: 0.13-1.40%) at 5 L/d, increasing to a median of 3.05% (95% CI: 1.07-8.19%) at 50 L/d. The model can be used in risk assessment and risk management to quantitatively predict transfer including credible intervals.
Prenatal exposure to polystyrene nanoplastics impairs offspring fertility in mice by disrupting meiotic recombination and chromatin accessibility in oocytes.
Zhou X, Zhang D, Zhang L … +7 more , Wang S, Shen W, Ou XH, Wang G, Sun QY, Zhang F, Li W
Arch Toxicol · 2026 Apr · PMID 42047698 · Publisher ↗
Polystyrene nanoplastics (PS-NPs) are ubiquitous environmental contaminants capable of crossing the placental barrier, yet their impact on mammalian germline development and the reproductive potential of the subsequent g...
Polystyrene nanoplastics (PS-NPs) are ubiquitous environmental contaminants capable of crossing the placental barrier, yet their impact on mammalian germline development and the reproductive potential of the subsequent generation remains poorly understood. To elucidate the intergenerational effects of prenatal PS-NPs exposure on female offspring fertility and dissect the underlying molecular mechanisms governing oocyte meiotic defects, we established a mouse model of prenatal PS-NPs exposure by administering daily oral gavage of PS-NPs (10 mg/kg/day) and employed an integrative multi-omics strategy combining single-cell transcriptomics (scRNA-seq), chromatin accessibility profiling (scATAC-seq), and functional cellular assays. We demonstrate that prenatal exposure to PS-NPs induced a marked decline in the fertility of female offspring. At the cellular level, PS-NPs delayed meiotic prophase I progression and severely compromised homologous recombination. Mechanistically, PS-NPs disrupted the global chromatin accessibility and epigenetic homeostasis of oocytes. Specifically, we observed aberrant histone modifications, characterized by reduced acetylation and increased ubiquitination/SUMOylation, along with restricted chromatin accessibility at loci critical for meiotic axis assembly and recombination. Furthermore, we identified a distinct subpopulation of arrested zygotene oocytes undergoing apoptosis and autophagy driven by this chromatin dysregulation. Collectively, our findings uncover a novel epigenetic mechanism by which environmental nanoplastics impair meiotic integrity, highlighting chromatin remodeling as a vulnerable target of nanotoxicity, and provide critical insights into the long-term reproductive risks posed by plastic pollution.
Methoxyacetic acid exposure in rats induces N-butyrylglycinuria consistent with beta-oxidation impairment.
Sala S, Kadyrov J, Bernal A … +15 more , Castillo AM, Naraprasertkul P, Paesalasakul N, Bekanan P, Dhitsuwon I, Kulthawatsiri T, Masuda R, Sharma M, Phetcharaburanin J, Car BD, Contreras JIS, Lindon JC, Wist J, Nicholson JK, Holmes E
Arch Toxicol · 2026 Apr · PMID 42047697 · Publisher ↗
Methoxyacetic acid (MAA) is a testicular toxin that targets spermatocytes and round spermatids by disrupting mitochondrial function, leading to cellular energy depletion. Male Sprague-Dawley rats were given single oral d...
Methoxyacetic acid (MAA) is a testicular toxin that targets spermatocytes and round spermatids by disrupting mitochondrial function, leading to cellular energy depletion. Male Sprague-Dawley rats were given single oral doses of MAA (150 or 650 mg/kg), resulting in no mortality but transient toxicity signs and modest body weight effects, especially at the higher dose. Histopathology revealed dose- and time-dependent testicular damage, with selective germ cell necrosis by 48 h and extensive germ cell loss, spermatic giant cells, and epididymal inflammation observed in high-dose animals by 168 h. Metabolic analysis using high resolution 1H NMR spectroscopy and OPLS-DA identified elevated urinary excretion of N-butyryl glycine, a marker of mitochondrial dysfunction and impaired β-oxidation. The persistence of N-butyryl glycine and altered energy metabolites up to 168 h indicates sustained mitochondrial stress and disruption of ATP-dependent processes essential for spermatogenesis. Moreover, the close structural similarity between MAA and butyrate raises the possibility that MAA interacts directly with enzymes involved in butyryl-CoA turnover during the terminal steps of β-oxidation in rodents.
