Frontiers in toxicology最新文献

Background: Folk medicine has long employed plants to treat diseases. Consumers believe herbal treatments are safe since they are natural. Studies suggest that some plant compounds can cause chromosomal damage at high concentrations, while some can mitigate the genotoxicity caused by toxic substances. Sonchus oleraceus L. is a popular medicinal herb in Saudi Arabia as well as in the rest of the world. It has antioxidant, anticancer, and other biological properties. Sodium benzoate (SB) is a versatile food preservative used in packaged food and drink industries; it has been found to cause genotoxicity and DNA damage. Therefore, it is necessary to investigate the biological activity of Sonchus oleraceus extract and its ability to mitigate Sodium Benzoate-induced cytotoxicity and genotoxicity.

Aim: The current study evaluates biological properties of S. oleraceus leaf extract and reveals its potential mitigating role against sodium benzoate by using the Allium cepa in vivo bioassay and molecular analysis.

Methodology: S. oleraceus aqueous extract and sodium benzoate was prepared. Then, the effective concentration (EC₅₀) was determined, and concentrations with control were selected for each group. Roots of A. cepa were treated for 24, 48, and 72 h with concentrations (21.5, 43, and 64.5 mg/mL) of extracts with or without combined treatment with 4 mg/mL of SB for 24 h. The cytotoxicity was investigated by using mitotic index (MI) and the genotoxicity by micronuclei (MN), chromosomal abnormalities (CA) and then using the ISSR-PCR markers for molecular analysis.

Results: Compared to the controls, S. oleraceus and SB application as a single treatment decreased root length and MI index, and CA were increased, especially in higher concentrations. DNA damage was reported by ISSR-PCR markers. However, SB toxicity was mitigated by the co-treatment of S. oleraceus extract, which showed partial improvement in all variables depending on the application concentration, possibly due to its antioxidant properties. The cytogenetic assay showed the best antimutagenic efficacy at 21.5 mg/mL with a moderate inhibition rate greater than 25%.

Conclusion: The results indicate that the aqueous extract of S. oleraceus leaves, as a single treatment, induces a genotoxic effect on A. cepa cells, especially at high concentrations, and that S. oleraceus leaf extract, as a co-treatment, acts as a mutagen at high concentrations and a moderate antimutagenic at low concentrations. The findings also indicate that the cytotoxic capacity of SB in A. cepa highlights potential concerns that warrant further investigation.

Green microalgae, particularly Chlorella vulgaris, are a rich source of bioactive and nutritional compounds, making them promising candidates for nutraceutical applications. This study evaluated the antioxidant capacity, phenolic composition, and potential health effects of Chlorella vulgaris supplementation (1% and 8%) in male BALB/c mice over 4 weeks, as well as its preventive role in a murine model of chronic obstructive pulmonary disease (COPD). The extract showed a high antioxidant potential, supported by its phenolic and carotenoid profile. Supplementation, especially at 8%, enhanced antioxidant defences without signs of liver or kidney toxicity. In the COPD model, C. vulgaris reduced inflammation, improved oxidative stress balance, and partially restored normal lung structure. Additionally, changes in caecal metabolites suggested a positive impact on gut microbiota and metabolic homeostasis. Overall, C. vulgaris supplementation demonstrated detoxifying, antioxidant, and anti-inflammatory benefits, supporting its potential use as a functional food, particularly under stress-related conditions such as COPD.

Background and objectives: Scorpion envenomation presents with a wide spectrum of clinical manifestations, ranging from mild local symptoms to severe systemic complications. This study aimed to evaluate the diagnostic and prognostic utility of GPX4, IL-13, periostin, SDF-4, and thiol/disulfide homeostasis parameters in adult patients with confirmed scorpion envenomation.

Materials and methods: This prospective observational study included 60 adult patients with confirmed scorpion stings and 33 healthy controls. Serum levels of GPX4, IL-13, periostin, and SDF-4 were measured using ELISA. Thiol/disulfide balance was evaluated by spectrophotometric assay. Clinical severity was graded using a four-level scale (Grade I-IV) based on local and systemic findings. Receiver operating characteristic (ROC) analysis and logistic regression were performed to assess the diagnostic performance and independent predictive value of biomarkers.

Results: Patients exhibited significantly lower GPX4, native thiol, and total thiol levels, and higher disulfide, IL-13, periostin, and SDF-4 levels compared to controls (p < 0.001). The disulfide/native thiol and disulfide/total thiol ratios were also elevated. GPX4 (AUC = 0.984), SDF-4 (AUC = 0.900), and periostin (AUC = 0.850) demonstrated excellent diagnostic accuracy. GPX4 and disulfide levels were identified as independent predictors of envenomation. Biomarker levels significantly correlated with clinical severity grades.

