Frontiers in toxicology最新文献

Introduction: The increase in e-cigarette use in the population has led to substantial interest in the health impacts associated with e-cigarette smoking. E-cigarette smoking represents a key external environmental cell stressor. Whilst there have been several studies to investigate the effect of nicotine-containing e-cigarette fluid, there is still a significant lack of understanding of how nicotine-free e-cigarette smoking can impact individuals. However, preliminary studies indicate that nicotine-free e-cigarette smoking can cause impaired endothelial function in humans.

Materials and methods: In the present study, we therefore used a common brand of nicotine-free e-cigarette and human umbilical vein endothelial cells to assess angiogenic processes in vitro.

Results: We observed a significant upregulation in endothelial cell adhesion, migration and new tube formation with exposure to nicotine-free e-cigarette condensate (eVape) which was abrogated with exposure to the antioxidant, N-acetyl cysteine. Proteome analysis demonstrated that eVape exposure increased expression of the pro-angiogenic factors, angiogpoeitin-2, endoglin (CD105), PIGF and VEGF, as well as the ADP ribosylation factor, ARF6, and ARF6-GEF, ARNO. Chemical inhibition of ARNO reduced eVape-induced oxidative stress, angiogenic processes, and release of angiogpoeitin-2, endoglin (CD105) and VEGF.

Discussion: These findings demonstrate that nicotine-free eVape causes aberrant upregulated angiogenesis in an in vitro model of the human endothelium through ARNO-dependent signalling. This study is the first to demonstrate the molecular mechanisms in response to the cellular stressor, nicotine-free eVape which underlie impaired vascular function.

Introduction: Cisplatin (CIS) is a commonly utilized chemotherapeutic agent, but its use is often accompanied by adverse effects such as neurotoxicity and cognitive impairments, collectively referred to as chemobrain. This condition impacts over 70% of cancer survivors, and currently, there are no established therapeutic interventions. This study aimed to evaluate the efficacy of tirzepatide in mitigating the neuropathy effects induced by cisplatin therapy.

Methods: Forty female Wistar albino rats were divided into four groups of ten: control (untreated), cisplatin (CIS), tirzepatide (TIRZ), and CIS/TIRZ. Treatments were administered intraperitoneally in two injections. The CIS group received cisplatin at a dosage of 5 mg/kg, while tirzepatide was administered at 1.35 mg/kg. In the CIS/TIRZ group, tirzepatide (1.35 mg/kg) was administered prior to cisplatin (5 mg/kg), with a 3-h interval between the two treatments. Post-treatment, behavioral assessments (Y-maze) and oxidative stress biomarkers were evaluated, including enzymatic antioxidants catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx-1), as well as oxidative damage markers such as reactive oxygen species (ROS) and malondialdehyde (MDA).

Results: Survival rates were 90% in both the TIRZ and CIS groups, and 70% in the CIS/TIRZ group, whereas all rats in the control group survived. All treatment groups experienced a reduction in body weight compared to the control group. Cisplatin administration resulted in impaired learning and memory in the Y-maze test, which was linked to decreased levels of the antioxidants GPx-1 and catalase, with no alteration in SOD levels. Additionally, ROS and MDA levels were slightly elevated in the CIS and TIRZ groups individually. Although tirzepatide did not ameliorate the memory deficits or antioxidant reductions caused by cisplatin, it did lead to a reduction in ROS and MDA levels.

Discussion: CIS therapy accelerates memory deficits in female rats by increasing oxidative stress. However, TRIZ did not alleviate the memory deficits or antioxidant reductions, although it did reduce ROS levels.

In 2018, the Cannabis Act and its regulations established a strict legal framework for controlling production, distribution, sale and possession of cannabis across Canada. At that time, smoking dried cannabis was the most prevalent mode of consumption, and remains so to date, but cannabis vaping products have become increasingly popular since they were made commercially available in late 2019. Heavy metals are a recognized class of impurities in cannabis products that can pose consumer health concerns. The Cannabis Regulations ensure a quality-controlled supply of cannabis by requiring good production practices (GPPs) and refer to pharmacopoeias for impurity tolerance limits. For elemental impurities, pharmacopoeias specify tolerance limits based on route of exposure and as a permitted daily exposure (PDE). This paper presents a risk assessment case study based on levels of metals measured in legal products that have been published by Health Canada on dried cannabis and cannabis vaping liquids to illustrate the challenges in assessing risks from a regulatory and quality control perspective, using daily or almost daily typical (50th percentile) and heavy (95th percentile) use as a worst case scenario. Applying PDEs from established pharmaceutical quality control standards for the newly legalized cannabis industry has its own challenges, characterized by existing uncertainties which must be addressed, in particular as they relate to exposure characterization. This risk assessment identifies that there is a low risk to health from heavy metals in Canadian legal and regulated inhaled cannabis products, especially as most cannabis consumers in Canada are not daily or almost daily users. These findings suggest that the goal of the Cannabis Act to mitigate risks to health by providing access to a quality-controlled supply of cannabis has been achieved in this regard.