Methodological reflections on ortho-phthalaldehyde genotoxicity assessment with human ALI airway cultures and in vitro assays.
Wang J, Zhang M, Zhu Z
Arch Toxicol · 2026 Apr · PMID 42047696 · Publisher ↗
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In vitro evidence for estrogen receptor activity of selected phase II isoflavone metabolites.
Grgic D, Bella-Velidou D, Dellafiora L … +4 more , Soukup ST, Kulling SE, Varga E, Marko D
Arch Toxicol · 2026 Apr · PMID 42047695 · Publisher ↗
The health benefits of soy and soy derived foods are often attributed to their isoflavone (ISFs) content, known to include phytoestrogens. However, EFSA has concluded that there is insufficient scientific evidence to est...
The health benefits of soy and soy derived foods are often attributed to their isoflavone (ISFs) content, known to include phytoestrogens. However, EFSA has concluded that there is insufficient scientific evidence to establish a causal relationship between ISFs consumption and the proposed health claims. Although phase-II metabolites of ISFs are often considered as detoxified products with reduced estrogenic effects, recent studies indicate that ISFs metabolites may contribute and even enhance the biological activity of ISFs. However, current knowledge on phase-II metabolites of ISFs is limited, even though representing the major ISFs metabolites circulating in the bloodstreams in humans. This study investigates the role of phase-II metabolism in the biological activity of ISFs, focusing on estrogenicity and cytotoxicity in estrogen-sensitive Ishikawa cells (expressing estrogen receptors (ER) α and β). ISFs concentrations from 0.001 to 10 µM, with 1:10 dilution steps, were tested. Cleavage to parent compounds during incubation was also evaluated using high-performance liquid chromatography tandem mass spectrometry.The results showed that phase-II metabolites, particularly sulfates, can still exhibit estrogenic activity, challenging the general assumption that phase-II metabolism always leads to the inactivation of ISFs. In particular, at 10 µM daidzein-4'-sulfate exhibited a comparable estrogenic activity to daidzein at the same concentration, and genistein-7-sulfate exhibited estrogenic potential at higher concentrations. Molecular dynamics simulations revealed that genistein and its conjugates can stably interact with ERβ. This study highlights the importance of phase-II metabolism for ISFs activity and suggests that the sulfates formed should be examined more closely in further investigations.
In vitro models for testicular steroidogenesis: current status and future perspectives.
Řehůřková E, Bajard L, Sovadinová I
Arch Toxicol · 2026 Apr · PMID 42047694 · Publisher ↗
Testicular steroidogenesis is fundamental to male reproductive health, but its disruption by environmental and emerging chemicals remains insufficiently characterized due to limitations in existing test systems. Traditio...
Testicular steroidogenesis is fundamental to male reproductive health, but its disruption by environmental and emerging chemicals remains insufficiently characterized due to limitations in existing test systems. Traditional animal models pose ethical and logistical challenges, while the validated H295R assay-based on a female adrenal carcinoma cell line-fails to reflect male gonadal steroidogenesis. This review uses a semi-systematic approach to evaluate over 1500 studies employing in vitro models, including primary Leydig cells, Leydig cell lines, stem cell-derived Leydig-like cells, and advanced 3D testicular systems. We assess species origin, developmental relevance, culture conditions, and the extent to which these models replicate key steroidogenic pathways. Most models rely on rodent-derived, cancerous cell lines cultured in two-dimensional monolayers, with limited representation of human and immature Leydig cells. A targeted full-text analysis examined the effects of 23 reference chemicals on testosterone, progesterone, androstenedione, and estrogen levels across the H295R assay and eight testicular in vitro models. Forskolin, genistein, prochloraz, and ketoconazole showed consistent effects and may serve as promising reference compounds. However, data for most chemicals in testicular models are scarce or inconsistent-particularly for androstenedione and progesterone-underscoring the need for improved model standardization. We propose future directions to enhance predictive power, including the development of hormone-responsive, species- and stage-specific models cultured under hormone-controlled conditions. Such advances are essential to improve chemical safety assessment and facilitate regulatory acceptance of alternative test methods.
