Frontiers in toxicology最新文献

Turmeric (Curcuma longa) and Indian gooseberry (Phyllanthus emblica) are widely used for their ethnopharmacological properties, particularly in ASEAN countries. Recently, our group has formulated Thai rice instant granules containing turmeric extract and P. emblica fruit pulp (TR instant granules); however, their toxicity profile has not been evaluated. This study investigated the long-term safety of TR instant granules in rats and assessed their effect on hepatic antioxidant status. Oral administration at doses of 200, 600, and 2,000 mg/kg body weight for 180 days resulted in no toxic effects, behavioral changes, mortality, or alterations in organ weights or hematological parameters. Significant changes were observed in biochemical markers, but there were no histopathological abnormalities. TR instant granules significantly upregulated hepatic antioxidant genes (Nrf2, GPx, CAT, GR, SOD, and HO-1). Phytochemical analysis identified chlorogenic acid and curcumin as major constituents. In silico molecular docking demonstrated that these compounds strongly bind multiple antioxidant enzymes and the Nrf2-Keap1 complex, supporting their potential as effective modulators of cellular antioxidant defenses. Overall, long-term administration of TR instant granules is safe and may enhance antioxidant mechanisms in rats. These findings support the potential development of TR instant granules as a safe functional food or nutraceutical with antioxidant benefits.

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) causes disabling cognitive-behavioral symptoms. While cortical atrophy is recognized as a correlate of long-term outcome, links between intracortical microstructural dynamics and clinical presentation remain largely unexplored. We followed a 51-year-old man with new-onset DEACMP for 5 months, using serial MRI combining cortical thickness with T1-weighted/T2-weighted (T1w/T2w) mapping as a proxy for intracortical microstructure. Despite progressive cortical thinning, T1w/T2w signals showed heterogeneous, region-specific trajectories. In the frontal networks, increases within premotor and dorsolateral prefrontal cortices aligned with improvements in executive function, whereas limited change in orbitofrontal/ventrolateral cortices was consistent with behavioral disinhibition. Overall, the clinical picture tracked more closely with intracortical signals than with morphometric atrophy. By combining T1w/T2w mapping with morphometry, this case provides the first longitudinal evidence of divergent cortical trajectories in subacute DEACMP-progressive thinning versus early intracortical improvement; confirmation in larger cohorts is warranted.

The use of Heated Tobacco Products (HTPs) is expected to have a reduced-risk potential for cardiovascular disease, including atherosclerosis, compared with combustible cigarettes (CCs) Because of the complex relationship between atherosclerosis and lifestyle factors, such as diet, physical activity, and smoking, focusing on the pathogenesis of atherosclerosis will help deepen our understanding of the reduced risk potential of HTPs. Organ-on-a-chip platforms are widely used to mimic human pathophysiology when studying such pathologic manifestations. In this study, a Vascular-on-a-Chip (VoC) model was used to mimic the characteristic physiology of the human vasculature and to establish an assessment model to measure three endpoints: endothelial barrier impairment, monocyte adhesion, and monocyte migration through vascular endothelial cells (VECs) which are the important initial key events in atherosclerosis. Macrophages were exposed to test cigarette smoke (CS) and HTP aerosol extracts, and conditioned medium was collected. VECs cultured on VoC were exposed to these conditioned media to mimic the effects on the vascular system caused by inflammatory responses elicited by inhaled substances. The HTP aerosol-exposed group had significantly reduced endothelial barrier impairment, monocyte adhesion, and monocyte migration compared with the CS-exposed group, and there was no significant difference with the solvent control. In summary, our model provided valuable insights into the reduced risk potential of an HTP compared with a CC by evaluating a series of endpoints in the early stage of atherosclerosis.

The Beibu Gulf, a representative semi-enclosed bay in the South China Sea, experiences microplastic transport and dispersion governed by a complex interplay of monsoons, ocean circulation, and extreme weather events, warranting systematic investigation. We developed a numerical modeling framework by coupling a three-dimensional hydrodynamic model with a Lagrangian particle-tracking module, and validated it against in observations. The model quantitatively demonstrates high accuracy, with maximum spatial deviations below 6 km and relative standard deviations within 7%, confirming its suitability for simulating microplastic transport. The simulation results indicate that the transport of microplastics in the Beibu Gulf is primarily controlled by the oceanic hydrodynamic environment, while also being indirectly affected by the monsoon. During winter and autumn, the northeast monsoon dominates, whereas in spring and summer, the southwest monsoon prevails, with the overall circulation exhibiting a counterclockwise coastal current pattern. In spring, microplastics can disperse up to 205 km, while in summer, southwest monsoon conditions lead to the formation of nearshore high-concentration zones (∼20 μg/m³). Vertical transport significantly modulates plume structure, with summer pollution coverage expanding by over 70% compared to scenarios excluding vertical motion.Storm surge events further intensify hydrodynamic conditions. As a case study, Typhoon Yagi induced significant alterations in the hydrodynamic conditions of the Beibu Gulf: prior to the storm, tidal forces governed periodic flow variations; during and after the storm, intense circulations generated prominent counterclockwise vortices, with velocities reaching 2.8 m/s, substantially enhancing long-range microplastic transport and extending their spatial distribution. This study reveals the key characteristics of microplastic transport in the Beibu Gulf under varying seasonal and hydrodynamic conditions, providing a rigorous theoretical foundation for understanding regional microplastic dispersal patterns.

