Particle and Fibre Toxicology最新文献

Background: While studies demonstrating the adverse effects of air pollution on human health are accumulating, studies on secondary organic aerosol (SOA) are scarce. However, SOA accounts for a significant portion of airborne particulate matter. In particular, pinene biogenic SOA contributes predominantly to SOA loading in the outdoor atmosphere of natural and urban areas and are also emitted indoors because of the presence of terpenes in numerous consumer products. Our aim was to study the immune consequences of acute exposure to β-pinene ozonolysis gaseous and SOA products in mice. This reaction was generated in an atmospheric simulation chamber, and the mice were exposed to the particulate and gaseous products, to the gaseous products only, or to synthetic air 2 h per day for 3 days in real time in a whole-body inhalation chamber. Exposures were performed in adulthood or in utero. Since some adverse effects only occur in individuals weakened by existing immune activation, such as low-grade inflammation, the immune response was measured in the steady state or in a state of moderate systemic inflammation induced by lipopolysaccharide administration.

Results: Exposure of healthy adult mice caused minor immunosuppression in the lungs. However, in adult mice weakened by moderate systemic inflammation, the same exposure conditions revealed that mice exposed to the β-pinene ozonolysis particulate and gaseous products presented deficient pulmonary and systemic immune responses, including excessive recruitment of B lymphocytes, CD4⁺ T lymphocytes, CD11b⁺ dendritic cells, inflammatory monocytes and neutrophils in the lungs and defective recruitment of regulatory T cells in the spleen. In offspring exposed to β-pinene ozonolysis products in utero, the LPS-induced upregulation of Ccl2, Cxcl10 and Icam1 mRNA levels in the lungs and the activation of dendritic cells in the spleen were excessive in female mice. The male offspring developed a normal response to moderate systemic inflammation, except for impaired activation of CD4⁺ T cells and increased activation of CD103⁺ dendritic cells in the spleen.

Conclusion: In mice, pulmonary and systemic immune reactions in response to moderate systemic inflammation are dysregulated by exposure to common secondary oxidation products, highlighting interest in the role of these neglected atmospheric compounds in immune disease development and susceptibility to infections.

Background: The Safe and Sustainable by Design (SSbD) concept facilitates the design of safer and more sustainable chemicals and materials and is a crucial approach towards reaching the goals set out in the European Green Deal. It is critical that suitable guidance is provided on how to use new approach methodologies (NAMs) to fill hazard data gaps for nanomaterials (NMs) to facilitate SSbD decisions. Here, we showcase a nano-specific in vitro SSbD case study. The five colloidal silica nanoforms (SiO₂-NFs) under investigation in this study are surface modified with varying amounts of glycerolpropyl-organosilane groups. In this study, we use a simple yet comprehensive in vitro test battery along with thorough particle characterization to investigate the effect of surface silanization on in vitro toxicity to inform SSbD decisions.

Results: Cytotoxic, pro-inflammatory and oxidative stress responses in A549, dTHP-1, and BEAS-2B cells after exposure to SiO₂-NFs submerged and at the air-liquid interface (ALI) decreased with increasing silane surface modification. None of the SiO₂-NFs showed surface reactivity or haemolytic potential. Deposition assessment using inductively coupled plasma - optical emission spectrometry (ICP-OES) revealed that increasing silane surface modification decreased particle settling. The two SiO₂-NFs with the highest amount of surface silanization did not reach the cells in a submerged exposure setting, and they were therefore only tested at the ALI. Identical dose-response curves were observed for both the submerged testing and testing at the ALI for the SiO₂-NFs without and with low/intermediate surface functionalization, again showing a decrease in effects with increasing surface functionalization.

Conclusion: We show that in vitro toxicity assays provide valuable information for SSbD decision making. In vitro cytotoxic, pro-inflammatory and oxidative stress responses can be reduced with increasing surface silane functionalization. The reduced deposition efficiency with increasing silane functionalization, however, highlights that thorough characterization of particle behaviour in cell culture medium should always be performed for SSbD hazard testing. The amount of silane required to reduce toxicity is important information for the future production of safer SiO₂-NFs and nano-enabled products. Exposure, functionality, and sustainability remain to be investigated to draw full SSbD conclusions.

Background: Multiple effects of ultrafine particles (UFP) on human subjects are known but there is less knowledge of how relative exposure levels between ultrafine and fine particles as typically encountered in large cities affect lung function and cardiovascular parameters.

