Archives Of Toxicology[JOURNAL]
Sun
200 papers
Regulatory mechanisms of microRNAs in reproductive toxicity induced by environmental pollutants: a mini review.
Chen Y, Huang X, Zhu G … +5 more , Xu T, Ran M, Chen W, Wang X, Lv Z
Arch Toxicol · 2026 Jun · PMID 41807786 · Publisher ↗
Environmental pollutants rise serious threats to human reproductive health, leading to disrupted gametogenesis, hormonal imbalance, and decreased fertility. Increasing evidence highlights microRNAs (miRNAs) as crucial po...
Environmental pollutants rise serious threats to human reproductive health, leading to disrupted gametogenesis, hormonal imbalance, and decreased fertility. Increasing evidence highlights microRNAs (miRNAs) as crucial post-transcriptional regulators mediating these toxic effects. miRNAs are small non-coding RNAs of about 22 nucleotides that regulate gene expression by binding to target messenger RNAs (mRNAs) to suppress translation or promote degradation, thereby influencing cellular processes such as proliferation, differentiation, apoptosis, and stress response. Recent studies have shown that environmental pollutants can significantly alter miRNA expression profiles, thereby modulating key molecular pathways involved in reproductive toxicity. Among the miRNAs identified, miR-199a-5p, miR-132-3p, miR-450b-3p, miR-21-5p, and miR-210-3p are most consistently dysregulated across various pollutant exposures. These miRNAs are implicated in signaling pathways including HIF-1/NF-κB, BCL2-CASPASE, Layilin-YAP, and TLR4/NLRP3, forming an interconnected regulatory network that governs apoptosis, inflammation, energy metabolism, and steroidogenesis. Collectively, these findings suggest that miRNA dysregulation represents a key epigenetic mechanism linking environmental exposure to adverse reproductive outcomes. Moreover, specific miRNAs may serve as sensitive biomarkers for pollutant exposure and early reproductive impairment. Further mechanistic and translational research is needed to clarify their regulatory roles and to inform preventive strategies aimed at reducing reproductive risks associated with environmental contaminants.
Characterization and quantitation of urinary metabolites of 3-monochloropropane-1,2-diol (3-MCPD) in rats.
Henning T, Goerdeler C, El-Khatib AH … +4 more , Meyer K, Bruer GG, Abraham K, Monien BH
Arch Toxicol · 2026 Jun · PMID 41807785 · Full text
Fatty acid esters of 3-monochloropropane-1,2-diol (3-MCPD) are heat-induced contaminants formed from fats and sodium chloride. The mode of action for the 3-MCPD mediated induction of renal tubule neoplasms in rats is sti...
Fatty acid esters of 3-monochloropropane-1,2-diol (3-MCPD) are heat-induced contaminants formed from fats and sodium chloride. The mode of action for the 3-MCPD mediated induction of renal tubule neoplasms in rats is still unclear, which is in part due to lacking metabolism data. In the current study, urinary metabolites were identified by one- and two-dimensional C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry following oral administration of 3-MCPD or [C]3-MCPD in rats. In addition to 3-MCPD itself, nine metabolites were identified. Four of those, N-acetyl-S-(2,3-dihydroxypropyl)cysteine (DHPMA), 3-MCPD sulfate, β-chlorolactic acid (β-ClLA) and oxalic acid have been reported before. Five novel metabolites in rat urine were thiodiglycolic acid (TDGA), thionyldiglycolic acid (TNDGA), 3-MCPD glucuronide (at least three isomers), 3-carboxy-2-hydroxypropyl mercapturic acid (CHPMA), and 3-(S-carboxymethyl)mercaptolactic acid (CMMLA). Only three metabolites were excreted at mean dose ratios > 1% (after treatment with 50 mg 3-MCPD/kg body weight in male and female rats), i.e. 3-MCPD (7.3%, 9.7%), DHPMA (3.5%, 1.7%) and TDGA (1.1%, 4.0%). The overall mean dose excretion in urine samples (males: 12.2%, females: 16.3%) supported hypotheses on formation of conjugates/adducts of reactive metabolites and the possibility that dechlorination leads to suitable building blocks for amino acid and fatty acid synthesis. The identification of TDGA indicated the interim formation 2-chloroacetaldehyde, previously identified to mediate specific nephrotoxic effects of the cytostatic ifosfamide in rats.
Differential endocrine and reproductive responses across generations: highlighting the need for holistic assessment in regulatory toxicology.
Manton JC, French JM, Schneider S … +2 more , Kluxen FM, Frericks M
Arch Toxicol · 2026 Jun · PMID 41807784 · Publisher ↗
In 2024, Bichlmaier published a retrospective statistical analysis of 112 Extended One-Generation Reproductive Toxicity Studies (EOGRTS), concluding that reproductive and endocrine effects rarely demonstrate cross-genera...