Functionalised thin multi-walled carbon nanotubes are less toxic to lung cells in vitro than their native counterparts.
Seidel C, Sébillaud S, Darne C … +5 more , Vigolo B, Emo M, Mascherin M, Cosnier F, Gaté L
Arch Toxicol · 2026 Apr · PMID 42047693 · Publisher ↗
Functionalisation of carbon nanotubes (CNTs), to make them more hydrophilic, is an essential step in their preparation for use in a wide range of industrial processes. The toxicological impact of these modifications has...
Functionalisation of carbon nanotubes (CNTs), to make them more hydrophilic, is an essential step in their preparation for use in a wide range of industrial processes. The toxicological impact of these modifications has been investigated. However, due to the diversity of experimental models used in studies, no consensus has yet been reached. Here, we studied the toxicity of multi-walled CNT (MWCNT) with or without hydroxyl or carboxyl functional groups in lung cell models-chosen due to the risk of inhalation exposure for employees during handling of nanomaterials. In this study, we investigated the induction of the epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells BEAS-2B following 6 weeks of treatment with MWCNTs ranging from 0.125 to 1 µg/cm. Epithelial and mesenchymal markers were modified following MWCNT treatment, confirming the induction of the EMT. The effect was more pronounced with non-functionalised MWCNTs than with functionalised ones. In the lung carcinoma cell line A549, IL-8 expression was measured following treatment for 24 h to 0.5-10 µg/cm MWCNTs. An equal to or lower level was observed after treatment with functionalised MWCNTs than non-functionalised MWCNTs. Finally, the rat alveolar macrophage cell line NR8383 were exposed to 0.125-10 µg/cm to MWCNTs for 24 h. Non-functionalised MWCNTs led to a higher proportion of binucleation than exposure to their functionalised counterparts. Functionalised MWCNTs induce toxicity in lung cell lines to a lower extent than non-functionalised MWCNTs. Because of this toxicity, all MWCNTs should be handled with care regardless of their functionalisation.
Immunomodulatory potential of Alternaria mycotoxins on immune and intestinal cells: a comparative systematic in vitro study.
Partsch V, Selimagić A, Crudo F … +1 more , Marko D
Arch Toxicol · 2026 Apr · PMID 42047692 · Publisher ↗
Alternaria species produce structurally diverse mycotoxins that frequently contaminate food and are discussed in association with adverse health effects. However, systematic knowledge of their immunosuppressive potential...
Alternaria species produce structurally diverse mycotoxins that frequently contaminate food and are discussed in association with adverse health effects. However, systematic knowledge of their immunosuppressive potential is limited. This study evaluated seven Alternaria mycotoxins-alternariol (AOH), alternariol monomethyl ether (AME), altenuene (ALT), alterperylenol (ALTP), altertoxin I (ATX-I), altersetin (AST), and tentoxin (TEN)-in immune and intestinal cells. NF-κB reporter gene assays were performed in THP-1 monocytes and phorbol 12-myristate 13-acetate-differentiated macrophages (0.01-25 µM), while cytokine transcription and secretion (IL-6, IL-8, IL-10, TNF-α) were analyzed in Caco-2 and HCEC-1CT cells (0.1–30 µM) applying qRT-PCR and ELISA. All mycotoxins suppressed NF-κB activation in immune cells, though with differing potency. AOH, ALTP, and ATX-I were active at concentrations ≥ 1 µM in both models. AME and AST were more potent in macrophages (≥ 0.01 µM) than monocytes (≥ 5 µM). TEN suppressed the pathway at ≥ 0.1 µM in macrophages and ≥ 5 µM in monocytes, while ALT at ≥ 5 µM in both cell types. In intestinal models, AOH, AME, ALTP, ATX-I, and TEN modulated cytokine transcription, with stronger responses in non-tumorigenic HCEC-1CT cells. ALTP emerged as the most potent immunosuppressive compound, reducing IL-6, IL-8, and/or TNF-α secretion at concentrations ≥ 0.1 µM. AOH showed dual activity, suppressing IL-6/IL-8 at 30 µM, while modulating TNF-α in a cell-type-dependent manner (increased secretion in Caco-2, decreased in HCEC-1CT). This comparative study reveals immunosuppressive profiles of Alternaria mycotoxins in immune and epithelial cells, highlighting their relevance as food contaminants capable of modulating both intestinal and systemic immune responses.
