Frontiers in toxicology最新文献

Introduction: Massive bupropion overdose in pediatric patients can result in refractory cardiogenic shock, seizures, and cardiac arrest requiring aggressive intervention. Although lipid emulsion (LE), therapeutic plasma exchange (TPE), and extracorporeal membrane oxygenation (ECMO) have been used, evidence guiding clinical management remains limited. We present a case of combined LE therapy and TPE in a pediatric patient with massive bupropion overdose.

Methods: An adolescent female with intentional ingestion of 27,000 mg bupropion XL and 2,250 mg metoprolol XL experienced cardiac arrest requiring veno-arterial ECMO. Lipid emulsion therapy was followed by serial therapeutic plasma exchange. Serial urine samples quantifying bupropion and hydroxybupropion elimination were analyzed.

Results: Following treatment with LE and plasma exchange, the patient rapidly improved clinically, with declining urine concentrations of bupropion and hydroxybupropion showing enhanced drug clearance.

Conclusion: This case supports using combined LE therapy and TPE to enhance drug elimination and improve outcomes in massive pediatric bupropion overdose.

Introduction: Exposure to long-chain perfluoroalkyl substances (PFASs) during development has been consistently associated with cognitive impairment and behavioural changes in humans. These concerns have led to regulatory restrictions and a shift towards short-chain PFASs as alternatives. However, experimental evidence on the neurodevelopmental impact of short-chain PFASs remains scarce, despite their increasing detection in drinking water and human biomonitoring studies.

Methods: This study provides the first experimental evidence of the neurodevelopmental toxicity of maternal exposure to the short-chain PFASs GenX and PFBA, administered before mating, throughout gestation, and during lactation.

Results: In a rat model, offspring from exposed dams displayed significant impairments in spatial learning and cognitive flexibility in the Morris water maze. Mechanistic investigations on PFBA exposure ex vivo revealed delayed neuronal maturation, reduced expression of MAP2, PSD95 and VGLUT. Impaired neurogenesis persisted into adulthood in the hippocampus, as shown by upregulation of nestin and downregulation of doublecortin, together with dysregulated expression of neuroinflammatory genes in the hippocampus for both tested molecules.

Discussion: Our findings indicate that even short-chain PFASs, currently considered safer substitutes, may disrupt brain development, leading to persistent neuroinflammation and impaired cognitive function. These results highlight an urgent need to reassess the developmental safety of short-chain PFASs and to include neurodevelopmental endpoints in future risk assessments and regulatory policies.

We reviewed the mode of action (MOA) underlying the effect of the chlorotriazines on female reproduction and mammary tumor development in rats. Age-associated changes in the HPO hormonal environment of the female drive the development of mammary gland tumors in several rat strains. The adverse outcome pathway for tumor development involves a disruption of the ovulatory surge of luteinizing hormone (LH) caused by changes in the hypothalamic control of LH release. The ensuing persistence of unruptured ovarian follicles produces elevated blood estradiol (E2) and prolactin, both known to induce mammary gland tumors. High doses of atrazine induce premature reproductive aging and elevated E2, which is commonly found later in aging female rats. The change in HPO in aging rodents is distinctly different from that seen in aging women. In humans, reproductive aging (menopause) is driven by the loss of ovarian follicles and ensuing low serum E2. Alternate MoAs were examined, including the effect of atrazine on estrogen synthesis, atrazine's potential to bind to estrogen receptors, Erα, Erβ, or G-protein coupled, estrogen receptors (GPER) in vitro. The chlorotriazines do not bind to ER receptors; high doses may have anti-E2 effects. MOAs hypothesized from in vitro studies were of limited utility in predicting in vivo effects of atrazine because of the effects of metabolism and the kinetics of elimination in vivo. A review of the epidemiology literature indicated there is no consistent evidence of a causal association between chlorotriazine exposure and the incidence of breast, ovarian, or uterine cancers in women.

