Particle and Fibre Toxicology最新文献

Background: Climate change and human activities have caused the drying of marine environments around the world. An example is the Great Salt Lake in Utah, USA which is at a near record low water level. Adverse health effects have been associated with exposure to windblown dust originating from dried lakebed sediments, but mechanistic studies evaluating the health effects of these dusts are limited.

Results: Monitoring data and images highlight the impact of local crustal and Great Salt Lake sediment dusts on the Salt Lake Valley/Wasatch front airshed. Great Salt Lake sediment and derived PM_< 3.1 (quasi-PM_2.5 or qPM_2.5) contained metals/salts, natural and anthropogenic chemicals, and bacteria. Exposure of mice via inhalation and oropharyngeal aspiration caused neutrophilia, increased expression of mRNA for Il6, Cxcl1, Cxcl2, and Muc5ac in the lungs, and increased IL6 and CXCL1 in bronchoalveolar lavage. Inhaled GSLD qPM_2.5 caused a greater neutrophilic response than coal fly ash qPM_2.5 and was more cytotoxic to human airway epithelial cells (HBEC3-KT) in vitro. Pro-inflammatory biomarker mRNA induction was replicated in vitro using HBEC3-KT and differentiated monocyte-derived (macrophage-like) THP-1 cells. In HBEC3-KT cells, IL6 and IL8 (the human analogue of Cxcl1 and Cxcl2) mRNA induction was attenuated by ethylene glycol-bis(β-aminoethyl ether)-N, N,N',N'-tetraacetic acid (EGTA) and ruthenium red (RR) co-treatment, and by TRPV1 and TRPV3 antagonists, but less by the Toll-like Receptor-4 (TLR4) inhibitor TAK-242 and deferoxamine. Accordingly, GSLD qPM_2.5 activated human TRPV1 as well as other human TRP channels. Dust from the Salton Sea playa (SSD qPM_2.5) also stimulated IL6 and IL8 mRNA expression and activated TRPV1 in vitro, but inhibition by TRPV1 and V3 antagonists was dose dependent. Alternatively, responses of THP-1 cells to the Great Salt Lake and Salton Sea dusts were partially mediated by TLR4 as opposed to TRPV1. Finally, "humanized" Trpv1^N606D mice exhibited greater neutrophilia than C57Bl/6 mice following GSLD qPM_2.5 inhalation.

Conclusions: Dust from the GSL playa and similar dried lakebeds may affect human respiratory health via activation of TRPV1, TRPV3, TLR4, and oxidative stress.

Background: The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis.

Methods: We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors.

Results: The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model's prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs.

Conclusions: The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.

Background: Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity.

Methods: Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes.

Results: DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis.

Conclusions: Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway.

Background: Hazard and risk assessment of nanomaterials (NMs) face challenges due to, among others, the numerous existing nanoforms, discordant data and conflicting results found in the literature, and specific challenges in the application of strategies such as grouping and read-across, emphasizing the need for New Approach Methodologies (NAMs) to support Next Generation Risk Assessment (NGRA). Here these challenges are addressed in a study that couples physico-chemical characterization with in vitro investigations and in silico similarity analyses for nine nanoforms, having different chemical composition, sizes, aggregation states and shapes. For cytotoxicity assessment, three methods (Alamar Blue, Colony Forming Efficiency, and Electric Cell-Substrate Impedance Sensing) are applied in a cross-validation approach to support NAMs implementation into NGRA.

Results: The results highlight the role of physico-chemical properties in eliciting biological responses. Uptake studies reveal distinct cellular morphological changes. The cytotoxicity assessment shows varying responses among NMs, consistent among the three methods used, while only one nanoform gave a positive response in the genotoxicity assessment performed by comet assay.

Conclusions: The study highlights the potential of in silico models to effectively identify biologically active nanoforms based on their physico-chemical properties, reinforcing previous knowledge on the relevance of certain properties, such as aspect ratio. The potential of implementing in vitro methods into NGRA is underlined, cross-validating three cytotoxicity assessment methods, and showcasing their strength in terms of sensitivity and suitability for the testing of NMs.

Background: Exposure to standard petrodiesel exhaust is linked to adverse health effects. Moreover, there is a mounting request to replace fossil-based fuels with renewable and sustainable alternatives and, therefore, rapeseed methyl ester (RME) and other biofuels have been introduced. However, recent toxicological research has indicated that biodiesel exhaust may also induce adverse health-related events.

Aim: To determine whether exposure to 100% RME biodiesel (BD100) exhaust would cause an acute airway neutrophilic recruitment in humans.

Methods: Fourteen healthy subjects underwent exposure to diluted BD100 exhaust and filtered air for 1-h, in a blinded, random fashion. Bronchoscopy with endobronchial mucosal biopsies, bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed six hours after exposure. Differential cell counts and inflammatory markers were determined in the supernatant and biopsies were stained immunohistochemically.

