Particle and Fibre Toxicology最新文献

Inhalation is a portal-of-entry for aerosols via the respiratory tract where particulate burden accumulates depending on sites of particle deposition, normal clearance mechanisms, and particle solubility. The time available for dissolution of particles is determined by the balance between the rate of particle clearance from a region and their solubility in respiratory solvents. Dissolution is a function of particle surface area divided by particle volume or mass (i.e., dissolution is inversely proportional to the physical diameter of particles). As a conservative approach, investigators commonly assume the complete and instantaneous dissolution of metals from particles depositing in the alveolar region of the respiratory tract. We derived first-order dissolution rate constants to facilitate biokinetic modeling of particle clearance, dissolution, and absorption into the blood. We then modeled pulmonary burden and total dissolution of particles over time as a function of particle size, density, and solubility. We show that assuming poorly soluble particle forms will enter the blood as quickly as highly soluble forms causes an overestimation of concentrations of the compound of interest in blood and other extrapulmonary tissues while also underestimating its pulmonary burden. We conclude that, in addition to modeling dose rates for particle deposition into the lung, physiologically based pharmacokinetic modeling of pulmonary and extrapulmonary tissues concentrations of moderately and poorly soluble materials can be improved by including estimates of lung burden and particle dissolution over time.

Background: Exposure to micro- and nanoplastic particles (MNPs) in humans is being identified in both the indoor and outdoor environment. Detection of these materials in the air has made inhalation exposure to MNPs a major cause for concern. One type of plastic polymer found in indoor and outdoor settings is polyamide, often referred to as nylon. Inhalation of combustion-derived, metallic, and carbonaceous aerosols generate pulmonary inflammation, cardiovascular dysfunction, and systemic inflammation. Additionally, due to the additives present in plastics, MNPs may act as endocrine disruptors. Currently there is limited knowledge on potential health effects caused by polyamide or general MNP inhalation.

Objective: The purpose of this study is to assess the toxicological consequences of a single inhalation exposure of female rats to polyamide MNP during estrus by means of aerosolization of MNP.

Methods: Bulk polyamide powder (i.e., nylon) served as a representative MNP. Polyamide aerosolization was characterized using particle sizers, cascade impactors, and aerosol samplers. Multiple-Path Particle Dosimetry (MPPD) modeling was used to evaluate pulmonary deposition of MNPs. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) cell content and H&E-stained tissue sections. Mean arterial pressure (MAP), wire myography of the aorta and uterine artery, and pressure myography of the radial artery was used to assess cardiovascular function. Systemic inflammation and endocrine disruption were quantified by measurement of proinflammatory cytokines and reproductive hormones.

Results: Our aerosolization exposure platform was found to generate particles within the micro- and nano-size ranges (thereby constituting MNPs). Inhaled particles were predicted to deposit in all regions of the lung; no overt pulmonary inflammation was observed. Conversely, increased blood pressure and impaired dilation in the uterine vasculature was noted while aortic vascular reactivity was unaffected. Inhalation of MNPs resulted in systemic inflammation as measured by increased plasma levels of IL-6. Decreased levels of 17β-estradiol were also observed suggesting that MNPs have endocrine disrupting activity.

Conclusions: These data demonstrate aerosolization of MNPs in our inhalation exposure platform. Inhaled MNP aerosols were found to alter inflammatory, cardiovascular, and endocrine activity. These novel findings will contribute to a better understanding of inhaled plastic particle toxicity.

Background: Microbial dysbiosis is a potential mediator of air pollution-induced adverse outcomes. However, a systemic comparison of the lung and gut microbiome alterations and lung-gut axis following air pollution exposure is scant. In this study, we exposed male C57BL/6J mice to inhaled air, CB (10 mg/m³), O₃ (2 ppm) or CB + O₃ mixture for 3 h/day for either one day or four consecutive days and were euthanized 24 h post last exposure. The lung and gut microbiome were quantified by 16 s sequencing.