The neonicotinoid insecticide, imidacloprid (IMI), is one of the widely used pesticides with well-documented serious health effects that are noticeable with long-term exposure. However, the long-term effects of IMI on cardiac tissues have not been fully elucidated. Herein, we investigated the mechanisms of IMI-induced cardiotoxicity. Additionally, we examined the potential protective effects of the natural alkaloid, berberine (BBR), against IMI-induced cardiotoxicity. Rats received IMI (45 mg/kg/day, orally) for 30 days, alone or in combination with BBR-loaded liposomes (BBR-Lip) at a dose of 10 mg/kg, intraperitoneally. Cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), oxidative stress, inflammatory markers, and histopathological alterations were assessed. IMI caused significant cardiac damage as shown by increased levels of cTnI and CK-MB and histopathological insults examined by H and E and transmission electron microscopy. These changes were accompanied by the induction of oxidative stress and inflammatory markers. Additionally, IMI inhibited the expression of Nrf2, a powerful regulator of cellular antioxidant defense and activated inflammatory pathways by inducing expressions of TLR-4, NF-κB, NLRP3-inflammasome and gasdermin. Moreover, IMI induced cardiac expressions of TGF-β, p-JAK, and p-STAT, which worsens the oxidative stress and inflammatory status. Co-administration of BBR-Lip attenuated the biochemical, histological and molecular dysregulation induced by IMI in cardiac tissues. Collectively, this study provides mechanistic insights into the cardiotoxic effects of IMI as well as the potential protective effects of BBR-Lip.

The reduction in the number of animals being used in experimental assays has been a concern of the scientific community. In this sense, non-animal alternative methods have been increasingly tested. This study intended to explore how cell-based responses compare to organismal outcomes and if the former models could contribute to minimizing the number of live animals needed in subsequent stages of hazard/risk assessment of chemicals on amphibians. For this, the toxicity of the commonly used solvent dimethyl sulfoxide (DMSO) was assessed in early life stages (embryos and tadpoles) of two anuran species (Xenopus laevis and Pelophylax perezi) and in 2 cell lines of X. laevis (A6 and XTC-2). In the in vivo assays, mortality, teratogenic effects, and biometric parameters were evaluated, while for in vitro assays, the assessed endpoint was viability. Overall, the obtained data suggest similar sensitivity of both species and life stages to DMSO. The 96 h-LC₅₀ estimated for embryos and tadpoles were, respectively, 2.19% and 2.56% for X. laevis and 3.19 and 3.41 for P. perezi. The solvent DMSO induced several malformations in early life stages, which may have implications for the fitness of organisms at later stages. A slightly higher sensitivity to DMSO was observed in the in vivo approaches comparatively to in vitro approach (72 h-LC₅₀ of 3.10% and 2.62% for A6 and XTC-2, respectively), though it can not be considered significantly different. As such, it is suggested that the latter approach may be considered to serve for first screenings of the ecotoxicity of organic solvents. Such a strategy of using in vitro assays as screening tools, has the potential to reduce the number of animals to be used in subsequent in vivo testing phases by providing information for the refinement of concentrations to be tested in in vivo assays, thereby supporting both reduction and replacement objectives.

Introduction: Atrazine (ATZ) stands as the most widely utilized herbicide globally and is known for its adverse impacts on the reproductive system. Although astragaloside IV (AS IV) is well known for possessing various health benefits, its protective effects against ATZ-induced toxicity remain unexplored. This study aimed to investigate the ameliorative potential of AS IV against ATZ-induced male reproductive toxicity in mice.

Methods: Eight-week-old CD-1 mice were allocated into four groups (n = 10). ATZ and AS IV were administered at doses of 100 mg/kg/day and 40 mg/kg/day, respectively. Treatments were continued for 21 days, after which the animals were sacrificed for plasma biochemical analyses and testes collection for histopathological examination. One-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test was used for data analysis. Molecular docking studies were performed to evaluate ATZ and AS IV interactions with oxidative stress- and inflammation-related proteins, including glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and Nrf2, NF-κβ, IL-1β, IL-6, TNF-α, cullin-3, and Keap-1.