Exposure to per- and polyfluoroalkyl substances (PFAS) and development of autoimmunity in humans and animals: a scoping review.
Holm-Larsen CE, Siggaard LWL, Sander SD … +2 more , Østengaard L, Husby S
Arch Toxicol · 2026 Jul · PMID 42034718 · Full text
PFAS are a group of persistent organic pollutants, that bioaccumulate and are associated with negative health effects. Reviews have suggested that the most critical effects of PFAS are on the immune system, but little is...
PFAS are a group of persistent organic pollutants, that bioaccumulate and are associated with negative health effects. Reviews have suggested that the most critical effects of PFAS are on the immune system, but little is known of effects on development of autoimmunity. Our objective was to map and summarize available evidence concerning exposure to any PFAS and development/presence of autoimmunity, in humans and animals. We assessed studies reporting potential associations between PFAS exposure and autoimmune disease and/or autoantibodies. We searched MEDLINE, Embase, CENTRAL, Scopus, and Web of Science (02.15.2024) and conducted complimentary searches. Results were presented descriptively and we categorized autoimmune diseases and autoantibodies into relevant outcome groups. 51 studies were included, distributed in the following groups: Autoimmune thyroid disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, celiac disease, other diseases and autoantibodies. Cross-sectional studies were most common, limiting opportunities for causal inference. 33 studies showed associations between higher PFAS and increased risk of autoimmunity, while nine studies found lower PFAS associated with increased autoimmunity risk. The results suggest that PFAS have negative health impacts with strongest evidence for celiac and inflammatory bowel disease, weaker evidence for rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes mellitus. No clear indications of association with autoimmune thyroid disease. The majority of the studies showed an association between PFAS and autoimmunity. There is a need for more longitudinal and dose-response studies, to improve our understanding of individual autoimmunity outcomes in the future.Protocol registration: OSF.io ( https://doi.org/10.17605/OSF.IO/3FEVQ ).
Fatal intoxications with nitazenes: postmortem findings, toxicology, and in vitro characterization at the μ-opioid receptor of six nitazene analogues.
Truver MT, Roman M, Gomonit MM … +3 more , Gréen H, Kronstrand R, Persson M
Arch Toxicol · 2026 Jul · PMID 42034717 · Publisher ↗
Nitazenes constitute a structurally diverse class of non-fentanyl synthetic opioids that have rapidly emerged in the European illicit drug market since 2019. Bridging analytical, seized drug epidemiology, and interpretat...
Nitazenes constitute a structurally diverse class of non-fentanyl synthetic opioids that have rapidly emerged in the European illicit drug market since 2019. Bridging analytical, seized drug epidemiology, and interpretative gaps would support meaningful interpretation of nitazene-related deaths. This study presents a fit-for-purpose LC-MS/MS method for the quantitation of six nitazenes, etazene, isotonitazene, N-pyrrolidino isotonitazene, metonitazene, N-pyrrolidino metonitazene, and protonitazene in postmortem blood. The method was applied to analyze 57 nitazene-positive autopsy cases received between December 2020 and December 2024 by the Swedish National Board of Forensic Medicine. During this period, metonitazene (n = 38) and protonitazene (n = 10) were the most encountered nitazenes, with femoral blood concentrations in mono-intoxicated cases ranging from 0.3 to 34 ng/g and 1.7 to 4.9 ng/g respectively. Complementary in vitro MOR activation studies using AequoScreen® assays demonstrated that these nitazenes possess potencies (0.17-6.0 nM) and efficacies comparable to, or exceeding, those of fentanyl. The predominance of metonitazene prompted further investigation into its metabolism and stability profile, where analysis of authentic postmortem cases indicated the presence of three possible metabolites (N-desethyl, acetamido, 5-amino metonitazene) alongside other amino-containing degradation products. Further studies elucidating true metabolites from postmortem or storage-related breakdown products would support interpretation of nitazene exposure in casework. These findings provide an overview of nitazenes in Swedish forensic casework and address a critical gap in region-specific data, underscoring the need for sustained analytical vigilance and proactive toxicovigilance strategies to ensure timely detection and accurate interpretation of nitazene-related mortalities in an evolving drug landscape.
