Frontiers in toxicology最新文献

The zebrafish (Danio rerio) has become an indispensable model in toxicological research, bridging environmental monitoring, disease modeling, and preclinical drug screening. This study presents a comprehensive bibliometric and methodological analysis of 20,291 publications from 2014 to 2024, revealing distinct trends and opportunities in the field. Acute toxicity studies dominate the literature (39.36%), followed by neurotoxicity (19.50%) and immunotoxicity (11.39%), reflecting the widespread adoption of high-throughput embryonic assays such as the Fish Embryo Acute Toxicity (FET) test. While the model's strengths in rapid hazard assessment are well-established, our analysis identifies a significant emphasis on early developmental stages (embryos and larvae), creating a critical gap in chronic toxicity evaluation and adult organism studies. Methodologically, zebrafish toxicology leverages a versatile toolkit including behavioral phenotyping, high-resolution imaging, molecular analyses, and omics technologies. However, applications often remain isolated within specific domains, highlighting the need for more integrative approaches. The field is characterized by strong growth led by China and the United States, with research published predominantly in environmental and multidisciplinary journals. Substantial numbers of studies investigating "Unclassified Compounds" indicate both innovation in studying emerging contaminants and challenges in metadata standardization. We conclude that future advancements require leveraging multi-omics integration and sophisticated transgenic tools to transform the zebrafish from a screening model into a predictive platform for systems toxicology. By addressing current limitations in life-stage representation, chronic exposure paradigms, and translational validation, zebrafish research can fully realize its potential in shaping regulatory policies and advancing personalized toxicology.

Computational toxicology plays an important role in chemical safety assessments. Computational methods are applied to early-stage screening in drug discovery, hazard identification, and regulatory safety assessment. This article presents an overview of the foundational skills, technical capabilities and regulatory literacy recommended to successfully apply and evaluate (Q)SAR ((Quantitative) Structure-Activity Relationship) methodologies (e.g., statistical and alert-based approaches) and read-across within established frameworks such as the (Q)SAR Assessment Framework (QAF), OECD validation principles and context-specific regulatory frameworks; for example, ICH M7. Additionally, the manuscript covers strategies that can be used to integrate theoretical and practical experience with foundational skills (e.g., internships, case studies, regulatory simulations). An overall educational framework that emphasises competency-based education through interdisciplinary exposure is presented. The framework outlines the progression from foundational knowledge to methodological understanding, context of use application and the ability to assess the reliability of outcomes. Although the integrated framework is applicable to both regulatory and non-regulatory use contexts, the manuscript presents regulatory focused use cases, which could be explored within educational settings. These use cases consider mature, as well as emerging regulatory applications, and therefore highlight the need to apply foundational principles (e.g., expert review, qualification of methods) in diverse contexts. This approach reinforces a context-of-use driven approach to curriculum design and provides opportunities for growth through real-world application and experiential learning, supported by collaborative initiatives and open-access resources.

Understanding the toxicological mechanisms of food contaminants is critical for assessing risks to human health. This review comprehensively examines their adverse effects, tracing the pathway from molecular initiation to systemic organ-level damage. A central focus is placed on the growing trust on computational methods as ethical and practical alternatives to traditional animal testing. The discussion encompasses a multi-scale assessment, detailing atomic-level interactions through Density Functional Tight Binding Molecular docking and Molecular Dynamics (MD) simulations, analyses of toxicity pathway, and prediction of systemic fate using Physiologically Based Pharmacokinetic (PBPK) modeling. We further explore how these in silico insights are integrated with experimental data to build predictive models, including Quantitative Structure-Activity Relationship and machine learning frameworks. Ultimately, this review aims to inform the development of effective strategies for mitigating contaminant risks, thereby advancing public health objectives and supporting the 3Rs principles (Replacement, Reduction, and Refinement) in toxicological science.

Alzheimer's disease (AD) is a complex neurodegenerative condition and the leading cause of dementia worldwide. Treatments that safely and effectively counteract disease progression are currently lacking. While the formation of amyloid plaques has long been considered the leading hypothesis of disease onset, growing evidence suggests that the emergence of AD could be driven by a combination of underlying factors that promote chronic neuroinflammation, including pathogenic infections, environmental toxicants, and disruptions along the gut-brain axis. Traditional nonclinical models of AD, such as monolayer cell cultures and transgenic mice, struggle to capture the complexity of the disease as it occurs in humans. Human-centered complex in vitro models (CIVMs), including cerebral organoids and microfluidic organ-on-a-chip (OOC) technologies, provide greater physiological relevance by more closely recapitulating key cellular and molecular features of the human brain and disease mechanisms. In this mini review, we evaluate recent advances in CIVMs and how they are being leveraged to investigate emerging hypotheses of AD etiology. Cerebral organoids and OOC platforms can consistently replicate neuropathological hallmarks of neurodegeneration in response to pathogenic or environmental insults, including blood-brain barrier disruption, amyloid-β accumulation, tau hyperphosphorylation, and glial activation. We also highlight early efforts to model the gut-brain axis using organoid and multi-OOC systems, demonstrating how microbiota-derived factors can affect neural processes. Collectively, these studies show that human-centered CIVMs can be applied to both recreate and mechanistically disentangle interrelated pathological processes to an extent beyond that afforded by animal models, thus offering new opportunities to identify causal mechanisms and potential therapeutic targets.

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.