In 2024, Bichlmaier published a retrospective statistical analysis of 112 Extended One-Generation Reproductive Toxicity Studies (EOGRTS), concluding that reproductive and endocrine effects rarely demonstrate cross-generational continuity. He contended that findings limited to a single generation should be interpreted independently and need not exhibit generational consistency to be toxicologically relevant. We question the underlying premise that there is no biological plausibility for continuity as this conflicts with prevailing scientific and regulatory approaches that emphasise biological coherence and mechanistic relationship. The current review presents a re-analysis of the data used by Bichlmaier and critically examines the analytical framework used, considers established toxicological principles and regulatory standards and draws on the critiques presented by Arts et al. (Arch Toxicol 99:3047-3305, 2025). Through a comprehensive weight-of-evidence critique, we demonstrate that the analytical assumptions underpinning Bichlmaier's study fail to account for core principles such as adversity, dose-response relationships, effect magnitude, and mechanistic coherence, thereby undermining the utility of the findings for regulatory toxicology.
Rifabutin boosts rifampicin accumulation in THP-1-derived M2 macrophages by inhibiting P-glycoprotein efflux activity.
Hamburg K, Bay C, Burhenne J … +3 more , Weiss J, Stingl JC, Theile D
Arch Toxicol · 2026 Jun · PMID 41807783 · Full text
M2 macrophages show higher efflux activity of the P-glycoprotein (P-gp) drug transporter and lower rifampicin uptake than M1 macrophages. Accordingly, in M2 macrophages rifampicin accumulation should be restored by poten...
M2 macrophages show higher efflux activity of the P-glycoprotein (P-gp) drug transporter and lower rifampicin uptake than M1 macrophages. Accordingly, in M2 macrophages rifampicin accumulation should be restored by potent P-gp inhibitors such as rifabutin. THP-1 cells were differentiated (200 nM phorbol-12-myristate 13-acetate for 72 h) and polarized (20 ng/mL interleukin 4 and interleukin 13 for 48 h) to M2 macrophages. P-gp inhibition by rifabutin was assessed through flow cytometry using rhodamine 123 (substrate) and compared to zosuquidar (positive P-gp inhibitor control). Ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS/MS) was used to evaluate the cellular rifampicin accumulation after 2 h of exposure to 0.05, 0.1, or 0.5 µM rifampicin, with or without co-treatment of cells with rifabutin (0.01 µM, 0.1 µM, 1 µM, 10 µM). Rifabutin (IC 0.8 µM) but not rifampicin inhibited P-gp efflux activity in M2 cells. When exposed to 0.05 µM rifampicin only, M2 cells accumulated 5.9 ± 1.1 ng rifampicin/ng protein, but took up significantly more rifampicin when co-treated with rifabutin (e.g. 10 µM rifabutin: 13.7 ± 3.5 ng rifampicin/ng protein). The same concentration-dependent boosting effect by rifabutin was detectable for the 0.1 µM and 0.5 µM rifampicin exposure levels. Together, rifabutin concentration-dependently inhibits P-gp and enhances rifampicin accumulation in M2 macrophages during concomitant drug exposure.
Interindividual variability in gut microbial formation of the hop phytoestrogen 8-prenylnaringenin results in elevated but sub-toxic internal exposures.
Stevanoska M, Cremona M, Beekmann K … +2 more , Sturla SJ, Aichinger G
Arch Toxicol · 2026 Jun · PMID 41807782 · Publisher ↗
The gut microbiome converts the prenylated polyphenol isoxanthohumol (iXN), a natural constituent of hops found in beer, into 8-prenylnaringenin (8-PN), a potent phytoestrogen associated with endocrine-disrupting effects...
The gut microbiome converts the prenylated polyphenol isoxanthohumol (iXN), a natural constituent of hops found in beer, into 8-prenylnaringenin (8-PN), a potent phytoestrogen associated with endocrine-disrupting effects. Following oral exposure, interindividual differences in microbiome composition may lead to variable systemic 8-PN concentrations and consequently to differences in susceptibility to toxicity. To characterize the contribution of gut microbiota to health effects of hop polyphenols, a human physiologically based kinetic (PBK) model that includes microbial 8-PN formation was developed. Ex vivo fecal fermentation coupled to LC–MS/MS revealed substantial interindividual variation in biotransformation capacity. Derived kinetic parameters were incorporated into the PBK model, which was subsequently used to predict systemic 8-PN exposure while accounting for interindividual variability. Model simulations indicated that high iXN metabolizers experience approximately two-fold more internal 8-PN exposure than low metabolizers. Estrogenicity of the predicted uterine 8-PN concentrations was assessed via alkaline phosphatase induction in Ishikawa cells. Even in high metabolizers, systemic 8-PN concentrations appeared to remain below levels of concern regarding endocrine disruption. These findings highlight the importance of accounting for interindividual variability in gut microbial biotransformation when predicting xenobiotic toxicokinetics and illustrate the applicability of microbiome-competent PBK modeling for predicting the systemic fate of gut microbial metabolites.
Towards a validation of the standard and enzyme-linked comet assay: a retrospective variability analysis.
Møller P, Ladeira C, Ziemann C … +11 more , Knasmueller S, Mišík M, Louro H, Silva MJ, Olsen AK, Azqueta A, Langie SAS, Bonassi S, Dusinska M, Gajski G, Collins A
Arch Toxicol · 2026 Apr · PMID 41807781 · Publisher ↗
The comet assay is one of the most popular tests for genotoxicity in cell cultures, non-animal species, animals and humans. It has high sensitivity to detect low levels of DNA damage, can be applied to non-proliferating...