Results: Biochemical analysis revealed significant reductions in GSH levels (p < 0.001), SOD activity (p < 0.001), and GPx activity (p < 0.05), along with elevated malonaldehyde levels (p < 0.01), following ATZ exposure. AS IV treatment in ATZ-exposed mice significantly improved these markers (p < 0.05). ATZ exposure led to significant decreases in testosterone (p < 0.001) and androgen-binding protein (ABP) levels (p < 0.001) within the ATZ group, whereas AS IV supplementation significantly improved these markers (p < 0.05). Histopathological examination revealed sloughed and collapsed seminiferous epithelia with vacuoles and poorly formed spermatids in ATZ-exposed mice, which were mitigated by AS IV treatment. The docking study revealed ATZ's moderate interactions with key oxidative stress and inflammation-related proteins (binding energies: -4.7 to -5.5 kcal/mol), with glutathione (GSH) (-5.5 kcal/mol) showing the strongest binding. Notable stabilizations include SOD (three hydrogen bonds) and modulation of antioxidant (SOD, Nrf2) and anti-inflammatory (IL-1β and TNF-α) pathways. Moreover, AS IV demonstrated significant binding interactions with GSH (-9.2 kcal/mol), cullin-3 (-9.1 kcal/mol), and keap-1 (-8.9 kcal/mol). Molecular dynamics (MD) simulations showed strong stability for GPx and IL-1β targets against ATZ, and AS IV exhibited strong stability for GSH and cullin-3.

Conclusion: AS IV appears to be a promising natural compound for preventing ATZ-induced male reproductive toxicity. Further investigations to elucidate the molecular mechanisms behind such positive effects are warranted.

Introduction: Combined exposures to airborne nanoparticles and acidic gases are plausible during industrial accidents and in military settings involving propellants. Aluminum oxide nanoparticles (Al₂O₃ NPs), widely used in industry and present in propellant formulations, together with hydrogen chloride (HCl), a corrosive combustion by-product, are relevant co-pollutants whose joint impact on lung remodeling remains poorly defined. This study aimed to investigate early airway responses to repeated apical exposures to Al₂O₃ NPs, HCl, or their mixture in a human air-liquid interface co-culture model of alveolar epithelial (hAELVi) and fibroblast (MRC-5) cells.

Methods: Cells were exposed daily for four days, and epithelial viability, barrier integrity, and mediator release were assessed. Conditioned media from exposed cultures were applied to naïve fibroblasts to evaluate proliferation and migration responses.

Results: Repeated exposures did not induce cytotoxicity, barrier disruption, or increases in canonical pro-fibrotic or pro-inflammatory mediators such as TGF-β1, CTGF, or IL-8. However, conditioned media from exposed epithelial cells consistently triggered fibroblast activation through non-canonical epithelial-mesenchymal signaling pathways. These effects occurred at sub-toxic exposure levels.

Discussion: These findings indicate that early sub-lethal co-exposure to Al₂O₃ NPs and HCl can trigger fibroblast activation independently of classical cytokine induction. This unconventional paracrine response suggests a mechanistic link between early epithelial stress and fibroblast-driven remodeling, underscoring the importance of investigating non-canonical pathways in lung responses to mixed environmental pollutants.

Introduction: We introduce MoltiTox, a novel multimodal fusion model for molecular toxicity prediction, designed to overcome the limitations of single-modality approaches in drug discovery.

Methods: MoltiTox integrates four complementary data types: molecular graphs, SMILES strings, 2D images, and ¹³C NMR spectra. The model processes these inputs using four modality-specific encoders, including a GNN, a Transformer, a 2D CNN, and a 1D CNN. These heterogeneous embeddings are fused through an attention-based mechanism, enabling the model to capture complementary structural and chemical information from multiple molecular perspectives.