Conclusion: Oxidative and inflammatory biomarkers, particularly GPX4, disulfide/native thiol ratio, IL-13, and periostin, provide diagnostic and prognostic value in scorpion envenomation. Incorporating these parameters into clinical assessment may enhance early risk stratification and guide management in the emergency setting.

Background: Exposure to the herbicide glyphosate may contribute to anxiety-related disorders. The mechanisms by which this occurs may involve effects on brain regions or alterations of gut microbiota implicated in emotions. Pre-clinical studies use unusually high doses to which humans may not normally be exposed. The effects of glyphosate on anxiety at doses considered safe are largely unexplored.

Methods: Adult male rats were administered glyphosate at a dose considered safe for 16 weeks. After 4 and 10 weeks, anxiety-like behaviors were tested in the open field and elevated plus maze, respectively. After 14 weeks, rats interacted with a novel neutral object, followed by a naïve rat of the same age and sex as a conspecific. Lastly, after 16 weeks, rats underwent fear conditioning, and freezing was quantified. Upon completion of the experiments, cellular activity was assessed using immunohistochemistry in brain regions implicated in anxiety and fear. Fecal pellets were collected to extract DNA and perform 16S rRNA community analyses.

Results: Glyphosate increases anxiety in the elevated plus maze after 10 weeks. Moreover, glyphosate decreases interaction to a novel object, but not to the conspecific, after 14 weeks. Furthermore, freezing increases to a novel neutral tone, but not a conditioned tone, after 16 weeks. Behavioral changes correspond to increases in cellular activity in the bed nucleus of the stria terminalis. Furthermore, we observed that glyphosate induces changes in the gut microbiota leading to a decrease in Lactobacillus species.

Conclusion: Glyphosate increases threat interpretation and alters cellular activity in brain regions implicated in promoting anxiety. Also, glyphosate induces gut dysbiosis and reduces the abundance of Lactobacillus, bacteria that play a role in the production of serotonin, which may further exacerbate the anxiogenic effect of glyphosate.

Introduction: The presence of central nervous system (CNS) safety concerns during early clinical testing that were not picked up in standard preclinical assessment is a major cause of attrition in drug development. It is also very expensive, time consuming and potentially dangerous for clinical trial participants. Rodent home cage monitoring approaches have previously been shown to deliver significant animal welfare benefits through group/social housing, minimal interventions avoiding stress that can confound results, and in some cases also animal reduction benefits with the multiplex data acquisition requiring fewer total animals. Here we looked at the utility of home cage monitoring to uncover potential CNS effects not identified using standard safety pharmacology tests.

Method: We hypothesised that longitudinal behavioural assessment-by capturing non-evoked behaviour and reducing sampling artefacts-would be more sensitive to adverse reactions in preclinical animal models (i.e., rodents). To test this, we selected three compounds which previously passed standard safety tests but were failed later including two during clinical trials. We validated the general methodology for using home cage monitoring in safety assessment study designs from single doses to repeat dosing for up to 4 weeks. We then re-tested the three compounds in single dose studies.

Results/discussion: We showed that the methodology fits well with standard study designs. More importantly we uncovered significant findings in all three compounds that were not observed in the original classic safety pharmacology tests. The lack of such effects observed in standard preclinical assessment likely reflects functional differences between the limited observational snapshots characteristic of this approach and the more comprehensive temporal resolution enabled by continuous home cage monitoring.

Introduction: This study evaluates the ecotoxicity of micro- and nano-sized titanium dioxide (TiO₂), either as active ingredients or incorporated into sunscreen formulations in the aquatic environment, by proposing a leaching protocol simulating a realistic scenario of human immersion in freshwater and seawater.

Methods: To this aim, an ecotoxicological screening of micro- and nano-TiO₂ active ingredients and incorporated into sunscreens was applied, by evaluating acute and sub-acute responses (bioluminescence and growth inhibition, immobilization, behaviour) in freshwater and marine bacteria, microalgae and crustaceans. Then, Ti concentration was measured in the leachates of sunscreens through Inductively Coupled Plasma mass spectrometry (ICP-MS).

Results and discussion: Toxic effects (EC₅₀s) were only found in microalgae and crustaceans exposed to TiO₂ active ingredients. No toxicity occurred with sunscreens formulations, although significant algal growth inhibition was determined, likely due to TiO₂ size rather than Ti concentration. By integrating a sunscreen leachate based methodology with a multi-species and multi-endpoint approach, this study introduces a novel ecosafety-oriented assessment of TiO₂ providing realistic ecotoxicological evidence relevant to freshwater and marine environments.

Introduction: Essential oils (EO), rich in bioactive metabolites with biocidal activity, present great potential for agricultural applications as new biopesticides. However, their high volatility and sensitivity to environmental conditions limits their application. To address these limitations, nanotechnology-based formulations have been developed, incorporating EO into natural clays such as montmorillonite (MMT). Due to its colloidal properties, high adsorption capacity, and modifiable surface, MMT serves as an effective carrier for stabilizing EO while controlling their release. Besides aiming to enhance EO efficacy, these MMT-based formulations also aim to minimize EO toxicity to non-target organisms.