The comet assay is one of the most popular tests for genotoxicity in cell cultures, non-animal species, animals and humans. It has high sensitivity to detect low levels of DNA damage, can be applied to non-proliferating cells, requires relatively few cells, is technically simple, and is low cost. The Organisation for Economic Co-operation and Development (OECD) adopted in 2016 the in vivo comet assay for measurement of DNA strand breaks in animal tissues. There is a desire to expand the comet assay to genotoxicity testing in cell cultures, including the detection of oxidatively damaged DNA by incubation of gel-embedded nucleoids with DNA repair enzymes, especially formamidopyrimidine DNA glycosylase (Fpg) which converts oxidised purines to DNA breaks. Based on available information in the literature, this review provides a retrospective evaluation of the validation status of this assay, focusing on accuracy and reliability in genotoxicity testing in vitro. Information on accuracy is scarce, although limited evidence suggests levels of Fpg-sensitive sites are similar to those obtained by Fpg-linked alkaline unwinding and alkaline elution assays. Several ring studies have shown that estimated background levels of DNA breaks vary within and between laboratories. However, ring studies indicate good intra- and inter-laboratory reproducibility of the standard assay on ionizing radiation-exposed and the Fpg-linked assay on potassium bromate exposed cells. Further studies are needed to assess the reproducibility in multiple laboratories using coded samples of non-genotoxins and genotoxins. Nevertheless, the available results indicate the comet assay is a reliable in vitro genotoxicity test.
A collagen hydrogel-based 3D Heparg model for enhanced hepatocyte function and assessment of cholestatic drug-induced liver injury.
Timor-López E, Tolosa L, Donato MT
Arch Toxicol · 2026 Jun · PMID 41807780 · Full text
Drug-induced liver injury (DILI) is a major clinical and regulatory challenge, with cholestasis representing a frequent mechanism of hepatotoxicity. Conventional two-dimensional (2D) hepatocyte cultures often fail to pre...
Drug-induced liver injury (DILI) is a major clinical and regulatory challenge, with cholestasis representing a frequent mechanism of hepatotoxicity. Conventional two-dimensional (2D) hepatocyte cultures often fail to predict such effects, underscoring the need for advanced models that better replicate liver architecture and function. In this study, a three-dimensional (3D) model was developed by encapsulating HepaRG cells within type I collagen hydrogels to enhance functional maturation and reduce differentiation time compared to standard 2D cultures. The 3D HepaRG model maintained long-term viability and exhibited improved hepatic functions, including urea and albumin production, xenobiotic metabolism, and antioxidant defense, particularly after 14 days of culture with a reduced amount of DMSO (1%) compared to the standard 2D protocol. When incubated with cholestatic antibiotics, such as cloxacillin, flucloxacillin, and nafcillin, the 3D model reproduced cholestatic DILI features, showing increased cytotoxicity in the presence of bile acids and after prolonged exposure. Transcriptomic profiling revealed dose-dependent modulation of genes involved in bile acid homeostasis. A more in-depth analysis of cloxacillin-toxicity using RNA-seq revealed an altered expression of genes involved in bile acid metabolism, oxidative stress, and endoplasmic reticulum stress. Functionally, cloxacillin induced oxidative stress, mitochondrial dysfunction, and activation of apoptotic signaling pathways. Overall, the collagen hydrogel-based 3D HepaRG model provided a robust and physiologically relevant platform for investigating antibiotic-induced cholestatic DILI and its underlying mechanisms, offering improved predictivity over traditional 2D systems and valuable potential for preclinical drug safety assessment.
Urinary metabolite elimination from inhaled propylene glycol butyl ether (PGBE) and propylene glycol methyl ether (PGME) in healthy participants.
Hopf NB, Kaspar S, Bouitbir J … +5 more , Pache J, Le Gludic S, Plateel G, Charriere N, Borgatta M
Arch Toxicol · 2026 Jun · PMID 41807779 · Publisher ↗
Glycol ethers are amphiphilic organic solvents, found as mixtures of α- (secondary alcohol) and β- (primary alcohol) isomers. Propylene glycol ethers (PGE) and ethylene glycol ethers (EGE) are the most common derivatives...
Glycol ethers are amphiphilic organic solvents, found as mixtures of α- (secondary alcohol) and β- (primary alcohol) isomers. Propylene glycol ethers (PGE) and ethylene glycol ethers (EGE) are the most common derivatives of the glycol ethers family. Among the PGE family, propylene glycol monomethyl ether (PGME, CAS # 107-98-2) and propylene glycol monobutyl ether (PGBE, CAS # 5131-66-8) are widely used. Regulations for PGME limit the β-isomer to < 5% due to its metabolism to alkoxy propionic acid, which has been associated reproductive and neurotoxic effects similar to those observed with ethylene glycol ethers. Other PGEs do not have such restrictions despite similar isomeric composition. Propylene glycol ethers are used in many commercial products, including cleaning products, and enter the body rapidly via lungs, skin, and ingestion. We hypothesized that PGBE is metabolized to 2-butoxypropionic acid (2-BPA), as suggested by in vitro hepatocyte experiments, and that 2-BPA would be quantifiable in urine from healthy participants (N = 17) following a 2-h exposure to a vapor mixture containing 15 ppm PGBE and 35 ppm PGME. Metabolites were quantified with liquid chromatography with quadrupole mass spectrometry (LC-MS/MS). Our in vitro hepatocyte experiments showed that PGBE was metabolized to 2-BPA. Urinary metabolite concentrations from the participants were greater for PGBE compared to PGME, and their peak elimination occurred at 1 h post exposure. Our findings show that β-isomers in commercial propylene glycol ethers can readily metabolize to the corresponding alkoxy propionic acid. However, current toxicological hazard assessments are insufficient to evaluate possible health implications.