Effect biomonitoring in a controlled firefighting setting: an untargeted metabolomic pilot study.
Boehler MP, Kersch C, Rossbach B … +2 more , Kaifie A, Schmitz-Spanke S
Arch Toxicol · 2026 Jul · PMID 42034716 · Full text
Exposure biomonitoring is limited to quantifying the internal dose of specific contaminants. However, it fails to capture the complex total biological burden comprising chemical mixtures (such as fire emissions) and phys...
Exposure biomonitoring is limited to quantifying the internal dose of specific contaminants. However, it fails to capture the complex total biological burden comprising chemical mixtures (such as fire emissions) and physical and psychological stress. Effect biomonitoring, particularly using untargeted metabolomics, is required to comprehensively assess the systemic health effects of these complex exposures. This pilot study aimed to identify metabolic changes by analyzing urine samples collected from two individual firefighters before and after two controlled training scenarios. One scenario measured physical stress (using respiratory protection only), while the other measured additional smoke exposure (using a controlled fire). Samples were derived from an established exposure biomonitoring study which confirmed relevant additional exposure for 10 polycyclic aromatic hydrocarbons (PAHs) in the fire scenario despite protective gear. Urinary metabolites were extracted and analyzed using untargeted gas chromatography-mass spectrometry, followed by data analysis using MetaboAnalyst and R software. 79 human metabolites were identified. Principal component analysis showed a clear separation of the metabolic profiles. A t-test identified four metabolites specifically and significantly regulated by fire exposure: a decrease in catechol and 3-hydroxyphenylacetic acid, and an increase in 5-hydroxy-L-tryptophan and serotonin. Pathway analysis confirmed that the tryptophan and catecholamine pathways were primarily impacted. The observed metabolic changes indicate a significant systemic stress response and biological effect caused by fire exposure. Although metabolic changes indicate biological effects, the study conditions do not allow for distinguishing between toxicological and non-toxicological stressors (i.e. heat). The study demonstrates the potential of urinary metabolomics as a non-invasive method for supplementing effect biomonitoring for firefighters.
Mechanistic insights into PFAS-induced effects on B lymphocyte activation and antibody secretion.
Iulini M, Beekmann K, Hoogenboom RLAP … +7 more , Galbiati V, Russo G, Pappalardo F, Fragki S, Paini A, Corsini E, Janssen AWF
Arch Toxicol · 2026 Jul · PMID 42026241 · Full text
Per- and polyfluoroalkyl substances (PFASs) are man-made organofluoride chemicals widely present in the environment, with exposure associated to various adverse health effects, including immunotoxicity. Recently, we show...
Per- and polyfluoroalkyl substances (PFASs) are man-made organofluoride chemicals widely present in the environment, with exposure associated to various adverse health effects, including immunotoxicity. Recently, we showed that PFASs can directly impair antibody production, leading to decreased immunoglobulin (Ig) M and IgG release in human peripheral blood mononuclear cells (PBMCs) obtained from both male and female healthy donors. However, the underlying molecular mechanisms remain largely unknown. In this study, we aimed to address this gap by performing RNA sequencing to identify pathways and genes potentially involved in the observed immunotoxic effects. PBMCs were exposed to selected PFASs for 24 h, and to assess effects on antibody secretion, a subset was subsequently stimulated with CpG oligodeoxynucleotide ODN2006 and rhIL-2 for an additional six days. Transcriptomic analysis indicated activation of the glucocorticoid receptor (GR) and associated signaling pathways, supported by the upregulation of several GR-target genes and the prediction of glucocorticoids or the GR agonist dexamethasone as upstream regulators in Ingenuity Pathway Analysis. Moreover, the inhibitory effects of PFASs on antibody secretion were shown to be reversable by the GR antagonist Mifepristone, supporting the involvement of the GR in PFAS-mediated suppression of antibody secretion. Overall, this research advances our understanding of PFAS-induced immunotoxicity and identifies potential biomarkers for evaluating PFAS exposure and its associated health effects.
