Frontiers in toxicology最新文献

Mycotoxins, as feed contaminants, pose serious health risks and cause significant economic losses on farms. The selection of an appropriate and effective adsorbent remains a key challenge for many researchers. Graphene oxide (GO) and its derivatives have garnered interest due to their exceptional physicochemical properties. However, the increasing use of GO necessitates a thorough investigation into its potential toxic impacts on animal and human health, as well as the environment. This study evaluates the effects of GO as a feed additive on calf health. Ten calves (100 ± 6 kg) participated in a 20-day experiment: five in the control group (C) and five in the experimental group (T). The control group (C) received feed without GO, while the experimental group (T) was fed a diet containing 30 g of GO/kg/day. Key parameters evaluated included growth performance, biochemical markers (ALT, AST, ALP), and mineral levels (Ca, P, Mg, K, Na, Cl, Fe, Cu, Zn). The average weight gain was 16.20 ± 0.32 kg in the control group and 15.40 ± 0.26 kg in the GO group, with no statistically significant difference (p > 0.05). Calves fed GO-enriched feed exhibited significant reductions in Fe (p = 0.041) and Zn (p = 0.0006) levels, while Mg increased significantly in the control group (p = 0.029). Liver parameters in group T showed significant increases in ALT (p = 0.022), AST (p = 0.027), and ALP (p = 0.015) after 20 days. Additionally, GPx activity was significantly decreased in the GO group (p = 0.011). These results suggest that GO at a dose of 30 g/kg/day in feed can negatively affect calf health.

Smoking and particulate matter 2.5 (PM2.5) expose millions to cadmium (Cd), a toxic heavy metal linked to pro-inflammatory responses, oxidative stress, and disease pathogenesis. In the oral cavity, chronic Cd exposure contributes to the progression of periodontal diseases and oral cancers. However, the direct effect of Cd on oral tissues and the underlying mechanisms remains unclear. This study explored the impact of environmentally relevant concentrations of Cd on human gingival fibroblasts (HGFs) by evaluating cell viability, pro-inflammatory cytokine secretion (IL-6 and IL-8), COX-2 expression, and the activation of key signaling pathways: Akt, ERK1/2, and JNK. Cd exposure significantly reduced HGF viability, elevated IL-6 and IL-8 secretion, and upregulated COX-2 expression. These effects were attenuated by inhibitors targeting Akt, ERK1/2, and JNK pathways. By integrating cytokine profiling, COX-2 expression, and inhibitor-based pathway analysis, our study provides mechanistic insights into how low-level Cd exposure triggers early inflammatory responses in gingival fibroblasts. Our findings reveal that Cd exerts pro-inflammatory and cytotoxic effects on HGFs, which may play a role as one of the factors in the pathogenesis of smoking-related oral diseases. Targeting Akt, ERK1/2, and JNK signaling pathways could offer therapeutic strategies to attenuate Cd-induced oral pro-inflammatory responses and tissue damage.

Reproductive toxicity is a concern critical to human health and chemical safety assessment. Recently, the U.S. Food and Drug Administration announced plans to assess toxicity with artificial intelligence-based computational models instead of animal studies in "a win-win for public health and ethics." In this study, we used a reproductive toxicity dataset using Simplified Molecular Input Line Entry Specifications (SMILES) to represent 1091 reproductively toxic and 1063 non-toxic small-molecule compounds. A repeated nested cross-validation procedure was applied, in which the dataset was randomly partitioned into five distinct folds in the outer loop, each time, one fold serving as the test set. In the inner loop, a similar procedure was also repeated five times, with 12.5% each time serving as the validation set. We first evaluated the performance of classical machine learning (ML) methods such as Random Forest and Extreme Gradient Boosting on predicting reproductive toxicity, using standard model evaluation metrics including accuracy score (ACC), the area under the curve (AUC) of the receiver operating characteristics curve (ROC) and F1 score. Our analyses indicate that these methods' overall results were mediocre and insufficient for high-throughput screening. To overcome these limitations, we adopted the Communicative Message Passing Neural Network (CMPNN) framework, which incorporates a communicative kernel and a message booster module. Our results show that our ReproTox-CMPNN model outperforms the current best baselines in both embedding quality and predictive accuracy. In independent test sets, ReproTox-CMPNN achieved a mean AUC of 0.946, ACC of 0.857 and F1 score of 0.846, surpassing traditional algorithms to establish itself as a new state-of-the-art model in this field. These findings demonstrate that CMPNN's deep capture of multi-level molecular relationships offers an efficient and reliable computational tool for rapid chemical safety screening and risk assessment.

