Particle and Fibre Toxicology最新文献

Background: The mucosal origins hypothesis of rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses in the lungs that contribute to joint disease onset. However, the relationship between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood.

Results: This study compared the development of inflammatory arthritis in two genetically susceptible mouse strains, the BXD2/TyJ (BXD2) and chimeric HLA-DR4-IE transgenic (DR4-Tg), following delivery of c-silica to the lungs via oropharyngeal aspiration. In BXD2 mice, c-silica exposure was associated with rapid arthritis development, marked by synovial cell hyperplasia, pannus formation, and severe erosion of cartilage and bone. These features were preceded by pulmonary inflammation characterized by lymphoid-like cell clusters lining vessels and bronchi which cell-specific immunofluorescent microscopy identified as organized lymphoid structures consistent with inducible bronchus-associated lymphoid tissue (iBALT). Inflammatory arthritis was also preceded by autoantibodies associated with RA and other systemic autoimmune diseases including anti-citrullinated protein autoantibodies (ACPA) and rheumatoid factor (RF) in bronchoalveolar lavage fluid (BALF). However, the most predominant autoantibodies in BALF were against extractable nuclear antigens (ENA). Anti-ENA were also prominent in serum and microarray autoantigen analysis confirmed the response as targeting components of Sm and RNP small nuclear ribonucleoproteins (snRNPs). In contrast, DR4-Tg mice had no signs of arthritis, milder lung inflammation lacking iBALT, and negligible autoantibody responses.

Conclusion: Genetic predisposition beyond HLA-DR4 alone is required for the immunological manifestations that lead to c-silica mediated inflammatory arthritis. These findings provide novel insights into the relationship between mucosal exposure and RA pathogenesis.

Background: Carbon based fibers are considered to exhibit a carcinogenic potency when inhaled into the deep lung. Mesotheliomas develop after intraperitoneal application of multi-walled carbon nanotubes (MWCNTs) exceeding a diameter of about 37 nm, whereas carcinogenic potency decreases for diameters below this threshold. While large MWCNT diameters are associated with a rigid fiber geometry, this study examined the effects of MWCNTs with smaller diameters ranging from 10 to 30 nm. Also, a sample of single-walled carbon nanotubes (SWCNTs) exhibiting single fiber diameters significantly below 10 nm and showing a flexible geometry was included since individual SWCNT fibers can aggregate to form bundles that exhibit increased rigidity. Additionally, the carcinogenic effect of pitch-based carbon fiber fragments was investigated. Carbon fibers are industrially produced with diameters larger than 4 µm and are thus not per se respirable. However, pitch-based fibers tend to break along their longitudinal axis, resulting in respirable fragments, partially of critical WHO dimensions. Four CNT samples with a geometric mean diameter (GMD) of 30 nm, 20 nm, 10 nm, and smaller than 10 nm, as well as one fragmented carbon fiber sample (GMD 1.3 µm) were intraperitoneally injected into rats in two dosages (0.1 × 10⁹ and 1 × 10⁹ WHO fibers or WHO-analog nanofibers) and observed for up to 24 months. A long amosite asbestos (GMD 0.37 µm) with known fiber-specific carcinogenic effect served as a positive control (0.1 × 10⁹ WHO fibers).

Results: A small number of mesotheliomas occurred in all fiber types, but not at all dosages. For the carbon fiber material, a possible weak carcinogenic potency is seen at the higher dosage. For the SWCNT fiber, low number of mesotheliomas likewise suggest a weak carcinogenic potency. In the case of the MWCNT fiber with a GMD of 30 nm, very low number of mesotheliomas indicate a possible very weak carcinogenic potency. No clear carcinogenic potency was observed for the MWCNTs with GMDs of 20 nm and 10 nm.

Conclusions: Carbon fiber fragments and thin but bundled MWCNTs showed weak carcinogenic potency. Non-bundled MWCNTs with a diameter below 30 nm did not show clearcarcinogenic potency at a dose up to 1 × 10⁹ WHO-analog nanofibers.

Background: Microplastics have been repeatedly detected in the human body, yet uncertainties surround their bioavailability and fate due to experimental challenges and limitations, especially regarding their nano-sized counterparts. Knowing that toxicokinetics information is essential for accurate risk assessment and management, this research aimed to (1) evaluate different sample preparation and quantification methods for nanoplastics particles in mammalian tissue, and (2) investigate the lung retention, bioavailability and fate of these particles.

Methods: In this study, rats inhaled aerosols with up to 50 mg/m³ of Nile Red-labeled polystyrene (PS-NR) or unlabeled polyamide particles (PA-6) particles for 28 days. The tissues were analyzed for the presence of polymer particles. PS-NR were quantified in formalin-fixed tissue by confocal fluorescence laser microscopy with semi-automatic imaging analysis, and PA-6 particles were quantified in dried tissues by pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS).