In vitro toxicity assessment of graphene quantum dots using a 3D HepG2 model.
Durmišević I, Haverić A, Žabkar S … +9 more , Štern A, Kološa K, Jenuš Belec P, Ćetković Pećar T, Hadžić Omanović M, Gutić S, Rozman I, Haverić S, Žegura B
Arch Toxicol · 2026 Jun · PMID 41807778 · Full text
In the present study, two types of graphene quantum dots (GQDs) were investigated: green-emitting (G-GQDs) and blue-emitting (B-GQDs). Physicochemical characterisation was performed using transmission electron microscopy...
In the present study, two types of graphene quantum dots (GQDs) were investigated: green-emitting (G-GQDs) and blue-emitting (B-GQDs). Physicochemical characterisation was performed using transmission electron microscopy (TEM), zeta potential, and hydrodynamic radius measurements to evaluate the morphology, particle size, aggregation behaviour, and colloidal stability of the GQDs in both water and cell culture medium. G-GQDs exhibited superior colloidal stability and more uniform dispersion than B-GQDs, whereas both types showed reduced aggregation and surface charge in cell culture medium due to protein corona formation. Toxicological characterisation was performed using an in vitro human hepatocellular carcinoma (HepG2) 3D spheroid model, with GQDs exposures up to 250 µg/mL (100 µg/cm2). Cytotoxicity was measured using the CellTiter-Glo luminometric assay, while genotoxicity was evaluated by the comet assay and flow cytometric analysis of γH2AX and phosphorylated histone H3 (p-H3) after 24 h of exposure. Both GQDs induced dose-dependent cytotoxic effects in HepG2 spheroids. At non-cytotoxic concentrations, a dose-dependent increase in DNA damage was observed, as determined by the comet assay. However, no evidence of DNA double-strand breaks (γH2AX) or elevated p-H3 levels was detected, suggesting the absence of clastogenic and aneugenic activity. The observed DNA single-strand breaks may be partly attributed to reactive oxygen species induction. These results indicate that, although GQDs induced cytotoxicity and single-strand DNA damage, no clear evidence of more severe genotoxic effects was observed under the tested conditions. Further studies are warranted to elucidate underlying mechanisms and comprehensively assess the safety profile of GQDs for biomedical applications.
Development of an integrated physiologically based toxicokinetic-toxicodynamic model for quantitative prediction of polyhexamethylene guanidine-induced human toxicity.
Jang JH, Park DH, Kim JJ … +5 more , Park YJ, Chung KH, Kim HJ, Kim H, Jeong SH
Arch Toxicol · 2026 Jun · PMID 41807777 · Publisher ↗
Polyhexamethylene guanidine (PHMG) is a hazardous environmental toxicant with proven lethality and severe societal consequences following the humidifier disinfectant disaster in South Korea. Despite its recognized pulmon...
Polyhexamethylene guanidine (PHMG) is a hazardous environmental toxicant with proven lethality and severe societal consequences following the humidifier disinfectant disaster in South Korea. Despite its recognized pulmonary toxicity via inhalation, no quantitative prediction system has been established to assess its in vivo kinetics and exposure-response relationship in humans. This study aimed to develop an integrated prediction system by constructing a physiologically based toxicokinetic (PBTK) model and a toxicodynamic (TD) model to simulate PHMG’s pulmonary toxicity in humans. The PBTK model was developed using in vivo data to describe PHMG distribution across major organs (lungs, gastrointestinal tract, etc.) and validated both qualitatively and quantitatively. The TD model was constructed based on PHMG exposure-cytotoxicity response data from human normal lung cells, capturing time- and dose-dependent toxicity patterns. A hybrid TD model combining a damage accumulation mechanism at lower concentrations and an Emax sigmoid response at higher concentrations was applied. Both models were co-linked to establish an integrated PBTK-TD model capable of predicting PHMG-induced lung toxicity under both single and repeated exposure scenarios. The PBTK model showed strong predictive performance across various exposure routes (intravenous, intratracheal, oral), and was successfully extrapolated to humans. The integrated model quantitatively simulated PHMG concentrations in lung tissue and their associated cytotoxic effects. Furthermore, the model enabled reverse dosimetry to estimate tissue-specific reference doses, population-based external exposure levels, and margins of safety. These features highlight the potential of the model for human health risk assessment and regulatory applications. In conclusion, this is the first system-based approach to integratively predict PHMG’s kinetic behavior and toxicity. It offers a novel and robust tool for quantitative toxicology, supporting future risk-based decision-making for PHMG and similar environmental toxicants.
PM exposure induces functional alterations in pregnant rats heart and in human stem cell derived cardiac spheroids.