Results: Compared with filtered air, BD100 exhaust exposure increased bronchial mucosal endothelial P-selectin adhesion molecule expression, as well as neutrophil, mast cell and CD68 + macrophage numbers. An increased influx of neutrophils and machrophages was also seen in BW.

Conclusion: Exposure to biodiesel exhaust was associated with an acute airway inflammation that appeared similar to preceding petrodiesel exposure studies. The present findings, together with the recently reported adverse cardiovascular effects after similar biodiesel exposure, indicate that biodiesel is not free of toxicity and may affect human health.

The effects of ultrafine particle (UFP) inhalation on neurodevelopment, especially during critical windows of early life, remain largely unexplored. The specific time windows during which exposure to UFP might be the most detrimental remain poorly understood. Here, we studied early-life exposure to clean ultrafine carbonaceous particles (UFP^C) and neurodevelopment and central nervous system function in offspring.Pregnant wild-type C57BL/6J mice were either sham-exposed (HEPA-filtered air) or exposed to clean ultrafine carbonaceous particles at a concentration of 438 ± 72 μg/m³ (mean ± SD) and a count median diameter of 49 ± 2 nm (CMD ± GSD) via whole-body exposure for four hours per day. For prenatal exposure, mice were exposed for two consecutive days in two exposure periods, while the postnatal exposure was conducted for four consecutive days in two exposure periods. The mice were divided into four groups: (i) sham, (ii) only prenatal exposure, (iii) only postnatal exposure, and (iv) both prenatal and postnatal exposure. Neurodevelopmental behaviour was assessed throughout the life of the offspring using a functional observation battery.Early-life UFP^C-exposed offspring exhibited altered anxiety-related behaviour in the open field test, with exclusively postnatally exposed offspring (567 ± 120 s) spending significantly more time within the border zone of the arena compared to the sham group (402 ± 73 s), corresponding to an increase of approximately 41% (p < 0.05). The behavioural alterations remained unaffected by olfactory function or maternal behaviour. Mice with both prenatal and postnatal exposure did not show this effect. No discernible impact on developmental behavioural reflexes was evident.Early life exposure to UFP^C, particularly during the early postnatal period, may lead to developmental neurotoxicity, potentially resulting in complications for the central nervous system later in life. The current data will support future studies investigating the possible effects and characteristics of nanoparticle-based toxicity.

Background: Inhalation of respirable crystalline silica particles, including quartz, is associated with an increased risk of developing pathologies, including persistent lung inflammation, fibrosis, cancer, and systemic autoimmunity. We demonstrated that the nearly free silanols (NFS) generated upon quartz fracturing trigger the early molecular events determining quartz toxicity. Here, we address the involvement of NFS in driving short- and long-term pathogenic responses, including lung inflammation, fibrosis, cancer, and autoimmunity in multiple mouse models.

Results: In vivo pulmonary responses to as-grown NFS-poor quartz (gQ) and fractured NFS-rich quartz (gQ-f) of synthetic origin were compared to two NFS-rich reference quartz dusts (Min-U-Sil 5, mQ-f). Acute and persistent inflammation, as well as fibrosis, were assessed 3 and 60 days, respectively, after administering one dose of particles (2 mg) via oropharyngeal aspiration (o.p.a.) to C57BL/6 mice. The carcinogenic potential was assessed in a co-carcinogenicity study using A/J mice, which were pre-treated with 3-methylcholanthrene (3-MC) and administered four doses of quartz particles (4 × 1 mg, o.p.a.), then sacrificed after 10 months. Autoimmunity was evaluated in autoimmune-prone 129/Sv mice 4 months after particle administration (2 × 1.25 mg, o.p.a). Mice exposed to NFS-rich quartz exhibited a strong acute lung inflammatory response, characterized by pro-inflammatory cytokine release and leukocyte accumulation, which persisted for up to 60 days. No inflammatory effect was observed in mice treated with NFS-poor gQ. Fibrosis onset (i.e., increased levels of pro-fibrotic factors, hydroxyproline, and collagen) was prominent in mice exposed to NFS-rich but not to NFS-poor quartz. Additionally, lung cancer development (tumour numbers) and autoimmune responses (elevated IgG and anti-dsDNA autoantibody levels) were only observed after exposure to NFS-rich quartz.

Conclusions: Collectively, the results indicate that NFS, which occur upon fracturing of quartz particles, play a crucial role in the short- and long-term local and systemic responses to quartz. The assessment of NFS on amorphous or crystalline silica particles may help create a predictive model of silica pathogenicity.