Results: PA-6 deposition was detected and quantified in lung and lymph nodes. Deposition of PS-NR was quantified in lungs and lung-draining lymph nodes, but no particles were detected in the liver, spleen, and kidneys. The lung burdens and translocation to the draining lymph nodes were similar for both particles, and particles were still detectable after the end of the exposure periods (five weeks for PS-NR and 13 weeks for PA-6).

Conclusions: This work highlights limitations and applicability of the various methods for sample preparation, detecting and quantifying polymer particles in mammalian tissues. In addition, it provides reliable data on the internal dose of inhaled polymer particles.

Background: Fine particulate matter 2.5 (PM_2.5), a key indicator of air pollution, is classified as a human carcinogen. However, the link between air pollution and bladder cancer (BC) progression remains unclear. Dysregulation of the Wingless-related integration site (Wnt)/β-catenin and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways is a key driver of tumorigenesis in multiple cancers, including BC.

Results: This study demonstrated that PM_2.5 exposure enhances BC cell migration and invasion. Ribonucleic acid (RNA) sequencing identified the Wnt signaling pathway as a key regulator in PM_2.5-exposed BC cells. Elevated protein levels of Wnt3A, Wnt5A, and β-catenin, along with the nuclear translocation of β-catenin, further highlighted the role of the PM_2.5-activated Wnt/β-catenin pathway in promoting BC progression. The interaction between the Wnt/β-catenin and MAPK/ ERK pathways was examined using inhibitors and shRNAs. MEK or ERK inhibition not only suppressed PM_2.5-induced upregulation of Wnt3A, Wnt5A, and β-catenin nuclear translocation but also significantly reduced the migration and invasion of PM_2.5-exposed BC cells. Both pathways represent promising therapeutic targets, and several existing pathway-specific inhibitors may be repurposed for the future clinical management of PM_2.5-induced BC progression.

Conclusions: PM_2.5 promotes BC progression through both the MAPK/ERK and Wnt/β-catenin signaling pathways. MEK/ERK inhibition suppressed PM_2.5-induced nuclear translocation of β-catenin, suggesting that the MAPK/ERK pathway functions upstream of the Wnt/β-catenin pathway. This study provides mechanistic insights into how PM_2.5 exposure drives BC progression and offers a potential foundation for developing targeted therapies for PM_2.5-associated BC.

Background: Understanding the impacts of inhaled insoluble nanomaterials as they are encountered in the environment and workplace, in injured lungs remains limited, particularly with respect to their role in the progression or mitigation of lung pathology. While some studies suggest potential protective effects of cerium(IV) oxide nanoparticles (CeO₂NPs) under certain conditions, their influence during active disease processes is unclear. This study builds on prior work to investigate the effects of CeO₂NP aerosols on bleomycin-induced pulmonary injury and active disease processes.

Method: To establish conditions of active pulmonary disease processes, bleomycin was used in both animal and airway epithelium models. Male Sprague-Dawley rats were intratracheally instilled with bleomycin or saline (control) followed by nose-only inhalation exposure to CeO₂NP aerosols (diameter of ~ 43 nm) or control for 3 h per day for 4 days per week for one or two weeks. At three days postexposure, the animals were sacrificed for analysis of bronchoalveolar lavage (BAL) fluid, lung histopathology and global mRNA expression. Comparative in vitro studies were conducted to investigate biological responses at the cellular level, using 3D human small airway epithelium cultures (SmallAir™) exposed to CeO₂NP aerosols (with a diameter of ~ 86 nm) at the air-liquid-interface at deposition doses comparable to those received in vivo in the small airway.

Results: In vivo, bleomycin treatment resulted in an increase in total BAL cells and fibrotic staining, and significant induction of inflammatory and oxidative stress, as shown by mRNA sequencing analysis. One week of exposure to CeO₂NPs modified these responses by attenuating fibrotic staining and reducing the expression of genes associated with lung function, inflammation and epithelial-mesenchymal transition (EMT). In vitro, CeO₂NP exposure modulated some bleomycin-induced cellular responses, although these models do not fully capture the complexity of whole body and tissue systems, highlighting limitations and considerations for future in vitro exposure studies.

Conclusions: In this study, inhaled CeO₂NPs modulated lung injury responses in the context of active disease, with both potential protective effects and adverse outcomes. These findings demonstrate that the timing of CeO₂NP exposure relative to disease progression is critical and highlight the need for hazard assessment frameworks to consider context-dependent effects, particularly in the presence of pre-existing lung injury.