Methods: Four sites with high/low levels of ultrafine particles and/or fine particles were selected in the city of Munich, Germany: control area (woodland), urban environment, heavy traffic site, biomass combustion (beech wood). In a randomized cross-over design, 26 young, healthy individuals were exposed at each site over 75 min to atmospheric pollutants, which were monitored continuously, while performing intermittent (5 min per 15 min) light exercise. Parameters assessed pre and post exposure comprised symptoms, spirometry, lung diffusing capacity for carbon monoxide (DLCO) and nitric oxide (DLNO), alveolar volume (AV), the fractional concentration of exhaled nitric oxide (FeNO), reactive hyperemia index (RHI), blood pressure, and heart rate. Outcomes were expressed as percent changes of parameters and analyses performed by either comparing the four sites or by multiple linear regression analyses using the measured pollutant levels.

Results: The sites showed the planned pattern of exposure levels but with large overlap. Outcomes showed no statistically significant differences between sites, except for symptoms which were elevated with heavy traffic site exposure and biomass combustion. In regression analyses, AV decreased by 0.92 (95% confidence interval (CI): 0.28 to 1.57) % per 10,000/cm³ UFP; similarly, for LDSA (lung-deposited surface area), which was highly correlated with UFP. Overall, FeNO slightly increased after exposure, but this increase was attenuated by 5.4 (95% CI: 1.8 to 9.2) % per 10 ppb ambient NO₂. Heart rate decreased after exposures overall; this decrease was enhanced by 2.1 (95% CI: 0.3 to 4.0) % per 10,000/cm³ UFP.

Conclusions: Short-term exposures to UFP elicited a reduction in the lung volume (AV) accessible to gas transport by diffusion and convection. FeNO was slightly elevated after all exposures, but this increase was significantly smaller at higher ambient NO₂ concentrations. While these effects were too small to be clinically relevant, they demonstrated that typical levels of urban air pollution had measurable acute effects in young, healthy individuals.

Background: Recent studies emphasize the significance of copper dyshomeostasis in neurodegenerative diseases, such as Alzheimer's and Parkinson's, thereby highlighting the role of copper in neurotoxicity. Cuproptosis, a novel mechanism of copper-dependent cell death, remains underexplored, particularly concerning environmental pollutants like polystyrene nanoplastics (PS-NPs). While PS-NPs are recognized for inducing neurotoxicity through various forms of cell death, including apoptosis and ferroptosis, their potential to trigger neuronal cuproptosis has not yet been investigated. This study aims to determine whether exposure to PS-NPs induces neurotoxicity via cuproptosis and to explore the preliminary molecular mechanisms involved, thereby addressing this significant knowledge gap.

Methods: Seven-week-old male C57BL/6 mice were exposed to PS-NPs at dose of 12.5 mg/kg, and were co-treated with the antioxidant N-acetylcysteine (NAC). Complementary in vitro experiments were conducted using SH-SY5Y neuronal cells exposed to PS-NPs at a concentration of 0.75 mg/mL, with interventions that included the copper chelator tetrathiomolybdate (TTM), NAC, and the MAPK inhibitor PD98059.

Results: Exposure to PS-NPs significantly increased cerebral copper accumulation (P < 0.05) and induced cuproptosis, characterized by lipid-acylated DLAT oligomerization, dysregulation of cuproptosis regulators (FDX1, LIAS, HSP70), and mitochondrial damage. In murine models, PS-NPs elicited neurotoxicity, as evidenced by neuronal loss, decreased Nissl body density, impaired synaptic plasticity, and suppressed oxidative stress markers (GSH, SOD, Nrf2), alongside activation of the ERK-MAPK pathway, ultimately resulting in deficits in learning and memory. Treatment with NAC alleviated these adverse effects. In SH-SY5Y cells, exposure to PS-NPs resulted in reduced cell viability (p < 0.01), an effect that was mitigated by TTM. Furthermore, NAC and PD98059 were found to reverse elevated copper levels, cuproptosis markers, and mitochondrial anomalies (p < 0.05).

Conclusion: This study presents preliminary evidence indicating that PS-NPs may induce neuronal cuproptosis, potentially through the oxidative stress-mediated activation of the ERK-MAPK pathway, which contributes to cognitive dysfunction in mice. These findings provide insights into the potential mechanisms underlying PS-NPs neurotoxicity and highlight possible therapeutic targets, such as copper chelation or MAPK inhibition, for mitigating the neurological risks associated with nanoplastic exposure, pending further validation in human-relevant models.