Bonalumi F, Burattini M, Statello R … +15 more , Hu M, Hoang ML, Delmonte N, Caputo A, Montanini B, Muzio FPL, Pinelli S, Mozzoni P, Modica J, Cattaneo A, Rossi F, Bergamaschi E, Bollati V, Rossi S, Miragoli M
Arch Toxicol · 2026 Jul · PMID 41786966 · Full text
Air pollution is a major cardiovascular risk factor, with particulate matter (PM) posing significant threats. The Po Valley remains among Europe's most polluted areas. While PM₂.₅ is linked to cardiac dysfunction, its ef...
Air pollution is a major cardiovascular risk factor, with particulate matter (PM) posing significant threats. The Po Valley remains among Europe's most polluted areas. While PM₂.₅ is linked to cardiac dysfunction, its effects during pregnancy-especially under hypertensive conditions-are poorly defined. We investigated how prolonged PM exposure from Milan's urban area affects cardiac electromechanical function in pregnant normotensive and hypertensive rats, and in a human embryonic stem cell-derived 3D cardiac spheroid. Pregnant normotensive and hypertensive (SHR) rats were exposed to saline solutions w/wo PM (2 mg/kg) three times weekly for 19 days. Cardiac spheroids were cultured in DMEM w/wo PM (10-50 µg/mL) for 8 days. We assessed cardiac function via in-vivo epicardial mapping and in-vitro optokinematic analysis. Inflammatory, toxicological, and molecular profiles were evaluated. Machine learning classified electrogram profiles in PM-exposed versus unexposed rats. In SHR rats, PM exposure increased rheobase (+ 39%), current threshold (+ 32%), and chronaxie (+ 71%), with a 21% rise in effective refractory period. Conduction velocity and anisotropy were also altered. Machine learning achieved > 86% and > 77% classification accuracy in normotensive and SHR, respectively. In human cardiac spheroids derived from embryonic stem cells, short-term PM exposure impaired relaxation (- 36% at 10 µg/mL; - 21.5% at 20 µg/mL) and contraction amplitude (- 42% and - 62%, respectively). Long-term evaluation disrupted calcium transients (- 20% and - 15%) and altered IL-6. Gene expression revealed dysregulation of calcium-handling genes. These findings emphasize the heightened risks of PM exposure during gestation, particularly in preeclampsia, and support the need for public health strategies to protect maternal and fetal cardiovascular health.
Comparative genotoxicity assessment of ortho-phthalaldehyde using human in vitro organotypic airway epithelial cultures and standard in vitro genotoxicity assays.
Le Y, Sun Y, Li X … +8 more , Wynne R, Twaddle N, Bishop ME, Beland FA, Gwinn WM, Heflich RH, Cao X, Wang Y
Arch Toxicol · 2026 Jun · PMID 41784632 · Publisher ↗
ortho-Phthalaldehyde (OPA) is a high-level chemical disinfectant used for sterilizing heat-sensitive medical equipment. OPA has been reported to be an airway irritant in animal studies, in human case reports, and in a hu...
ortho-Phthalaldehyde (OPA) is a high-level chemical disinfectant used for sterilizing heat-sensitive medical equipment. OPA has been reported to be an airway irritant in animal studies, in human case reports, and in a human in vitro organotypic air-liquid-interface (ALI) airway culture model; there are also data indicating that it may be a direct-acting bacterial mutagen. In this study, we investigated the genotoxic potential of OPA using human ALI airway cultures, human lymphoblastoid TK6 cells, and the Ames test. Human airway cultures were exposed to OPA aerosol deposition doses ranging from 0.74 to 5.85 µg/cm for 4 h/day over 5 days, followed by a 28-day recovery period. Cytotoxicity, cilia beat frequency, and DNA damage were evaluated after 3 days of OPA aerosol exposure, while mutagenicity was assessed by Duplex Sequencing (DS) after the 28-day recovery following the 5-day exposure. While OPA was cytotoxic, no DNA damage was detected in ALI cultures using the Comet-Chip and Multi-flow assays, and no mutagenicity was observed in the DS analysis. In contrast, treating TK6 cells with up to 2.5 µg/mL OPA did not induce DNA damage but produced small increases in frequency of micronuclei, and mutations in the HPRT and TK genes. Additionally, OPA was negative in the Ames test both with and without S9 activation. Taken together, OPA was weakly positive in mammalian cell assays measuring genotoxic hazard, but not in more complex organotypic human ALI airway cultures, even at a highly cytotoxic concentration, suggesting that the airway model may possess detoxification systems that mitigate OPA's genotoxic potential.
Doxorubicin induces immediate transcriptional change and apoptosis in spermatogonia from prepubertal rats.
Beaud H, Hug E, Scott-Boyer MP … +4 more , Rwigemera A, Tremblay A, Droit A, Delbes G
Arch Toxicol · 2026 May · PMID 41762288 · Publisher ↗
Chemotherapy can compromise the fertility of boys with cancer, yet no standard protocols exist to preserve their reproductive potential. Before puberty, germ cells are almost exclusively spermatogonia that can be the tar...