In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments.

Introduction: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that accumulate in living organisms, posing significant human health risks. The toxicity mechanisms of PFAS include mitochondrial dysfunction and bioenergetic failure.

Methods: This study evaluates the structure-activity relationship of PFAS compounds with mitochondrial toxicity by comparing the Mito Tox Index (MTI) of perfluoroalkyl carboxylic acids (PFCAs) varying carbon chain lengths. The MTI quantifies the extent to which substances disrupt mitochondrial function by distinguishing between mitochondrial inhibition and uncoupling. This was followed by an assessment of the effect of PFCAs on total cellular bioenergetics and impedance-based real time cell viability measurement.

Results and discussion: Both inhibition and uncoupling MTI values increased with the chain length of PFCAs and severe mitochondrial inhibition was observed when uncoupling was maximized by PFCAs containing seven or more carbons within hours of exposure. The mitochondrial toxicity corresponded well to the bioenergetic failure measured by real-time ATP production rates. In contrast, there was a substantial difference between cytotoxicity and mitochondrial toxicity, despite a common trend of increased toxicity with longer chain lengths. The results suggest that PFCA-induced mitochondrial dysfunction is a key mechanism of PFAS-mediated cellular damage, primarily driven by proton leak-mediated ETC uncoupling, leading to impaired mitochondrial energy production. It also implies that MTI-based mitochondrial toxicity evaluation increases data precision in comparing PFAS effects on mitochondrial function, even identifying the mode of action, which is expected to improve in vitro toxicity prediction models.

Introduction: Type 2 diabetes mellitus (T2DM) is a major global health concern frequently related with chronic low-grade inflammation and a spectrum of cognitive impairments, including deficits in learning and memory. Mercury chloride (HgCl₂), a widespread environmental pollutant, is recognized for its neurotoxic properties and its capacity to trigger inflammatory responses, particularly in patients with metabolic disorders such as T2DM.

Aim: This study aimed to evaluate the subchronic effects of HgCl₂ on cognitive performance and neuroinflammation in a rat model of T2DM, with a particular focus on the roles of BDNF and acetylcholinesterase (AChE).

Materials and methods: The experimental design included four groups: control, HgCl₂-treated, diabetic, and diabetic rats treated with HgCl₂. T2DM was induced by intraperitoneal injections of streptozotocin (STZ) and nicotinamide (NA). Rats in the HgCl₂-exposed groups received an oral dose of 0.375 mg/kg/day for 45 consecutive days. Cognitive performance was assessed using behavioral tests targeting spatial learning, recognition memory, and working memory. Additionally, hippocampal and prefrontal cortex (PFC) levels of TNF-α, IL-6, BDNF, and AChE activity were measured to evaluate neuroinflammatory and neurotoxic responses.

Results: The findings revealed a significant increase in fasting blood glucose levels in both diabetic and HgCl₂-treated diabetic groups compared to controls (P < 0.001). Moreover, HgCl₂ administration in diabetic rats led to a more pronounced impairment in cognitive functions compared to untreated diabetic rats (P < 0.05). These deficits were associated with enhanced neuroinflammatory markers (TNF-α and IL-6), decreased AChE activity, and reduced BDNF expression in the PFC and hippocampus (P < 0.05).

Conclusion: Overall, these results highlight the synergistic impact of hyperglycemia and HgCl₂ exposure in exacerbating neuroinflammation and cognitive decline, suggesting a critical interaction between metabolic and environmental neurotoxic factors.