Results: Evaluated on the Tox21 benchmark across 12 endpoints, MoltiTox achieves a ROC-AUC of 0.831, outperforming all single-modality baselines.

Discussion: These findings highlight that integrating diverse molecular representations enhances both the robustness and generalizability of toxicity prediction models. Beyond predictive performance, the inclusion of ¹³C NMR data offers complementary chemical insights that are not fully captured by structure or language-based representations, suggesting its potential contribution to mechanistic understanding of molecular toxicity. By demonstrating how multimodal integration enriches molecular representations and enhances the interpretability of toxicity mechanisms, MoltiTox provides an extensible framework for developing more reliable models in computational toxicology.

Read-across has matured from an expert-driven extrapolation based largely on structural analogy into a rigorously documented, mechanistically informed cornerstone of next-generation risk assessment. Three pivotal frameworks are compared that now shape its regulatory use: the European Food Safety Authority's (EFSA) 2025 guidance for food and feed safety, the European Chemicals Agency's (ECHA) Read-Across Assessment Framework (RAAF) for industrial chemicals under REACH, and the community-driven Good Read-Across Practice (GRAP) principles. Using five analytical lenses-conceptual structure, scientific rigor, implementation tools, regulatory acceptance, and practical impact-we identified areas of complementarity and divergence. EFSA provides a seven-step, uncertainty-anchored workflow that actively embeds new approach methodologies (NAMs) and adverse outcome pathway reasoning, offering applicants a transparent "how-to" template. RAAF, in contrast, operates as an evaluator's rubric: six scenario types and associated assessment elements delineate what evidence must be delivered, thereby standardizing regulatory scrutiny but leaving dossier construction to the registrant. GRAP supplies the conceptual glue, emphasizing mechanistic plausibility, exhaustive analogue selection, explicit uncertainty characterization, and the strategic use of NAMs; its influence is evident in both EFSA's and ECHA's evolving expectations. (Terminology note: the acronym "NAM" was popularized at an ECHA workshop in 2016; earlier documents such as RAAF and initial GRAP papers therefore may not use the term explicitly). Regulatory experience under REACH demonstrates that dossier quality and acceptance rates rise markedly when RAAF criteria are met, while EFSA's new guidance is poised to catalyze similar gains in food and feed assessments. Globally, the convergence of these frameworks-reinforced by OECD initiatives and NAM-enhanced case studies-signals an emerging international consensus on what constitutes defensible read-across. In conclusion, harmonizing EFSA's procedural roadmap with RAAF's evaluative rigor and GRAP's best-practice ethos can mainstream reliable, animal-saving read-across across regulatory domains, paving the way for fully mechanistic, AI-enabled chemical safety assessment.

Background: While excessive oral intake of clozapine is known to cause severe complications, this case report highlights that even conventional doses of clozapine ingested after alcohol consumption-without reaching toxic concentrations-can lead to the rare complication of rhabdomyolysis when synergistic effects occur between the two substances.

Case presentation: We report a case of a 39-year-old male patient who presented with impaired consciousness 1 day after consuming 500 g liquor followed by ingestion of 8 clozapine tablets (200 mg total). Toxicology screening upon admission indicated subtoxic levels of clozapine. Laboratory findings confirmed rhabdomyolysis, acute kidney injury, and myocardial damage. During hospitalization, the patient underwent hemopurification and fluid resuscitation. His consciousness improved significantly, accompanied by marked improvement in creatine kinase (CK) levels, renal function, and cardiac enzymes. At 15-day follow-up, renal function, CK levels, and cardiac enzymes had returned to within normal limits.

Conclusion: In patients consuming clozapine after alcohol intake, dynamic monitoring of CK and myoglobin should be implemented regardless of whether toxicology results are within normal limits. Early implementation of blood purification can effectively disrupt the rhabdomyolysis-renal injury cascade, thereby securing a critical therapeutic window for clinical intervention.