Frontiers in toxicology最新文献

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.

Cadmium (Cd) and glyphosate (Gly) are widespread aquatic contaminants known to impair reproductive function in freshwater fish. This study evaluated the effects of Cd, Gly, and their combined exposure on sperm quality and fertilization success in Prochilodus magdalenae, a commercially and ecologically important Neotropical species. Adult males were exposed to environmentally relevant concentrations of Cd, Gly, and a Cd + Gly mixture. Sperm motility parameters, membrane and mitochondrial integrity, DNA fragmentation, fertilization rate, and hatching success were assessed. Cd exposure significantly reduced sperm motility at 25 mg/L (45.0%), while Gly induced motility impairment at concentrations above 10 mg/L. Co-exposure to Cd and Gly further exacerbated the decline in motility (p < 0.05). Cd also caused significant mitochondrial and membrane damage at 25 mg/L, whereas Gly produced moderate alterations (p < 0.05). Fertilization rates declined across all treatments, with complete inhibition (0.0%) observed at the highest combined concentrations (Cd 25 mg/L + Gly 40 mg/L). No significant differences were found in sperm DNA fragmentation. This study shows that combined exposure to cadmium and glyphosate has a stronger negative impact on fish sperm quality than individual exposure. The effects depend on concentration, involving oxidative stress and alterations in motility and membrane integrity. These results contribute to understanding how mixed contaminants affect fish reproduction and emphasize the need for long-term studies under realistic environmental conditions.

In this study, we report that inhaled nanosized elongated mineral particles (EMPs) reach the human central nervous system (CNS) via two neuronal pathways, cranial nerve I (olfactorius) and cranial nerve V (trigeminus), from deposits on the nasal mucosa. High-resolution analytical imaging of autopsied brain tissues from eleven members of a Religious Orders Study (ROS) cohort (Rush Alzheimer's Disease Center) indicated that EMPs translocate from their nasal deposits to the brain either by the olfactory pathway (presence in the olfactory bulb (OB), olfactory tract, and amygdala) or by the trigeminal pathway (presence in the cerebellum). Sub-nanometer imaging and immunohistochemical (IHC) labeling were used to detect corpora amylacea (CA), abundant numbers of endogenous ferritin nanoparticles, and myelin damage as indicators of inflammation or oxidative stress. The majority of EMPs in the OB were identified as inorganic crystalline and amorphous SiO₂ fibers. Amphibole-like fibers (Mg/Si/Fe) were present (length from 25 up to 200 nm), along with lengthened nanoplastics and metallic or carbonaceous fibers. Extensive and consistent demyelination, phosphorylation, wall thickening, and CA bodies (size ranging from 10 nm to ∼10 μm) are present in all studied brain tissues. EMPs are frequently observed inside and outside of CA bodies that occur in close proximity to neurons with myelin damage. The majority of EMPs show shedding of nanosized fiber fragments and ions from their long fiber surfaces and the formation of carbon-rich coronas (physiochemical alterations: bioprocessing). Similar to spherical nanoparticles, EMPs show a tendency to bioprocess, which involves interacting with microglia, astrocytes, and CA. In conclusion, we note that although the presence of ambient EMPs in the OB, amygdala, and cerebellum of human brains is consistent with neuronal translocation from nasal deposits of inhaled EMPs to the human CNS, it remains important to further investigate the potential contribution of nano-EMPs entering from the blood compartment by crossing the blood-brain barrier (BBB) and other potential routes to the CNS.

Introduction: Ultrasonic water (UW) is a novel category of functional drinking water. This study aimed to investigate its laxative efficacy and underlying mechanisms using a constipation model in SD rats, while also conducting a comprehensive safety evaluation.

Methods: A rat constipation model was established to assess the purgative effect of UW. Safety was systematically evaluated through acute oral toxicity tests, subacute oral toxicity tests, a bone marrow cell micronucleus test, and an Ames test. Serum levels of gastrointestinal hormones-including motilin, substance P, vasoactive intestinal peptide, acetylcholinesterase, and somatostatin-were measured to explore potential mechanisms.

Results and discussion: UW significantly improved constipation symptoms of the test SD rats, with a significant increase in body weight (16.03 ± 5.32%) compared to the model group (8.67 ± 4.02%, P < 0.05). Compared to the model group, serum levels of excitatory gastrointestinal hormones were significantly elevated 4.20% (motilin), 10.87% (substance P), 36.69% (vasoactive intestinal peptide) and 12.89% (acetylcholinesterase) (P < 0.05), while somatostatin, was markedly reduced 22.40% (P < 0.05), respectively. Acute oral LD50 values of UW were higher than 20000 mg/kg, indicating practical non-toxicity. In the subacute toxicity test, compared to those in the control group, performances, blood routine indexes and serum biochemical indexes of the rats in the UW group showed no statistical difference (P > 0.05), and all the organs and tissues of the rats in both groups maintained normal morphology. Micronucleus effect of UW was not found when the dosage of UW was up to 20000 mg/kg. UW also showed no mutagenic activity on standard test strains. In summary, UW exhibited favorable purgative effect and safety.

Microplastic (MP) and nanoplastic (NP) pollution represents a pervasive environmental issue, raising significant concerns regarding potential neurotoxicity and impacts on brain health. This review synthesizes recent research findings to provide a comprehensive overview of the effects of MPs/NPs on the brain. Evidence demonstrates that MPs/NPs can cross critical biological barriers, including the blood-brain barrier and the placenta, gaining access to the central nervous system (CNS) and the developing fetal brain, influenced by particle size, charge, and the biomolecular corona. Once present, MPs/NPs trigger multiple detrimental pathways, including oxidative stress, persistent neuroinflammation involving microglia and astrocytes, mitochondrial dysfunction leading to energy deficits, disruption of crucial neurotransmitter systems, and direct neuronal damage. Critically, NPs have been shown to promote the aggregation of proteins implicated in neurodegeneration, such as alpha-synuclein. These mechanistic disturbances translate into observable adverse outcomes in experimental models, ranging from cognitive impairments in learning and memory to behavioral abnormalities and pathologies resembling human neurodegenerative and neurodevelopmental disorders. Toxicity is modulated by particle characteristics, co-exposures, and host factors like age and sex, with indirect effects via the gut-brain axis also playing a significant role. While current evidence, primarily from animal models often using high doses, strongly indicates a neurotoxic potential, significant research gaps remain concerning human risk assessment under chronic, low-level environmental exposure conditions and the effects of environmentally aged, mixed-plastic particles. Future research should prioritize human studies, environmentally realistic exposure scenarios, and differentiating direct versus indirect neurotoxic mechanisms to accurately evaluate the threat MPs/NPs pose to human brain health.