Particles often require dispersion in aqueous media to allow assessment of their hazard profile. The approach used to disperse particles is not consistent in the published literature, with approaches including stirring, vortexing, shaking or sonication, and the use of biological or chemical stabilisers. Such variations in the dispersion protocol can influence the physico-chemical (PC) identity and toxicity of particles. To better understand the protocol variations and their impacts on human health, this work identified and critically reviewed publications with a specific focus on titanium dioxide (TiO₂), which was dominated by nanomaterials (NMs). This review included consideration of both in vitro and in vivo studies, as well as other NMs to help address knowledge gaps and identify any lessons that can be learnt and applied to TiO₂. Overall, the evidence gathered showed that variations in the dispersion protocol, specifically the method and parameters of sonication (e.g. power and duration), as well as the dispersion medium choice (and inclusion of biological and chemical stabilisers), were impactful on NM agglomerate size. There is no consensus as to whether a reduction or increase in NM agglomeration enhances or reduces NM toxicity with the outcome of the study dependent on the experimental design (e.g. PC properties of the NM being tested, test model used, time point, and concentrations/doses assessed). Whilst standard protocols for NM dispersion have been generated, they have not been widely adopted and there is unlikely to be one protocol that can be applied to all NMs and test models. Instead, more guidance is needed to inform the considerations that should guide preparation of NM suspensions for hazard testing. These include a recommendation that pilot studies are performed to identify the most suitable dispersion protocol before embarking on a toxicology study. Improved knowledge of the impact of dispersion protocols on PC identity and toxicity of TiO₂ will assist in the interpretation of existing toxicology data and feed into the design of future studies which assess TiO₂ toxicity.

Background: Micro-/nanoplastics (MNPLs) are widely found in the environment and have toxic effects on various organs and systems. However, the role of the gut-cardiac axis in cardiotoxicity induced by MNPLs has not yet been elucidated through research.

Results: In this study, we examined the effects of 80 nm polystyrene nanoplastics (PS-NPs) on the heart and human cardiomyocytes (AC16) cells. Histopathological examination showed that NPs caused impaired cardiac function and increased myocardial collagen deposition. In view of the potential influence of gut microbiota and its metabolites on cardiac function, we conduct this study to investigate the specific effects they have on cardiac function. Analysis of cecal contents by 16 s ribosomal RNA (rRNA) and short chain fatty acids (SCFAs) revealed that colonic tissue damage, intestinal flora disorder, and reduction of propionic acid induced by PS-MPs were closely related to cardiac function. Further transcriptomic analysis of heart and colon tissues indicated that propionic acid may reduce cardiac function by reducing the expression of fructose-1, 6-biphosphatase 1 (FBP1). The hypothesis was further verified by in vitro intervention experiments with sodium propionate and FBP1 activator (BML-275).

Conclusions: In summary, our study systematically demonstrated the role of gut-heart axis in NPs-induced cardiac injury, and the specific process was that NPs exposure reduced propionate level, which in turn inhibited FBP1 expression to impair cardiac function. These findings provide new insights into NPs-induced cardiotoxicity and identifie potential therapeutic targets, providing clues for the prevention and treatment of NPs-induced cardiac injury in the future.

Background: Both excess brain Fe and air pollution (AP) exposures are associated with increased risk for multiple neurodegenerative disorders. Fe is a redox-active metal that is abundant in AP and even further elevated in U.S. subway systems. Exposures to AP and associated contaminants, such as Fe, are lifelong and could therefore contribute to elevated brain Fe observed in neurodegenerative diseases, particularly via nasal olfactory uptake of ultrafine particle AP. These studies tested the hypotheses that exogenously generated Fe oxide nanoparticles could reach the brain following inhalational exposures and produce neurotoxic effects consistent with neurodegenerative diseases and disorders in adult C57/Bl6J mice exposed by inhalation to Fe nanoparticles at a concentration similar to those found in underground subway systems (~ 150 µg/m³) for 20 days. Olfactory bulb sections and exposure chamber TEM grids were analyzed for Fe speciation. Measures included brain volumetric and diffusivity changes; levels of striatal and cerebellar neurotransmitters and trans-sulfuration markers; quantification of frontal cortical and hippocampal Aβ42, total tau, and phosphorylated tau; and behavioral alterations in locomotor activity and memory.