Background: Ferric oxide (Fe₂O₃) nanoparticles are widely used in industrial and biomedical applications, raising concerns regarding inhalation exposure, particularly in occupational settings. Although the inhalation toxicity of magnetite (Fe₃O₄) was reported, no studies have addressed the pulmonary clearance, biotransformation, or systemic distribution of Fe₂O₃ nanoparticles. In this study, male rats were exposed nose-only to aerosols of γ-Fe₂O₃ nanoparticles at concentrations of 0.56, 1.63, and 4.92 mg/m³ for 6 h/day, 5 d/week, over 28 d, followed by recovery periods of 7 and 28 d. Particulate and ionic iron were separately collected via proteinase K digestion and quantitatively and qualitatively evaluated using elemental quantification and electron microscopy.

Results: The toxicity study showed no treatment-related effects, including clinical signs, body weight, hematology, serum biochemistry, or histopathology. Lung burden analysis revealed a clearance half-life of 3.6-3.91 d, with ~ 25% of the initially deposited iron (Fe) retained after 28 d of recovery. At this time point, the retained Fe persisted as particulates biotransformed into fragments of a few nanometers, with a smaller portion present as ionic Fe. The extrapulmonary distribution showed ionic Fe in the liver and spleen, whereas particulate Fe was confined to the lung-associated lymph nodes. This study provides the first inhalation toxicity and biodistribution data for γ-Fe₂O₃ nanoparticles obtained under regulatory testing conditions, demonstrating subacute inhalation toxicity outcomes and revealing their persistence in the lungs without systemic translocation of intact particles. This study is the first subacute inhalation toxicity study conducted under regulatory testing conditions and includes a comprehensive in vivo biokinetic and biotransformation analysis, revealing the long pulmonary biopersistence of γ-Fe₂O₃ nanoparticles and the absence of systemic translocation of intact particles, with only limited extrapulmonary distribution of their ionic biotransformation products.

Conclusions: Although γ-Fe₂O₃ nanoparticles persist in the lungs without overt toxicity, their prolonged retention and biotransformation into smaller particles may ultimately lead to overload-driven oxidative stress and chronic pulmonary effects.

Background: Titanium dioxide (TiO₂) is a compound that is often used as a white pigment. Commercial TiO₂, such as the food additive E171, contains a mix of particle sizes, including a fraction in the nanoscale range (< 100 nm). It is an ingredient in everyday products such as toothpaste, dietary supplements, and pharmaceuticals. Although the oral and gastrointestinal (GIT) tracts are the initial sites of exposure, in vivo studies have shown that TiO₂ can cross the intestinal epithelium, enter systemic circulation, and accumulate in vital organs, where elimination is slow. This accumulation has been associated with oxidative stress, inflammation, cytotoxicity, and altered cellular function.

Main body: This systematic review assesses titanium (Ti) accumulation in vital organs of rats and mice following oral TiO₂ exposure, focusing on dose- and time-dependent patterns across acute, subacute, subchronic, and chronic durations. Following PRISMA guidelines, 3,012 records were identified and screened by title and abstract, with 54 studies meeting predefined inclusion criteria. The findings reveal that acute oral exposure to TiO₂ consistently results in minimal titanium accumulation across all major organs, indicating limited gastrointestinal absorption and rapid excretion. In contrast, subacute and subchronic exposures lead to significant, dose-dependent titanium accumulation, especially in the liver, spleen, kidneys, gastrointestinal tract, and brain. Chronic exposure studies, though fewer, indicate persistent Ti presence, especially in the liver, kidneys, and colon. Ti was also found in the brain, pancreas, and reproductive tissues, with histopathological changes indicating broader systemic effects. A few studies reported negligible accumulation even at high doses.

Conclusion: This review highlights the organ-specific and exposure-dependent biodistribution of titanium following oral TiO₂ intake in rodents. The evidence emphasizes the need for standardized reporting and experimental methodologies to improve data comparability across studies. Importantly, it underscores significant gaps in our understanding of chronic and low-dose exposures, conditions more reflective of real-world human scenarios, warranting further investigation to better assess long-term health risks.

Background: Epidemiological studies suggest an association between air pollution and ventricular arrhythmias, with reactive oxygen species (ROS) playing a crucial role. However, the causal relationship and long-term effects remain uncertain, and the effectiveness of interventions aimed at reducing ROS requires further investigation. Here we aimed to evaluate the effects of a 3-weeks exposure to diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, explore the underlying mechanisms, and assess the potential of cerium oxide nanoparticles (CeO₂NP) as a ROS-detoxifying intervention.