Results: Multiple CB + O₃ exposures induced an increase in the lung inflammatory cells (neutrophils, eosinophils and B lymphocytes), reduced absolute bacterial load in the lungs and increased load in the gut. CB + O₃ exposure was more potent as it decreased lung microbiome alpha diversity just after a single exposure. CB + O₃ co-exposure uniquely increased Clostridiaceae and Prevotellaceae in the lungs. Serum short chain fatty acids (SCFA) (acetate and propionate) were increased significantly only after CB + O₃ co-exposure. A significant increase in SCFA producing bacterial families (Ruminococcaceae, Lachnospiraceae, and Eubacterium) were also observed in the gut after multiple exposures. Co-exposure induced significant alterations in the gut derived metabolite receptors/mediator (Gcg, Glp-1r, Cck) mRNA expression. Oxidative stress related mRNA expression in lungs, and oxidant levels in the BALF, serum and gut significantly increased after CB + O₃ exposures.

Conclusion: Our study confirms distinct gut and lung microbiome alterations after CB + O₃ inhalation co-exposure and indicate a potential homeostatic shift in the gut microbiome to counter deleterious impacts of environmental exposures on metabolic system.

Background: As one of the environmental risk factors for human health, atmospheric fine particulate matter (PM_2.5) contributes to cognitive deterioration in addition to respiratory and cardiovascular injuries. Recently, increasing evidence implicates that PM_2.5 inhalation can affect neurological functions in offspring, but the sex-specific outcomes and the underlying biological processes are largely unknown.

Objectives: To observe the influence of prenatal PM_2.5 exposure on cognitive performance in offspring, to elucidate the neuronal morphological alterations and possible transcriptional regulation based on mRNA-sequencing (mRNA-Seq) data after birth, and to determine the key components of PM_2.5 contributing to the adverse effects.

Methods: Pregnant C57BL/6J mice were exposed to sterile saline or PM_2.5 suspension. Morris water maze test was used to assess the cognitive function in weanling offspring. Microscopic observation was applied to detect neuronal morphogenesis in vivo and in vitro. The cortex tissues from male offspring were collected on postnatal days (PNDs) 1, 7, and 21 for mRNA-Seq analysis. The organic and inorganic components of PM_2.5 were separated to assess their contributions using primary cultured neurons.

Results: Prenatal PM_2.5 exposure impaired spatial learning and memory in weanling male mice, but not female mice. The sex-specific outcomes were associated with mRNA expression profiles of the cortex during postnatal critical windows, and the annotations in Gene Ontology (GO) of differentially expressed genes (DEGs) revealed that the exposure persistently disrupted the expression of genes involved in neuronal features in male offspring. Consistently, axonal growth impairment and dendritic complexity reduction were observed. Importantly, Homeobox A5 (Hoxa5), a critical transcription factor regulating all of the neuronal morphogenesis-associated hub genes on PNDs 1, 7, and 21, significantly decreased in the cortex of male offspring following PM_2.5 exposure. In addition, both inorganic and organic components were harmful to axonal and dendritic growth, with organic components exhibiting stronger inhibition than inorganic ones.

Conclusion: Prenatal PM_2.5 exposure affected spatial learning and memory in male mice by disrupting Hoxa5-mediated neuronal morphogenesis, and the organic components, including polycyclic aromatic hydrocarbons (PAHs), posed more adverse effects than the inorganic components.

Background: The biological effects of cerium dioxide nanoparticles (CeO₂NPs), a novel material in the biomedical field, have attracted widespread attention. Our previous study confirmed that exposure to CeO₂NPs during pregnancy led to abnormal trophoblast invasion during early placental development, thereby impairing placental development. The potential mechanisms may be related to low-quality decidualization triggered by CeO₂NPs exposure, such as an imbalance in trophoblast invasion regulators secreted by decidual cells. However, the intermediate link mediating the "dialogue" between decidual cells and trophoblasts during this process remains unclear. As an important connection between cells, exosomes participate in the "dialogue" between endometrial cells and trophoblasts. Exosomes transfer bioactive microRNA into target cells, which can target and regulate the level of mRNA in target cells.

Results: Here, we constructed a mice primary uterine stromal cell-induced decidualization model in vitro, and detected the effect of CeO₂NPs exposure on the expression of decidual-derived exosomal miRNAs by high-throughput sequencing. Bioinformatics analysis and dual-luciferase reporter assays were performed to identify target genes of the screened key miRNAs in regulating trophoblast invasion. Finally, the role of the screened miRNAs and their target genes in regulating trophoblast (HTR-8/SVneo cells) invasion was confirmed. The results showed that CeO₂NPs exposure inhibited trophoblast invasion by promoting miR-99a-5p expression in decidual-derived exosomes, and Ppp2r5a is a potential target gene for miR-99a-5p to inhibit trophoblast invasion.