Chemotherapy can compromise the fertility of boys with cancer, yet no standard protocols exist to preserve their reproductive potential. Before puberty, germ cells are almost exclusively spermatogonia that can be the target of anticancer drugs. Doxorubicin (DXO), a widely used anthracycline in pediatric oncology, has been associated with infertility in adulthood, but its immediate effects on prepubertal germ cells remain poorly understood. In the present study, a preclinical rat model of prepubertal DXO exposure was developed to characterize the mechanisms underlying immediate DXO-induced germ cell damage. Six-day-old pups, received a single intraperitoneal injection of DXO (5 mg/kg) and effects were measured after 24 or 48 h. DXO exposure significantly reduced relative testis weight from 24 h and significantly increased apoptosis and germ cell loss at 48 h, while circulating testosterone remained unchanged, suggesting a selective germline effect. RNA-seq was done on GFP-positive germ cells purified at 24 h. Transcriptomic analysis confirmed the enrichment in spermatogonial stem cells (SSCs) in the GFP-sorted population. Moreover, DXO induced 51 differentially expressed genes (49 upregulated, 2 down regulated) that were mostly related the p53-dependant apoptosis pathway. Pro-apoptotic genes (Cdkn1a, Bbc3/Puma, Tp53inp1, Fas) and oxidative stress regulators (Sesn2, Eda2r, Abhd4) were induced, whereas DNA repair genes (Mgmt, Xrcc1, Polh, Gadd45α, …) were not activated. Our data revealed the DXO-induced immediate transcriptomic response after 24 h, leading to germ cell death observed by histology at 48 h. These findings suggest that SSCs respond to DXO by favoring apoptosis and stress regulation, a strategy that may preserve germline integrity and reduce the risk of transmitting genetic damage to the next generation.
Microplastics induce mitochondrial dysfunction and accelerate cardiovascular pathogenesis.
Chen TH, Chu IT, Chang RY … +4 more , Wang HC, Chung CJ, Tsai TH, Chou CK
Arch Toxicol · 2026 May · PMID 41762287 · Full text
Microplastics and nanoplastics (MNPs) are becoming ubiquitous environmental pollutants, with increasing evidence of their systemic toxicity. MNPs are increasingly detected in human tissues, including the cardiovascular s...
Microplastics and nanoplastics (MNPs) are becoming ubiquitous environmental pollutants, with increasing evidence of their systemic toxicity. MNPs are increasingly detected in human tissues, including the cardiovascular system, and have been implicated in the pathogenesis of cardiovascular disease through mitochondrial dysfunction. This review integrates mechanistic insights into how MNPs impair mitochondrial integrity, induce oxidative stress, disrupt calcium signaling, and promote genomic instability in cardiac tissue. MNPs also exacerbate inflammation, cellular senescence, mitophagy dysfunction, and pro-atherosclerotic remodeling. Furthermore, this review examines sex-specific mitochondrial responses and developmental vulnerabilities. Understanding the molecular crosstalk between MNPs exposure and mitochondrial damage may provide a foundation for targeted interventions to mitigate environmental cardiovascular risks.
Cross-continental venom narratives: proteo-transcriptomic insights into Hydrophis cyanocinctus of India and China.
Prajapati P, Bhaiyya R, Singh RP … +4 more , Shah N, Gadhvi IR, Nathani N, Mootapally C
Arch Toxicol · 2026 May · PMID 41748762 · Publisher ↗
Hydrophis cyanocinctus, annulated sea snake, is a widely distributed marine elapid whose venom composition and gene-expression architecture remain poorly characterized across its geographic range. Here, we present the fi...
Hydrophis cyanocinctus, annulated sea snake, is a widely distributed marine elapid whose venom composition and gene-expression architecture remain poorly characterized across its geographic range. Here, we present the first high-resolution proteo-transcriptomic profile of venom and venom gland of this species from India. This research underscores RNA-seq comparison of Indian and Chinese H. cyanocinctus venom gland gene expression to elucidate population-level variation in venom gland machinery, gene diversity, and other regulatory biology. LC–MS/MS profiling of Indian venom identified 2260 peptide hits corresponding to major elapid toxin families. Short-chain three-finger neurotoxins, and myotoxins, along with multiple long-chain neurotoxins, diverse phospholipase A₂ isoforms, and a suite of anti-hemorrhagic and PLA₂/metalloprotease inhibitors were detected, which likely mediate endogenous toxin regulation. Complementary RNA-seq, which generated 191 million reads from the Indian venom gland revealed 16,117 expressed genes. Differentially expressed genes uncovered 7644 up-regulated and 8557 down-regulated genes between populations, with 6089 consistently differentially expressed between HC of India (n = 1) and China (n = 3). Functional enrichment analysis revealed profound upregulation of pathways associated with translation, peptide biosynthesis, ribosome biogenesis, RNA processing, mitochondrial respiration, and ATP synthesis in the Indian population, indicating a hyperactive venom-production state with elevated bioenergetic investment. On the other hand, de novo RNA-Seq assembly and serpent-associated mining recovered ~ 63,000 hits, including expanded repertoires of SVMPs, PLA₂s, and neurotoxins with distinct patterns. Together, these findings demonstrate extensive proteomic and RNA-Seq diversification in H. cyanocinctus, revealing enhanced biosynthetic and metabolic activation in the Indian venom gland, and provide key insights into the venom profile of Indian annulated sea snake.