Results: Sprague-Dawley rats underwent intratracheal instillation of saline without or with DEPs (7.5 g/Kg for 1-3 weeks). Ventricular arrhythmia inducibility was then assessed in isolated hearts using a protocol of programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed using histology, Western blot, RT-qPCR, and measurement of malondialdehyde content. The potential protective effects of CeO₂NP (0.5 mg/Kg/week, i.p.) were also tested. DEP exposure for 3 weeks increased the incidence and duration of sustained ventricular tachyarrhythmias (VTs), a finding that correlated with a moderate increase in interstitial collagen (from 3.11 ± 0.12% in controls to 4.80 ± 0.21% in DEP-exposed rats, p < 0.001), and an early upregulation in the expression of collagen and other fibrotic and inflammatory markers. These effects associated with prolonged QRS complex and enhanced malondialdehyde content (356.7 ± 21.2 vs. 455.3 ± 17.2 μmol/g tissue, p = 0.0066) after 3 weeks. CeO₂NP treatment reduced oxidative stress and myocardial fibrosis, reversed electrocardiographic changes and attenuated DEP-induced pro-arrhythmic effects.

Conclusions: DEP exposure increases the incidence and duration of sustained VTs, collagen deposition and oxidative stress in rats. Treatment with CeO₂NP attenuate these effects, arising as a potential novel strategy to mitigate the deleterious effects of air pollution.

Background: Silica nanoparticles (SiO₂NPs) are widely used in industrial products. Surface modification of SiO₂NPs is one of the promising strategies to develop safer nanomaterials by design. The present study was designed to determine the effects of amino or carboxyl functionalization of rhodamine-labeled SiO₂NPs on cellular uptake and cytotoxicity.

Methods: In the in vivo arm of the study, male mice were randomly divided into seven groups (n = 6, each) and exposed to either amino (NH₂)- or carboxyl (COOH)-functionalized, or non-functionalized (OH)-rhodamine-labeled SiO₂NPs at 2 or 10 mg/kg bw, or endotoxin-free water as a control, by pharyngeal aspiration. At 24 h after administration, the mice were euthanized and bronchoalveolar lavage fluid (BALF) was collected for differential cell count and assessment of silica nanoparticle uptake using confocal microscopy. In the in vitro arm of the study, murine RAW264.7 macrophages were exposed to NH₂-or COOH-functionalized or OH- rhodamine-labeled SiO₂NPs. Nonspecific caspase inhibitor, necroptosis inhibitor, pyroptosis inhibitor and autophagy inhibitor were used to determine the roles of cell death signaling in cytotoxicity.

Results: The in vivo studies demonstrated significant increase in lung weight at 2 and 10 mg/kg bw by OH-SiO₂NPs but not the other two SiO₂NPs. At 10 mg/kg bw, COOH-SiO2NPs induced a significant increase in BALF macrophages, whereas OH- SiO₂NPs significantly decreased macrophages. OH-SiO₂NPs at 2 mg/kg bw and NH₂- and COOH-SiO₂NPs at 10 mg/kg bw significantly increased BALF neutrophiles. The in vitro studies showed greater NH₂-SiO₂NPs internalization into RAW264.7 macrophages than OH-SiO₂NPs, while OH-SiO₂NPs induced cytotoxicity and upregulation of IL-1β and TNF-α to greater extent than the other two types. Co-treatment with pan-caspase inhibitor and necroptosis inhibitor attenuated (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) cytotoxicity of OH-SiO₂NPs.

Conclusion: NH₂- or COOH-functionalization reduced the harmful changes observed with OH- SiO₂NPs, which included increase in lung weight and BALF neutrophils at low dose in mice as well as decrease in cell viability and upregulation of proinflammatory cytokines in RAW264.7 macrophages. The results suggested that OH-SiO₂NPs-induced cytotoxicity against macrophages was mediated at least in part through apoptotic/necroptotic signaling but was not related to internalization of particles. The results imply possible development of safer silica nanoparticles by amino- or carboxyl-functionalization of their silanols.

Environmental pollutants like PM_2.5 threaten hematopoietic homeostasis, yet how real-world exposure disrupts blood cell production, especially locally in the lung and systemically in the bone marrow (BM), remains poorly understood. Previous studies often used artificial particles or lacked mechanistic insights into systemic effects. Hypoxia-inducible factor-1alpha (HIF-1α) is essential for hematopoietic stem cell (HSC) maintenance. Herein, we utilized a real-ambient PM_2.5 exposure system and conducted a detailed characterization of hematopoietic and downstream immune cell populations in mice with myeloid lineage-specific knockout of HIF-1α (mHIF-1α^-/-) and their wild-type littermate controls. Our findings demonstrate that real-ambient PM_2.5 exposure induces a HIF-1α-dependent myeloid-biased hematopoiesis within both the lung and BM. This bias results in an accumulation of mature myeloid cells, particularly neutrophils and macrophages, in peripheral organs such as the liver and spleen. Critically, this cellular redistribution precipitates inflammatory injury in a HIF-1α-dependent manner. These results provide novel insights into how environmental contaminants, exemplified by PM_2.5, perturb hematopoiesis, highlighting the critical role of HIF-1α in mediating lineage-specific hematopoietic responses and subsequent inflammatory sequelae.