AHAK: a new effective medical countermeasure against percutaneous intoxication by Novichok chemical warfare agents.
Nili U, Nahum V, Smolkin B … +2 more , Ashkenazi N, Bloch-Shilderman E
Arch Toxicol · 2026 Jul · PMID 42010129 · Full text
Novichoks are the latest known and most toxic class of organophosphorus chemical warfare agents (OP CWAs) to have been developed. Among the documented Novichoks, A-232 is the most toxic and most potent inhibitor of AChE,...
Novichoks are the latest known and most toxic class of organophosphorus chemical warfare agents (OP CWAs) to have been developed. Among the documented Novichoks, A-232 is the most toxic and most potent inhibitor of AChE, as well as the most resistant to reactivation by oximes, and thus likely the most challenging to treat. Here we characterize the intoxication following dermal exposure to the Novichok A-232 in swine, and describe a novel countermeasure against it. Our results demonstrate that percutaneous poisoning by a lethal dose of A-232 (2 mg/kg) is characterized by slow appearance and exacerbation of intoxication signs. We further show that conventional antidotal treatment against such poisoning, administered upon appearance of intoxication signs, provides only temporary relief after which intoxication signs reoccur, and that further repeated such treatment is not sufficient to enable survival. The above likely stem from formation of a dermal depot of A-232 from which the agent slowly penetrates into the bloodstream, coupled with its resistance to reactivation by oximes. Accordingly, we developed the AHAK lotion (potassium acetohydroxamate in DMSO/HO, derived from the FDA approved medication acetohydroxamic acid (AHA)), intended to act as a 'catch-up therapy' enabling both skin surface and intradermal decomposition of persistent low-volatility OP CWAs. We demonstrate that combining conventional antidotal treatment with dermal application of AHAK following percutaneous poisoning by a lethal dose of A-232, leads to survival of all animals. Additionally, using a low dose (0.33-0.41 mg/kg) of A-232, we show that AHAK is expected to exert a beneficial effect also following late application. Hence, the results of the current study, coupled with our previous results regarding the contribution of AHAK to countering percutaneous intoxication by VX and the safety of prolonged whole-body application of AHAK, delineate the aptness of AHAK to serve as a generic medical countermeasure against percutaneous intoxication by persistent low-volatility OP CWAs, of both the V and Novichok families.
Navigating through toxicological data: review of toxicological databases and sources in the interdisciplinary context including-chemicals, cosmetics, pharmaceuticals and forensics.
Jurowski K, Niżnik Ł, Noga M … +5 more , Kobylarz D, Frydrych A, Fijałkowska O, Nepovimova E, Kuca K
Arch Toxicol · 2026 Jul · PMID 42010128 · Full text
UNLABELLED: Toxicology, an interdisciplinary and critical field in environmental and public health safety, is based heavily on the comprehensive analysis and application of toxicological data. This review addresses the u...
UNLABELLED: Toxicology, an interdisciplinary and critical field in environmental and public health safety, is based heavily on the comprehensive analysis and application of toxicological data. This review addresses the use and visibility of toxicological databases that are instrumental in the assessment of chemical risks and the information of regulatory decisions. Despite the critical nature of these databases, there is a notable gap in their effective use within the regulatory and scientific communities. Our systematic overview of existing toxicological databases highlights the significant resources available, including databases that consolidate vast amounts of chemical hazard, exposure, and risk assessment data. We categorise these databases based on their functionalities, discuss the challenges associated with their use, and propose solutions to enhance their accessibility and integration across different platforms. This review not only underscores the importance of these databases in shaping informed regulatory policies, but also sheds light on the need for improved standardisation and technological enhancements to maximise their potential. The findings aim to foster a deeper understanding among toxicologists, regulators, and policymakers, ultimately contributing to stronger and more effective public health protections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-026-04379-y.
Chemicals in plastics differentially affect the transcriptome of MCF-7 breast cancer cells.