PEGylated liposomal fluopsin C triggers cuproptosis and ferroptosis pathways and suppresses 3D tumor spheroid growth in NCI-H460 cells.
de Lima LVA, da Silva MF, de Oliveira LM … +14 more , de Assis MCT, Carvalho ICO, Fuzinatto IM, Semprebon SC, de Oliveira Nocetti RV, Lazarin-Bidoia D, Nakamura CV, Felicidade I, Lepri SR, Favaron PO, Dealis ML, Cabeça LF, Filho GA, Mantovani MS
Arch Toxicol · 2026 May · PMID 41748761 · Full text
Copper-based metallodrugs are promising anticancer agents, but their toxicity limits clinical translation. This study evaluated the toxicological and molecular effects of PEGylated Fluopsin C (PEG-FlpC) in in vitro human...
Copper-based metallodrugs are promising anticancer agents, but their toxicity limits clinical translation. This study evaluated the toxicological and molecular effects of PEGylated Fluopsin C (PEG-FlpC) in in vitro human non-small-cell lung carcinoma (NCI-H460) cells cultured as 2D monolayer and 3D spheroids. Cells were exposed to PEG-FlpC at its IC50 (1.0 µM) for 24 h. Flow cytometry revealed G₁-phase arrest and non-apoptotic cell death. PEG-FlpC markedly suppressed spheroid growth, with 2 × IC50-treated spheroids growing only 58.1% compared to 131.6% in the control. Ultrastructural analyses showed mitochondrial clustering and swelling, ER dilation, and cytoplasmic vacuolization. Gene profiling demonstrated downregulation of TP53 and BECN1, with upregulation of TP73 and SQSTM1, consistent with autophagy blockade and stress activation. PEG-FlpC modulated ferroptosis-related (GPX4, SLC7A11, and TFRC) and cuproptosis-related (ATP7B, MTF1, DLAT, and CDKN2A) genes. Pharmacological inhibition confirmed a predominantly copper-mediated mechanism, as TTM (10 µM) restored 77.7% of metabolic activity. Combined inhibition with TTM and Fer-1 (1 µM) further increased viability to 89.4%, indicating that PEG-FlpC induces non-apoptotic regulated cell death through an interconnected cuproptosis–ferroptosis mechanism associated with mitochondrial dysfunction.
Quercetin mitigates size-dependent oxidative and metabolic toxicity of citrate-coated silver nanoparticles in human erythrocytes.
Santos I, Costa VM, Carvalho F … +2 more , Fernandes E, Freitas M
Arch Toxicol · 2026 May · PMID 41699316 · Full text
Silver nanoparticles (AgNP) are extensively used in consumer and medical products, making systemic exposure increasingly plausible. Once in circulation, AgNP directly interact with erythrocytes; however, AgNP effects on...
Silver nanoparticles (AgNP) are extensively used in consumer and medical products, making systemic exposure increasingly plausible. Once in circulation, AgNP directly interact with erythrocytes; however, AgNP effects on human erythrocytes remain poorly characterised, despite the central role of erythrocytes in maintaining blood homeostasis and the likelihood of direct nanoparticle contact following human exposure. Quercetin, a dietary flavonoid with potent antioxidant and anti-inflammatory activities, has shown cytoprotective potential against oxidative damage in various cell types, but its ability to counteract AgNP-induced erythrotoxicity has not yet been established. Accordingly, we (i) evaluated the effects of citrate-coated AgNP of 5, 10, and 50 nm on human erythrocytes and (ii) investigated the potential protective role of quercetin against AgNP-induced toxicity. The results showed that all citrate-coated AgNP induced haemolysis in human erythrocytes. Exposure to all three nanoparticle sizes markedly increased intracellular levels of pro-oxidant reactive species (RS). In particular, 10 and 50 nm AgNP caused a significant decrease in total glutathione (GSH) levels. Additionally, all tested AgNP also induced ATP decrease. Moreover, the 5 and 10 nm AgNP increased intracellular calcium levels. Remarkably, pre-treatment with quercetin conferred protection against almost all tested cytotoxic endpoints. However, quercetin failed to prevent total GSH loss and even exacerbated ATP depletion. Collectively, these findings provide the first integrated evidence of three sizes of AgNP-induced toxicity in human erythrocytes, demonstrating that quercetin confers broad, though not universal, protection. This underscores its potential as a modulator of nanoparticle-induced oxidative and metabolic damage.
Okadaic acid triggers NFκB and STAT3 phosphorylation followed by a release of inflammatory markers in human and mouse endothelial cells.
Nyback K, Alfonso A, Alvariño R … +5 more , Suzuki T, Watanabe R, Uchida H, Vieytes MR, Botana LM
Arch Toxicol · 2026 May · PMID 41699315 · Full text
Okadaic acid (OA) is a lipophilic phycotoxin that causes acute diarrhoea when ingested. OA is an inhibitor of protein phosphatase 2 A, but the mechanism of toxicity behind the diarrhoea remains unclear. OA modulated infl...