Introduction: Despite the availability of control animal data sets from toxicological studies, the influence of external factors, such as age of animals, test site and study conditions, on clinical laboratory parameters in rats is only sparsely characterized.

Objective: In order to analyze the covariates of study design, we leveraged the largest available curated collection of control animal data from toxicological studies, sourced from five European pharmaceutical companies. We investigated the influence of external factors on commonly measured clinical chemistry, enzyme activity and hematology parameters in Han Wistar rats of both sexes.

Materials and methods: 457,605 control group clinical laboratory data points from 1,288 legacy toxicity studies on Han Wistar rats were curated and analyzed by ANOVA and partial eta squared to discern their effect sizes.

Results: Our analysis revealed that bodyweight, used as a surrogate for age in rats, significantly influences some parameters, while demonstrating stability in others. Descriptive statistics and tolerance intervals are provided for 20-g body weight class intervals. The effect size of these body weight classes, as calculated by partial eta squared, is large for parameters that change during development (e.g., phosphate or alkaline phosphatase) but was negligible for more stable parameters (e.g., calcium and alanine aminotransferase). For parameters which are less dependent on body weight class, the relative influence of other factors, namely, the company providing the study data, as well as study year is more prominent. These factors likely act as summary factors for various influences such as changes in analytical protocols, diet or housing conditions.

Conclusion: This analysis provides a comprehensive overview of parameter variability and offers critical guidance for parameters which need to be controlled when utilizing historical control data to establish reference intervals or generate virtual control groups.

The advancement of human pluripotent stem cell (hPSC) culture systems has revolutionized the landscape of preclinical drug discovery and toxicological evaluation. Progressing innovations from feeder-dependent and xenogeneic matrices to chemically defined, xeno-free, and fully synthetic platforms have addressed long-standing challenges in reproducibility, safety, and clinical translation. Developments in recombinant extracellular matrix proteins, synthetic peptide substrates, and polymer-based coatings have enabled the generation of Good Manufacturing Practice (GMP)-compliant, scalable hPSC cultures while minimizing biological variability and immunogenic risks. Integration of automation, artificial intelligence (AI), and three-dimensional (3D) bioprocessing technologies aims at further enhancement of standardization, quality control, and throughput. In the context of pharmaceutical research, hPSC-derived cellular models now underpin high-throughput drug screening and mechanistic toxicological assays, offering superior human relevance compared to traditional animal models. Despite these advances, barriers such as cellular immaturity, inter-batch variability, and limited regulatory acceptance persist, underscoring the need for further protocol standardization and technological refinement. This review provides a comprehensive analysis of current animal-free hPSC culture platforms, critically examines their strengths and limitations, and discusses future directions for advancing their application in drug discovery and predictive toxicology. The ongoing evolution of hPSC technologies promises to accelerate the development of safer, more effective therapeutic agents and to reshape the future of human disease modeling and pharmacological research.

The accumulation of microplastics (MPs) in aquatic environments is a contemporary concern of great relevance, however, freshwater ecosystems, particularly reservoirs, have received less attention. This study evaluates the MPs in Rabagão and Aguieira Portuguese reservoirs, and their role in ecological quality assessments. Along 2023, sub-surface water samples were collected to assess Ecological Potential, under Water Framework Directive (WFD) metrics, and to characterize MPs by type, colour, size, and chemical composition. Reservoirs were also characterized by land use, soil occupation, and anthropogenic pressures. Results confirm MPs contamination in both reservoirs, predominantly fibres, with Rabagão exhibiting higher total abundance (Rabagão 5,862 vs Aguieira 1,658 MPs). Microplastic concentrations varied across sampling sites and periods in both reservoirs, with the Rabagão reservoir exhibiting greater spatial variation among sites within sampling periods and more pronounced seasonal fluctuations. In both study areas, the highest abundances were consistently recorded near the dams. In both reservoirs, the predominant colours were blue, black, and grey, and the most observed size ranged from 0.1 to 0.5 mm. ATR-FTIR analysis identified polyethylene, polyethylene terephthalate, polyester, nylon, polyvinyl chloride, and polyvinyl acrylate. Anthropogenic pressures including aquaculture, wastewater discharges, and recreational activities were identified as potential pollution sources. Despite fewer pressures and better ecological status (according to the parameters evaluated following the WFD approach), Rabagão had higher microplastic contamination. On the contrary, Aguieira, which exhibited poorer ecological quality, had lower microplastic concentrations. This finding emphasizes that conventional water quality indicators may not adequately reflect the presence and influence of MPs, reinforcing the need to incorporate them into ecological assessment frameworks, especially in reservoirs used for human purposes.