Matteo G, Eickmeyer DC, Bradford LM … +6 more , Meier MJ, Williams A, Barton-Maclaren T, Corton JC, Yauk CL, Atlas E
Arch Toxicol · 2026 Jul · PMID 42010127 · Full text
Humans are exposed to chemicals that leach from plastics, yet many remain data-poor and lack toxicological evaluation. High-throughput transcriptomics (HTTr) provides a scalable way to screen chemicals and generate mecha...
Humans are exposed to chemicals that leach from plastics, yet many remain data-poor and lack toxicological evaluation. High-throughput transcriptomics (HTTr) provides a scalable way to screen chemicals and generate mechanistic insights relevant to human health risk assessment. We applied HTTr in MCF-7 breast cancer cells to assess chemicals across several concentrations (0.001-50 µM) used in plastics and dyes. Transcriptomic points of departure (tPODs) were derived from general gene perturbations, including pathway-level and estrogen receptor α (ERα)-specific changes. We also used transcriptomic biomarkers to evaluate ERα activity and cellular stress responses. Most plastic chemicals showed similar toxicological potency, with tPODs falling within one order of magnitude. Bisphenol K was the most potent, activating ERα at the lowest concentrations, followed by plastic additive 08 and bisphenol A (BPA). Despite similar overall potency, transcriptomic biomarkers revealed distinct mechanisms. Chemicals structurally similar to BPA activated ERα, whereas others with different functional groups inhibited the ERα biomarker. Pathway and upstream regulator analyses further indicated that BPA-like chemicals consistently perturbed ERα-related pathways, while other chemicals enriched fewer gene sets and often produced opposite directional responses. At the highest concentrations tested, several chemicals also activated stress-response biomarkers and suppressed proliferation. Overall, these results suggest that while many plastic chemicals exhibit comparable in vitro potency, they diverge in ERα regulation and downstream biological pathways. This study demonstrates the reproducibility and value of HTTr for chemical screening, supports grouping ERα-active plastic chemicals for read-across, and underscores the need for additional evaluation of plastic chemicals.
Novel endogenous protein-based strategies to inhibit clinically relevant bacterial AB-type toxins including pertussis toxin.
Lietz S, Barth H
Arch Toxicol · 2026 Jul · PMID 41991729 · Full text
Many highly infectious and severe diseases such as pertussis, diphtheria, anthrax, and infections are caused by bacteria which release symptom-inducing AB-type protein toxins. These diseases are treated using antibiotic...
Many highly infectious and severe diseases such as pertussis, diphtheria, anthrax, and infections are caused by bacteria which release symptom-inducing AB-type protein toxins. These diseases are treated using antibiotics or preventive measures including vaccination. However, despite preventive measures, increasing case numbers have been reported in past years. Therefore, novel therapeutic options against toxin-mediated disease are urgently required. Since the toxins are the causative agents of the diseases, the development of pharmacological inhibitors that specifically neutralize individual toxins should be a relevant strategy to further support the current therapies. Huge potential to identify toxin inhibitors lies within the human proteome/peptidome that might contain endogenous toxin inhibitors as yet unknown part of the innate immunity. Screening of human peptide libraries and systematic testing of proteins/peptides with antimicrobial activity led to the identification of proteins/peptides with specific anti-toxin activities. Consequently, defensins, α-antitrypsin and derived peptides, human serum albumin, and in silico predicted angiogenin-derived peptides were identified as potent inhibitors for bacterial toxins including toxins TcdA, TcdB and CDT, diphtheria, anthrax, and pertussis toxin, and clostridial binary iota and C2 toxins. This review summarizes the current state of identified endogenous proteins/peptides as novel inhibitors for clinically relevant bacterial AB-type toxins.
Therapeutically relevant rimonabant exposure drives epigenetic remodeling in neuronal cells and rat brain tissue.
Marques SI, de Moura MB, Panza F … +8 more , Pereira-Teixeira C, Stevanović V, Kovačević A, Savić MM, Carmo H, Sá SI, Carvalho F, Silva JP
Arch Toxicol · 2026 Jul · PMID 41991728 · Full text
Rimonabant (SR141716A), an inverse agonist of the cannabinoid receptor type 1 (CB), once approved for treating obesity and metabolic disorders, was withdrawn shortly after due to psychiatric and psychological adverse eve...