Polyethylene microplastics (PE-MPs), now pervasive environmental contaminants, have been implicated in reproductive toxicity, but their mechanistic effects on testicular function remain poorly defined. This study investigates the mechanistic basis of PE-MPs-induced male reproductive toxicity in a rodent model (Wistar rats), with a specific focus on testicular mitochondrial redox homeostasis and oxidative phosphorylation. By integrating mitochondrial bioenergetics, redox signaling, histopathology, and reproductive endpoints, the work advances mechanistic toxicology insights relevant to environmental reproductive health. Fifteen male rats were randomly divided into three groups: control, and PE-MPs treated groups receiving 15 or 60 mg/kg body weight orally for 28 days. Testicular mitochondria were isolated to evaluate activities of tricarboxylic acid (TCA) cycle enzymes, citrate synthase (CS), isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH), as well as respiratory chain complexes I-IV. Mitochondrial redox balance indices, including malondialdehyde (MDA), myeloperoxidase (MPO), reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), were also assessed. PE-MP exposure induced a dose-dependent suppression of TCA cycle and electron transport activities, with CS and SDH inhibited by up to 50% at the highest dose suggesting a broad inhibition of electron transport and ATP synthesis. These mitochondrial impairments coincided with elevated MDA and MPO levels, and significant depletion of GSH, CAT, and SOD, indicating profound mitochondrial oxidative distress. These mitochondrial disturbances correlated with histological evidence of testicular degeneration and decreased testosterone levels. Collectively, the findings of this study highlight that PE-MPs compromise testicular bioenergetics and function by disrupting testicular oxidative phosphorylation and redox homeostasis, leading to mitochondrial dysfunction, structural degeneration, and impaired steroidogenesis, providing mechanistic insight into microplastic-induced male infertility. Understanding this bioenergetic collapse provides a biochemical framework for assessing the reproductive toxicity of microplastics and underscores the urgency of mitigating their exposure in vulnerable populations.

Clinical research on cannabinoids relies on purified compounds and controlled dosing, creating a data gap that ignores the realities of illicit markets. This perspective, informed by thirteen years of firsthand experience within India's prohibited cannabis ecosystem, argues that unregulated products like Ganja and Charas pose significant, overlooked toxicological risks. These risks arise not primarily from cannabinoids themselves, but from unpredictable potency, pesticide contamination, and adulteration in the absence of quality control. Personal consumption patterns reveal that inconsistent products make precise dosing impossible and that standard clinical assessments fail to capture users' sought-after effects, such as cognitive enhancement. To address this public health challenge, this paper calls for: 1) the chemical analysis of illicit products, 2) qualitative research on real-world use, 3) the development of user-centered outcome measures, and 4) ultimately, a transition from prohibition to regulation as the most effective intervention for consumer safety and informed choice.

Bisphenol A (BPA) is a widely used endocrine-disrupting chemical that is used to manufacture epoxy resins and polycarbonate plastics. Dietary intake is considered the primary source of human exposure through leaching into food and beverages in contact with storage containers. BPA alters brain function through a wide variety of mechanisms, including oxidative stress, endocrine disruption, developmental toxicity, inflammation, epigenetic modifications, and altered neurotransmission systems. Long-term exposure to even small concentrations of BPA has been associated with neurotoxicity. Mechanistic underpinning of neurotransmitters and free radical-mediated neurotoxicity of BPA is linked with Glutamate (Glu), which plays a vital role in normal brain functioning. Excitatory amino acid transporters (EAATs) play a crucial role in maintaining normal levels of Glu in the synaptic cleft, and EAAT dysfunction leads to excitotoxicity. We studied the effect of oral BPA exposure (40 μg/kg and 400 μg/kg doses) for 60 days in male mice. BPA exposure caused altered spatial learning and deteriorated sensorimotor coordination in exposed animals. These findings were supported by a decrease in acetylcholinesterase (AChE) activity and an increase in monoamine oxidase (MAO), coupled with nitrosative and oxidative overload in the cerebral cortex. A significant upregulation in expression of EAATs and xCT was observed in BPA-treated animals compared to controls at mRNA and protein levels in the cerebral cortex. BPA also caused histopathological changes in the cortical and hippocampal regions of exposed mice. Results of our study prove that even low-dose BPA exposure caused neurotoxicity and altered the expression of Glu-transporters with putative behavioral changes.

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.