Results: Particle speciation confirmed similarity of Fe oxides (mostly magnetite) found on chamber TEM grids and in olfactory bulb. Alzheimer's disease (AD) like characteristics were seen in Fe-exposed females including increased olfactory bulb diffusivity, impaired memory, and increased accumulation of total and phosphorylated tau, with total hippocampal tau levels significantly correlated with increased errors in the radial arm maze. Fe-exposed males showed increased volume of the substantia nigra pars compacta, a region critical to the motor impairments seen in Parkinson's disease (PD), in conjunction with reduced volume of the trigeminal nerve and optic tract and chiasm.

Conclusions: Inhaled Fe oxide nanoparticles appeared to lead to olfactory bulb uptake. Further, these exposures reproduced characteristic features of neurodegenerative diseases in a sex-dependent manner, with females evidencing features similar to those seen in AD and effects in regions in males associated with PD. As such, prolonged inhaled Fe exposure via AP should be considered as a source of elevated brain Fe with aging, and as a risk factor for neurodegenerative diseases. The bases for dichotomous sex effects of inhaled Fe nanoparticles is as of yet unclear. Also as of yet unknown is how duration of such Fe exposures affect outcome, and/or whether exposures to inhaled Fe during early brain development enhances vulnerability to subsequent Fe exposures. Collectively, these findings suggest that regulation of air Fe levels, particularly in enclosed areas like subway stations, may have broad public health protective effects.

Background: Chronic inhalation of titanium dioxide or carbon black can lead, at high exposure, to lung overload, and can induce chronic inflammation and lung cancer in rats. Whether this rat adverse response is predictive for humans has been questioned for more than 40 years. Currently, these particles are conservatively considered as possible human carcinogens.

Objective: To clarify the mechanisms of the adverse rat response to lung overload and its human relevance.

Methods: Primary rat and human alveolar macrophages were exposed in vitro to control, non-overload or overload doses of titanium dioxide (P25) or carbon black (Printex 90) particles, and their activation profile was examined by untargeted transcriptomics.

Results: Rat macrophages were largely the most responsive to particle overload. In particular, eighteen genes were identified as robust markers of P25 and Printex 90 overload in rat cells. The known functions of these genes can be related to the potential mechanisms of the adverse outcomes recorded in rats in vivo. Most of these 18 genes were similarly modulated in human macrophages, but with a markedly lower magnitude. In addition, a 16 gene signature was observed upon overload in human macrophages, but not in rat macrophages.

Conclusions: These findings provide insights into the mechanisms of lung overload and inflammation in rats, and highlight similarities and differences in transcriptomic responses of rat and human alveolar macrophages.

Background: We have previously reported that inhalation exposure to titanium dioxide nanoparticles (TiO₂ NPs) for 13 weeks causes early pneumoconiosis lesions in the alveolar region of F344 rats. We defined these characteristic lesions as pulmonary dust foci (PDF). In this report, we re-evaluate and detail the histopathological data regarding particle-induced pneumoconiosis lesions, including progressive lesions of the early PDF lesions, that developed in F344 rats exposed TiO₂ NPs by whole body inhalation over a period of two years.

Methods: Male and female F344 rats were exposed to 0.5, 2, and 8 mg/m³ anatase type TiO₂ NPs for 6 h/day, 5 days/week for 104 weeks using a whole-body inhalation exposure system. After the final exposure, the rats were euthanized. In the present study, the collected lungs were re-evaluated macroscopically and histopathologically.

Results: Rats exposed to TiO₂ NPs developed macroscopic white lesions, primarily in the subpleural and hilar regions of the lung, which increased in size and number with exposure concentration. Histologically, two lesion types were identified: (1) Fibrotic Pulmonary Dust Foci (fPDF), characterized by collagen deposition, inflammatory infiltration, and disrupted alveolar epithelial differentiation, and (2) Dust Macules (DM), characterized by macrophage accumulation without significant fibrosis or inflammation. fPDFs, but not DMs, were observed after 13 weeks exposure to TiO₂ NPs, indicating that the DM-type pneumoconiosis lesions required a longer time to develop compared to fPDF-type pneumoconiosis lesions. Histopathological analysis revealed that the DM-type pneumoconiosis lesions that developed in rats exposed to TiO₂ NPs were similar to DM-type pneumoconiosis lesions that develop in humans.

Conclusions: Inhalation exposure to TiO₂ NPs caused the development of two types of pneumoconiosis lesions in rats with distinct pathological features, fPDFs and DMs. The histopathological similarity of the DM-type pneumoconiosis lesions that developed in rat lung in the present study with the DM-type pneumoconiosis lesions that develop in the human lung adds strong support to the conclusion that humans exposed to airborne TiO₂ NPs are at risk of developing pneumoconiosis.