This paper examines the global communities' regulatory and scientific advancements in nanotechnology and nanomaterials since 2000. It explores some similarities and differences in nanomaterial safety compared to general chemical safety. The paper provides an overview of the encountered challenges and how far they have been resolved, as well as information on how different countries' legislators have addressed nanomaterials, including safety assessment in (new) legislation. Challenges arose due to the unique physico-chemical properties of some nanomaterials and included the lack of i) a regulatory definition, ii) applicable regulatory test methods, including methods for physico-chemical characterization and for ecotoxicological effects, as well as sample preparation and dosimetry, iii) assessment and modelling of human, especially occupational, and environmental exposure to nanomaterials, iv) quantification of nanomaterial in complex media, v) systems for collecting the data generated and ensuring FAIR (Findable, Accessible, Interoperable and Re-usable) and quality data, vi) reference nanomaterials, and vii) a frame for nanotechnology governance. The paper highlights the role of the Organisation for Economic Co-operation and Development (OECD) in building a global, regulatory understanding of nanotechnology and nanomaterials, as well as the OECD's achievements of developing nano-specific test guidelines. The paper identifies areas, such as alternative test methods, availability of reference nanomaterials, comparable data and FAIR data, analytical tools for quantifying nanomaterials in (complex) matrices that are still under-addressed. It gives a wider perspective of Governance of Advanced Materials including nanomaterials, also illustrated by carbon nanotubes used in batteries for electric vehicles, to also aid their commercialization. In the EU, the policy context is moving towards a holistic governance approach embracing sustainability dimensions.

Arsenic is an ubiquitous environmental toxicant with harmful physiological effects, including neurotoxicity. Modulation of arsenic-induced gene expression in the brain cannot be readily studied in human subjects. However, Drosophila allows quantification of transcriptional responses to neurotoxins at single cell resolution across the entire brain in a single analysis. We exposed Drosophila melanogaster to a chronic dose of NaAsO₂ that does not cause rapid lethality and measured survival and negative geotaxis as a proxy of sensorimotor integration. Females survive longer than males but show earlier physiological impairment in climbing ability. Single-nuclei RNA sequencing showed widespread sex-antagonistic transcriptional responses with modulation of gene expression in females biased toward neuronal cell populations and in males toward glial cells. However, differentially expressed genes implicate similar biological pathways. Evolutionary conservation of fundamental processes of the nervous system enabled us to translate arsenic-induced changes in transcript abundances from the Drosophila model to orthologous human neurogenetic networks.

Aims: In silico methods provide a resourceful toolbox for new approach methodologies (NAMs). They can revolutionize chemical safety assessment by offering more efficient and human-relevant alternatives to traditional animal testing. In this study, we introduce two Liver Physiological Maps (PMs); comprehensive and machine-readable graphical representations of the intricate mechanisms governing two major liver functions.

Methods: Two PMs were developed through manual literature curation, integrating data from established pathway resources and domain expert knowledge. Cell-type specificity was validated using Human Protein Atlas datasets. An interactive version is available online for exploration. Cross-comparison analysis with existing Adverse Outcome Pathway (AOP) networks was performed to benchmark physiological coverage and identify knowledge gaps.

Results: The LiverLipidPM focuses on liver lipid metabolism, detailing pathways involved in fatty acid synthesis, triglycerides, cholesterol metabolism, and lipid catabolism in hepatocytes. And the LiverBilePM represents bile acid biosynthesis and secretion processes, detailing biosynthesis, transport, and secretion processes between hepatocytes and cholangiocytes. Both maps integrate metabolism with signaling pathways and regulatory networks. The interactive maps enable visualization of molecular pathways, linkage to external ontologies, and overlay of experimental data. Comparative analysis revealed unique mechanisms to each map and overlaps with existing AOP networks. Chemical-target queries identified new potential targets in both PMs, which might represent new molecular initiating events for AOP network extension.

Conclusion: The developed liver PMs serve as valuable resources for hepatology research, with a special focus on hepatotoxicity, supporting the refinement of AOP networks and the development of human-oriented in vitro test batteries for chemical toxicity assessment. These maps provide a foundation for creating computational models and mode-of-action ontologies while potentially extending their utility to systems biology and drug discovery applications.

[This corrects the article DOI: 10.3389/ftox.2025.1572486.].