Materials and methods: In this study, the toxicity of Satureja montana EO (SM EO), of its dispersant agent Tween 20^®, of the MMT nanoclay and of the nanoclay-EO formulation was evaluated using aquatic (Aliivibrio fischeri, Raphidocelis subcapitata, Lemna minor and Daphnia magna), and terrestrial (Folsomia candida and soil microbiota) non-target model organisms, following standard protocols.

Results: Among the tested species, R. subcapitata and D. magna, exhibited the highest sensitivity, with D. magna showing an EC₅₀ of 0.011 mg mL^-1 and a complete growth inhibition being observed for R. subcapitata at concentrations ≥0.021 mg mL^-1, for the nanoclay-EO formulation. F. candida reproduction was also significantly reduced for all tested concentrations of the nanoclay-EO formulation. In contrast, it was observed a stimulatory effect on soil microbial activity particularly for dehydrogenase and acid phosphatase enzymes.

Discussion: These findings suggest that the nanoclay-EO formulation did not reduce the toxicity of SM EO, and in some cases, may even raise ecotoxicological concerns, particularly for aquatic and soil invertebrates. This study highlights the importance of detailed ecotoxicological evaluations of biopesticide formulations based on plant-based and materials as essential oils, and other natural materials, as they cannot be assumed as safe compounds. To the best of our knowledge ecotoxicological data is limited for most of the EO including some that already in the market. Based on these results, the concentrations to be tested for efficacy against target organism (safe to non-target organism) should be lower than 0.007 mg mL^-1.

New approach methodologies (NAMs) aim for animal-free chemical risk assessments. However, many in vitro NAM models still depend heavily on Matrigel and collagen despite the ethical, reproducibility, and biomedical concerns regarding the use of animal-derived materials. As awareness regarding this problem grows, several animal-free extracellular matrix hydrogel alternatives have emerged in the market. However, NAM studies with alternative hydrogels are rather scarce. The present study provides a concise review of commercially available animal-free hydrogels as well as an experimental screening approach to identify biocompatible candidates for HepaRG cell culturing under static and dynamic conditions in a 96-well plate and an OrganoPlate 3-lane device (Mimetas B.V.), respectively. The hydrogels evaluated herein include PeptiMatrix Core and PuraMatrix as synthetic peptides, VitroGel Organoid-3 as a synthetic polysaccharide, GrowDex as a wood-derived polysaccharide, and a Matrigel-collagen mix as the animal-derived reference. The health and functionality of the HepaRG cells were assessed via viability, lactate dehydrogenase leakage, albumin and bile acid secretion, CYP3A4 enzyme activity, and gene expression analyses. All animal-free hydrogels tested herein supported HepaRG cell proliferation in both culture conditions, although the cells had inadequate structure support and exhibited lower hepatic synthetic capacity in the OrganoPlate microphysiological system device. Notably, the cells grown in PeptiMatrix 7.5 showed promising metabolic competence under perfusion, making it a potential candidate for xenobiotic metabolism studies after further optimisation. These findings serve as a starting point to encourage scientists to take steps towards more animal-free cell culturing.

Botanicals (e.g., extracts derived from plants, algae, or fungi) are increasingly utilized by consumers with the hope of enhancing their health, managing symptoms, or preventing ailments; however, these products have often had limited pre-market toxicity testing. Traditional toxicity testing (e.g., rodent testing) is complicated by the nature of botanicals as complex mixtures and the potential for lot-to-lot variability in chemical constituents. Cardiotoxicity is a key area of concern, as adverse effects on the cardiovascular system can have severe consequences, and although not commonly reported, there have been reports of adverse cardiac events. New approach methodologies (NAMs) offer human-relevant, efficient, innovative, and cost-effective solutions for evaluating the cardiotoxicity of botanicals. The Botanical Safety Consortium (BSC) was established to focus on identifying suitable NAMs to screen for potential toxicities associated with these widely used products. This manuscript outlines the BSC Cardiotoxicity Working Group's approach for evaluating NAMs for assessing the potential cardiotoxicity of botanicals. These NAMs leverage in vitro models, such as human-induced pluripotent stem cell-derived cardiomyocytes, and techniques like microelectrode arrays, voltage and calcium optical mapping, contractile force measurement, and mitochondrial function assays to evaluate botanical-induced effects on the cardiovascular system. Using well-characterized botanical extracts as case studies, the BSC aims to refine a toolkit for high-throughput and human-relevant cardiotoxicity screening. This foundational work supports the broader goal of improving botanical safety assessment practices and advancing the application of NAMs in regulatory toxicology.