Conclusions: This study revealed the molecular mechanism by which CeO₂NPs exposure inhibits trophoblast invasion from the perspective of decidual derived exosomal miRNAs. These results will provide an experimental basis for screening potential therapeutic targets for the negative biological effects of CeO₂NPs exposure and new ideas for studying the mechanism of damage to trophoblast cells at the decidual-foetal interface by harmful environmental or occupational factors.

Background: Synthetic amorphous silica nanoparticles (SAS-NPs) are widely employed in pharmaceutics, cosmetics, food and concretes. Workers and the general population are exposed daily via diverse routes of exposure. SAS-NPs are generally recognized as safe (GRAS) by the Food and Drug Administration, but because of their nanoscale size and extensive uses, a better assessment of their immunotoxicity is required. In the presence of immune "danger signals", dendritic cells (DCs) undergo a maturation process resulting in their migration to regional lymph nodes where they activate naive T-cells. We have previously shown that fumed silica pyrogenic SAS-NPs promote the two first steps of the adaptative immune response by triggering DC maturation and T-lymphocyte response, suggesting that SAS-NPs could behave as immune "danger signals". The present work aims to identify the mechanism and the signalling pathways involved in DC phenotype modifications provoked by pyrogenic SAS-NPs. As a pivotal intracellular signalling molecule whose phosphorylation is associated with DC maturation, we hypothesized that Spleen tyrosine kinase (Syk) may play a central role in SAS-NPs-induced DC response.

Results: In human monocyte-derived dendritic cells (moDCs) exposed to SAS-NPs, Syk inhibition prevented the induction of CD83 and CD86 marker expression. A significant decrease in T-cell proliferation and IFN-γ, IL-17F and IL-9 production was found in an allogeneic moDC:T-cell co-culture model. These results suggested that the activation of Syk was necessary for optimal co-stimulation of T-cells. Moreover, Syk phosphorylation, observed 30 min after SAS-NP exposure, occurred upstream of the c-Jun N-terminal kinase (JNK) Mitogen-activated protein kinases (MAPK) and was elicited by the Src family of protein tyrosine kinases. Our results also showed for the first time that SAS-NPs provoked aggregation of lipid rafts in moDCs and that MβCD-mediated raft destabilisation altered Syk activation.

Conclusions: We showed that SAS-NPs could act as an immune danger signal in DCs through a Syk-dependent pathway. Our findings revealed an original mechanism whereby the interaction of SAS-NPs with DC membranes promoted aggregation of lipid rafts, leading to a Src kinase-initiated activation loop triggering Syk activation and functional DC maturation.

Background: Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated.

Results: Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM_2.5 concentration of 95.77 µg/m³. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice.

Conclusions: These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.

Background: Interactions between air pollution and infectious agents are increasingly recognized and critical to identify, especially to protect vulnerable populations. Pregnancy represents a vulnerable period for influenza infection and air pollution exposure, yet interactions during pregnancy remain unclear. Maternal exposure to ultrafine particles (UFPs, [Formula: see text] 100 nm diameter), a class of particulate matter ubiquitous in urban environments, elicits unique pulmonary immune responses. We hypothesized that UFP exposure during pregnancy would lead to aberrant immune responses to influenza enhancing infection severity.

Results: Building from our well-characterized C57Bl/6N mouse model employing daily gestational UFP exposure from gestational day (GD) 0.5-13.5, we carried out a pilot study wherein pregnant dams were subsequently infected with Influenza A/Puerto Rico/8/1934 (PR8) on GD14.5. Findings indicate that PR8 infection caused decreased weight gain in filtered air (FA) and UFP-exposed groups. Co-exposure to UFPs and viral infection led to pronounced elevation in PR8 viral titer and reduced pulmonary inflammation, signifying potential suppression of innate and adaptive immune defenses. Pulmonary expression of the pro-viral factor sphingosine kinase 1 (Sphk1) and pro-inflammatory cytokine interleukin-1β (IL-1 [Formula: see text]) was significantly increased in pregnant mice exposed to UFPs and infected with PR8; expression correlated with higher viral titer.