Rimonabant (SR141716A), an inverse agonist of the cannabinoid receptor type 1 (CB), once approved for treating obesity and metabolic disorders, was withdrawn shortly after due to psychiatric and psychological adverse events (PPAEs), including depression and suicidality. Although its primary pharmacological mechanism of action is well-characterized, the molecular basis underlying these neuropsychiatric effects remains unclear. Here, we investigated the epigenetic impact of rimonabant exposure, both in vitro and ex vivo, at therapeutically relevant concentrations and doses, with a focus on histone modifications and DNA methylation. In SH-SY5Y human neuroblastoma cells, after 24 and 96 h treatment with 0.01 and 1 µM rimonabant significantly increased global histone H3 and H4 acetylation by 2.7- and 1.4-fold, respectively, without altering global DNA methylation levels. The effects on histone acetylation were partially reversed by a CB receptor agonist, indicating a role for CB in the observed epigenetic modulation. Rimonabant also decreased histone deacetylases (HDAC) activity and reduced the levels of H3K4me3 and H3K27me3, marks that have been previously identified in psychiatric perturbations. Moreover, 4-week oral administration of 3 or 15 mg/kg rimonabant to rats produced region- and dose-specific alterations in H3K4me3, H3K27me3, H3K9ac, and 5-methylcytosine levels across the prefrontal cortex, hippocampus, and nucleus accumbens, in line with epigenetic profiles characteristic of depression, anxiety, and schizophrenia. Collectively, these findings demonstrate that rimonabant disrupts key epigenetic regulatory mechanisms in the brain and support the hypothesis that epigenetic dysregulation contributes to its psychiatric liabilities. This work strengthens the value of incorporating epigenetic endpoints into neuropharmacological safety assessments.
Multidimensional modeling reveals drivers of neonicotinoids penetration across the human blood-cerebrospinal fluid barrier.
Liu R, Shang J, Gao K … +3 more , Li W, Wang S, Lu L
Arch Toxicol · 2026 Jul · PMID 41991727 · Publisher ↗
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Aryl hydrocarbon receptor orchestrates transcriptomic, non-coding and splicing programs that drive human lung epithelial responses to vaporized cannabis in vitro.
Wilson ET, Eidelman DH, Baglole CJ
Arch Toxicol · 2026 Jul · PMID 41984095 · Publisher ↗
Cannabis vaping is increasingly consumed as an alternative to cannabis smoke, yet its health consequences remain poorly defined. Vaporization may reduce the formation of combustion-related toxicants, but emerging data su...
Cannabis vaping is increasingly consumed as an alternative to cannabis smoke, yet its health consequences remain poorly defined. Vaporization may reduce the formation of combustion-related toxicants, but emerging data suggest that cannabis vaping still elicits deleterious effects in respiratory epithelial cells. While the actions of cannabis are commonly attributed to cannabinoid receptors, other molecular targets such as the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, may play a role. In this study, we used wild-type (A549) and AhR-knockout (A549) human alveolar epithelial cells cultured at the air-liquid interface (ALI) to investigate whether AhR mediates the response to cannabis vapor. Cells were exposed using the expoCube to achieve THC levels of ~ 2 μg. Under basal conditions, AhR supported cell proliferation and regulated long non-coding RNAs (lncRNA) associated with cell cycle progression. Cannabis vapor exposure increased cell growth in an AhR-dependent manner. Transcriptomic profiling revealed that both protein-coding genes and lncRNA affiliated with cell cycle were upregulated in A549 but not in A549 cells, indicating AhR is required to promote the transcriptional response to cannabis vapor. The AhR also modulated alternative splicing events in response to cannabis vapor, with increased splicing alterations observed in A549 cells compared to A549 cells, signifying the AhR coordinates distinct post-transcriptional responses to cannabis vapor exposure. These results suggest a potential link between cannabis vapor exposure and oncogenic signaling, highlighting AhR as a molecular sentinel that shapes epithelial cell response to cannabis vapor through coordinated transcriptional and post-transcriptional regulation.
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