A recent study has suggested that plastics may contain more than 16,000 chemicals, including additives, processing aids, starting substances, intermediates and Non-Intentionally Added Substances. Plastic chemicals are released throughout the plastic life cycle, from production, use, disposal and recycling. Most of these chemicals have not been studied for potential hazardous properties for humans and in the environment. To refine the risk assessment of these leachable chemicals, additional hazard data are needed. The PlasticLeach project within the EU co-funded Partnership for the Assessment of Risks from Chemicals (PARC) aims to address this data gap by screening several plastic products in daily use. Leachates will be prepared from a number of these plastic items, and these chemical mixtures will be further tested using several test guideline compliant assays and New Approach Methodologies covering both human health and environmental endpoints. The most toxic leachates will be characterized using a non-targeted analysis pipeline to identify chemicals in the leachate. When single chemicals of concern are identified, these will be further tested to determine hazardous properties and identify the respective potency factors to better understand their specific hazard profiles. A tiered approach for hazard testing will be followed. The experimental work will be complemented by in silico toxicological profiling, using publicly available toxicity databases and tools, including Artificial Intelligence tools that cover both human and environmental endpoints. A comprehensive array of endpoints, including cytotoxicity, endocrine disruption, genotoxicity, immunotoxicity, reproductive toxicity and effects related to ecotoxicity will be evaluated. In this paper, we outline the plastic products to be tested and the battery of assays that will be used to identify hazards relevant to both human health and the environment. Data generated from in silico, in vitro, and in vivo approaches will be reported using standardized formats, stored within a centralized repository, and harmonized to adhere to the FAIR data principles (Findable, Accessible, Interoperable, and Reusable). This integrated strategy will not only advance our understanding of the risks associated with plastic-derived chemicals but will also provide critical support for regulatory decision-making and facilitate the development of safer, and more ecofriendly plastic materials in the future.

Aluminum is toxic to both humans and animals. Exposure to AlCl₃ can lead to kidney function damage, yet the specific underlying mechanism remains elusive. This study aimed to investigate whether ferroptosis is involved in the renal toxicity induced by AlCl₃ exposure in mice and to elucidate its potential molecular mechanism. Forty-eight C57BL mice were randomly assigned to six groups, with eight mice in each group: a control group, low -, medium -, and high - dose aluminum exposure groups, a ferroptosis inhibitor group, and a ferroptosis inhibitor + high - dose aluminum exposure group. Mice in the aluminum exposure groups received intraperitoneal injections of different doses of AlCl₃ solution for 4 weeks (5 times per week), while the ferroptosis inhibitor group was intraperitoneally injected with Fer - 1 for 4 weeks (2 times per week). After the experimental period, multiple indicators were examined. The results demonstrated that AlCl₃ exposure impaired the renal function and structure of mice. It also led to an increase in lipid peroxidation products, Fe²⁺, and Al content in renal tissue. Moreover, the expression levels of genes and proteins such as GPX4 and Nrf2 were decreased, whereas the expression levels of the ACSL4 gene and protein were increased.However, after pretreatment with Fer - 1, the aforementioned indicators were ameliorated. Specifically, the expression of ACSL4 decreased, and the expression of GPX4 and other related factors increased.In conclusion, this study suggests that AlCl₃ exposure may trigger ferroptosis in renal tissue cells by inhibiting the NRF2 pathway, thereby causing kidney function damage in mice. These findings provide a novel perspective on the mechanism of AlCl₃ - induced renal toxicity.

Introduction: Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, impairs male reproductive health via oxidative stress, hormonal dysregulation, and hypothalamic-pituitary-gonadal (HPG) axis disruption. Flavonoids, widely present in plant-derived foods and medicinal herbs, possess antioxidant and steroidogenic modulatory properties that may counteract BPA toxicity, yet preclinical findings remain inconsistent. This study aims to systematically evaluate and quantitatively synthesize preclinical evidence on the protective effects of flavonoids against BPA-induced male reproductive toxicity.

Methods: Using PRISMA 2020 guidelines, Web of Science, Scopus, and PubMed were searched up to September 2024. Eligible studies involved BPA exposure in male rodents with flavonoid co-treatment and reported reproductive endpoints. Hormonal and oxidative stress biomarkers were pooled using a random-effects model, expressed as standardized mean differences (SMDs), with heterogeneity assessed by I² statistics. Twenty studies were included.

Results: BPA significantly reduced testosterone (SMD = -4.91), estradiol (SMD = -2.72), follicle-stimulating hormone (FSH) (SMD = -7.71), and luteinizing hormone (SMD = -5.54), while increasing malondialdehyde and reducing antioxidant enzymes (SOD, CAT, GPx, and GSH).

Discussion: Flavonoid co-treatment significantly improved hormonal profiles and oxidative balance, with the greatest recovery in FSH. High heterogeneity (I² > 84%) reflected variability in doses, treatment duration, compound purity, and species. Flavonoids exhibit marked ameliorative potential against BPA-induced reproductive toxicity in preclinical models, largely through hormonal regulation and oxidative stress mitigation. Standardized protocols and dose-response studies are essential to enhance reproducibility and translational relevance.