Conclusions: Results from our model provide initial insight into how maternal UFP exposure during pregnancy enhances respiratory viral infection risk. This model is an important first step in establishing future regulatory and clinical strategies for protecting pregnant women exposed to UFPs.

Background: Toxicokinetics of nanomaterials, including studies on the absorption, distribution, metabolism, and elimination of nanomaterials, are essential in assessing their potential health effects. The fate of nanomaterials after inhalation exposure to multiple nanomaterials is not clearly understood.

Methods: Male Sprague-Dawley rats were exposed to similar sizes of silver nanoparticles (AgNPs, 10.86 nm) and gold nanoparticles (AuNPs, 10.82 nm) for 28 days (6-h/day, 5-days/week for four weeks) either with separate NP inhalation exposures or with combined co-exposure in a nose-only inhalation system. Mass concentrations sampled from the breathing zone were AuNP 19.34 ± 2.55 μg/m³ and AgNP 17.38 ± 1.88 μg/m³ for separate exposure and AuNP 8.20 μg/m³ and AgNP 8.99 μg/m³ for co-exposure. Lung retention and clearance were previously determined on day 1 (6-h) of exposure (E-1) and on post-exposure days 1, 7, and 28 (PEO-1, PEO-7, and PEO-28, respectively). In addition, the fate of nanoparticles, including translocation and elimination from the lung to the major organs, were determined during the post-exposure observation period.

Results: AuNP was translocated to the extrapulmonary organs, including the liver, kidney, spleen, testis, epididymis, olfactory bulb, hilar and brachial lymph nodes, and brain after subacute inhalation and showed biopersistence regardless of AuNP single exposure or AuNP + AgNP co-exposure, showing similar elimination half-time. In contrast, Ag was translocated to the tissues and rapidly eliminated from the tissues regardless of AuNP co-exposure. Ag was continually accumulated in the olfactory bulb and brain and persistent until PEO-28.

Conclusion: Our co-exposure study of AuNP and AgNP indicated that soluble AgNP and insoluble AuNP translocated differently, showing soluble AgNP could be dissolved into Ag ion to translocate to the extrapulmonary organs and rapidly removed from most organs except the brain and olfactory bulb. Insoluble AuNPs were continually translocated to the extrapulmonary organs, and they were not eliminated rapidly.

Background: Montmorillonite (Mt) and its derivatives are now widely used in industrial and biomedical fields. Therefore, safety assessments of these materials are critical to protect human health after exposure; however, studies on the ocular toxicity of Mt are lacking. In particular, varying physicochemical characteristics of Mt may greatly alter their toxicological potential. To explore the effects of such characteristics on the eyes, five types of Mt were investigated in vitro and in vivo for the first time, and their underlying mechanisms studied.

Results: The different types of Mt caused cytotoxicity in human HCEC-B4G12 corneal cells based on analyses of ATP content, lactate dehydrogenase (LDH) leakage, cell morphology, and the distribution of Mt in cells. Among the five Mt types, Na-Mt exhibited the highest cytotoxicity. Notably, Na-Mt and chitosan-modified acidic Na-Mt (C-H-Na-Mt) induced ocular toxicity in vivo, as demonstrated by increases corneal injury area and the number of apoptotic cells. Na-Mt and C-H-Na-Mt also induced reactive oxygen species (ROS) generation in vitro and in vivo, as indicated by 2',7'-dichlorofluorescin diacetate and dihydroethidium staining. In addition, Na-Mt activated the mitogen-activated protein kinase signaling pathway. The pretreatment of HCEC-B4G12 cells with N-acetylcysteine, an ROS scavenger, attenuated the Na-Mt-induced cytotoxicity and suppressed p38 activation, while inhibiting p38 activation with a p38-specific inhibitor decreased Na-Mt-induced cytotoxicity.

Conclusions: The results indicate that Mt induces corneal toxicity in vitro and in vivo. The physicochemical properties of Mt greatly affect its toxicological potential. Furthermore, ROS generation and p38 activation contribute at least in part to Na-Mt-induced toxicity.