Background: Inorganic ultraviolet filters such as titanium dioxide nanoparticles are frequently used in sunscreens. Numerous toxicological studies in vitro and in vivo have been conducted using pristine standard reference nanomaterials of these inorganic filters. While convenient, this approach is not realistic because the complex environment of sunscreen formulations could change the physicochemical properties of the nanoparticles and lead to vastly different toxicological outcomes. Therefore, this study focused on characterizing nanoparticles extracted from commercial sunscreen and evaluating the associated toxicological impacts upon exposure to human keratinocytes and human skin explants.

Results: Titanium dioxide nanoparticles were extracted from commercial sunscreens and thoroughly characterized. The identity of the associated molecular corona on the extracted nanoparticles was also evaluated. Cell metabolic and proliferation profiles, mitochondrial superoxide activity, reactive oxygen species levels, and genotoxicity induced through exposure to the nanoparticles were studied in vitro using a human keratinocyte cell line. The cell response was significantly different after treatment with pristine nanoparticles compared to corresponding sunscreen-extracted nanoparticles. Pristine spherical nanoparticles resulted in more pronounced toxicity in 2D cultured keratinocytes compared to extracted nanoparticles but did not impact wound-edge migration significantly in 3D ex vivo human skin explant models. Additionally, extracted rod-shaped nanoparticles had greater toxic impacts in keratinocytes in vitro and retarded wound-edge migration in the ex vivo model compared to the extracted spherical nanoparticles. Nevertheless, these heightened cell responses were not associated with any increase in phosphorylated γH₂AX (which is indicative of DNA damage) both in vitro and ex vivo.

Conclusions: This study shows the feasibility of extracting nanoparticles from personal care products such as sunscreens to obtain relevant forms to model real-life exposure scenarios. Overall, sunscreen-extracted nanoparticles were found to be less toxic compared to pristine equivalents but retarded wound-edge migration more significantly. Skin explant cultures provide a more realistic alternative to monolayer cell cultures, although the differential outcomes between the models need more in-depth evaluation.

Airborne micro- and nanoplastics (AMNPs) are ubiquitously present in human living environments and pose significant threats to respiratory health. Currently, much research has been conducted on the relationship between micro- and nanoplastics (MNPs) and cardiovascular and gastrointestinal diseases, yet there is a clear lack of understanding regarding the link between AMNPs and respiratory diseases. Therefore, it is imperative to explore the relationship between the two. Recent extensive studies by numerous scholars on the characteristics of AMNPs and their relationship with respiratory diseases have robustly demonstrated that AMNPs from various sources significantly influence the onset and progression of respiratory conditions. Thus, investigating the intrinsic mechanisms involved and finding necessary preventive and therapeutic measures are crucial. In this review, we primarily describe the fundamental characteristics of AMNPs, their impact on the respiratory system, and the intrinsic toxic mechanisms that facilitate disease development. It is hoped that this article will provide new insights for further research and contribute to the advancement of human health.

Background: Human exposure to micro- and nanoplastic particles (MNPs) is inevitable but human health risk assessment remains challenging for several reasons. MNPs are complex mixtures of particles derived from different polymer types, which may contain plenty of additives and/or contaminants. MNPs cover broad size distributions and often have irregular shapes and morphologies. Moreover, several of their properties change over time due to aging/ weathering. Case-by-case assessment of each MNP type does not seem feasible, more straightforward methodologies are needed. However, conceptual approaches for human health risk assessment are rare, reliable methods for exposure and hazard assessment are largely missing, and meaningful data is scarce.

Methods: Here we reviewed the state-of-the-art concerning risk assessment of chemicals with a specific focus on polymers as well as on (nano-)particles and fibres. For this purpose, we broadly screened relevant knowledge including guidance documents, standards, scientific publications, publicly available reports. We identified several suitable concepts such as: (i) polymers of low concern (PLC), (ii) poorly soluble low toxicity particles (PSLT) and (iii) fibre pathogenicity paradigm (FPP). We also aimed to identify promising methods, which may serve as a reasonable starting point for a test strategy.

Results and conclusion: Here, we propose a state-of-the-art modular risk assessment framework for MNPs, focusing primarily on inhalation as a key exposure route for humans that combines several integrated approaches to testing and assessment (IATAs). The framework starts with basic physicochemical characterisation (step 1), followed by assessing the potential for inhalative exposure (step 2) and includes several modules for toxicological assessment (step 3). We provide guidance on how to apply the framework and suggest suitable methods for characterization of physicochemical properties, exposure and hazard assessment. We put special emphasis on new approach methodologies (NAMs) and included grouping, where adequate. The framework has been improved in several iterative cycles by taking into account expert feedback and is currently being tested in several case studies. Overall, it can be regarded as an important step forward to tackle human health risk assessment.