Okadaic acid (OA) is a lipophilic phycotoxin that causes acute diarrhoea when ingested. OA is an inhibitor of protein phosphatase 2 A, but the mechanism of toxicity behind the diarrhoea remains unclear. OA modulated inflammatory markers in epithelial cells, however, the effect on endothelial cells, with a key role in the inflammatory cascade, has not been previously addressed. Therefore, the aim of the present work was to test the effect of OA in human (HMEC-1) and mouse (MS1) endothelial cells. After 3, 6 and 24 h of incubation in the presence of OA (10-1000 nM) cell viability was significantly reduced, showing a higher effect on human cells with half inhibitory concentrations (IC) in HMEC-1 cells five times lower than in mouse cells. Furthermore, when cells were treated with OA, significant amounts of the proinflammatory mediators ROS, CD147, IL-6 and monocyte chemoattractant protein 1 (MCP-1) were detected. Some of these effects were observed only in HMEC-1 cells and around three hours earlier, pointing again to a higher sensitivity in human models. Finally, OA triggered phosphorylation of NFκB at 100 nM after 3 and 6 h of treatment, while the signal transducer and activator of transcription 3 (STAT3) was increased after 3 h but decreased after 6 h in both cell lines. Altogether, these data suggest that the toxic effect of OA in endothelial cells could be related with the activation of the inflammatory cascade.
In vitro hepatic clearance of enniatin B1: interspecies and cell model comparison.
Mahdjoub M, Dubreil E, Gendre C … +2 more , Le Hégarat L, Henri J
Arch Toxicol · 2026 May · PMID 41699314 · Publisher ↗
Enniatin B1 (EnnB1) is a Fusarium-produced mycotoxin contaminating cereals and cereal-based products, which represent the main source of human exposure to the toxin. EnnB1 belongs to the "emerging mycotoxins" group that...
Enniatin B1 (EnnB1) is a Fusarium-produced mycotoxin contaminating cereals and cereal-based products, which represent the main source of human exposure to the toxin. EnnB1 belongs to the "emerging mycotoxins" group that are not regulated due to data gaps on their toxicokinetic and toxicodynamic profiles. The aim of this study was to determine the in vitro hepatic clearance of EnnB1 based on parent compound depletion. To do this, we used two in vitro experimental assays-a conventional and a media loss assay-and compared hepatic clearance between (i) species, using primary rat and human hepatocytes, (ii) cell types, namely primary human hepatocytes and the HepaRG human hepatic cell line, and (iii) cell models by comparing 2D and 3D HepaRG. Hepatic clearance (Cl) was calculated from in vitro hepatic intrinsic clearance using in vitro to in vivo extrapolation. We found that the derived Cl was faster in rats compared to humans, i.e., 3.4 L/(h·kg) and 1 L/(h·kg), respectively. Cl was comparable between primary human hepatocytes and HepaRG 2D, while HepaRG 3D showed slower Cl of 0.58 L/(h·kg). We found that the media loss depletion assay revealed an initial phase of rapid uptake, then a slope parallel to that of the conventional depletion assay. We observed that the conventional depletion assay was appropriate to determine the Cl of EnnB1. Furthermore, the pooled primary hepatocytes, considering inter-individual variability, allowed the determination of a reliable Cl to be used in the development of a physiologically based pharmacokinetic model.
Building trust in the integration of artificial intelligence into chemical risk assessment: findings from the 2024 ECETOC workshop.
Gant TW, Boxall A, Burgwinkel D … +20 more , Zare Jeddi M, Djidrovski I, Friedrichs S, Hardy B, Hartung T, Holland D, Karwath A, Kienhuis A, Kleinstreuer N, Lin Z, Marczylo EL, Marvuglia A, Qian H, van Ravenzwaay B, Rees P, Sarimveis H, Tralau T, Wilmot L, Zalewski A, Rouquié D
Arch Toxicol · 2026 May · PMID 41699313 · Full text
Artificial Intelligence (AI) is increasingly influencing chemical risk assessment, enabling faster, more comprehensive, and potentially more ethical assessments. The application of AI in chemical risk assessment refers t...
Artificial Intelligence (AI) is increasingly influencing chemical risk assessment, enabling faster, more comprehensive, and potentially more ethical assessments. The application of AI in chemical risk assessment refers to both generative and predictive algorithms encompassing machine learning, to analyse complex chemical, biological, and environmental data and provide insights into adverse effect potential for humans and ecosystems. AI systems support the prediction of chemical hazards, exposure levels, and adverse effects by learning from experimental results, mechanistic models, and regulatory datasets, thereby enhancing the efficiency of safety evaluations.In October 2024, ECETOC held an international workshop, with experts from academia, industry, and regulatory bodies, to reflect upon the historical challenges in integrating multidimensional omics technologies into chemical regulation and explore the current capabilities and future potential of AI in toxicology and regulatory science. Discussions emphasised that implementation of Findable, Accessible, Interoperable, and Reusable (FAIR) data principles is not just a best practice but rather a prerequisite for building transparent, reliable, and unbiased AI systems. The reliability of AI in producing scientifically valid and socially responsible outcomes depends fundamentally on the availability of FAIR data. However, ensuring trustworthiness also requires robust governance frameworks that go beyond data and human oversight. Critical enablers of responsible AI in chemical risk assessment are rigorous governance, explainability, fit-for-purpose applications, and human oversight. ECETOC supports the development of flexible and iterative frameworks advancing development, validation, transparency, accountability, and trust in AI applications in chemicals regulation.
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