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Nanoparticles and the Brain: Cause for Concern?
Abstract
Engineered nanoparticles (NPs) are in the same size category as atmospheric ultrafine particles, < 100 nm. Per given volume, both have high numbers and surface areas compared to larger particles. The high proportion of surface atoms/molecules can give rise to a greater chemical as well as biological activity, for example the induction of reactive oxygen species in cell-free medium as well as in cells. When inhaled as singlet particles, NPs of different sizes deposit efficiently in all regions of the respiratory tract by diffusion. A major difference to larger size particles is the propensity of NPs to translocate across cell barriers from the portal of entry (e.g., the respiratory tract) to secondary organs and to enter cells by various mechanisms and associate with subcellular structures. This makes NPs uniquely suitable for therapeutic and diagnostic uses, but it also leaves target organs such as the central nervous system (CNS) vulnerable to potential adverse effects (e.g., oxidative stress). Neuronal transport of NPs has been described, involving retrograde and anterograde movement in axons and dendrites as well as perineural translocation. This is of importance for access of inhaled NPs to the CNS via sensory nerves existing in the nasopharyngeal and tracheobronchial regions of the respiratory tract. The neuronal pathway circumvents the very tight blood brain barrier. In general, translocation rates of NP from the portal of entry into the blood compartment or the CNS are very low. Important modifiers of translocation are the physicochemical characteristics of NPs, most notably their size and surface properties, particularly surface chemistry. Primary surface coating (when NPs are manufactured) and secondary surface coating (adsorption of lipids/proteins occurring at the portal of entry and during subsequent translocation) can significantly alter NP biokinetics and their effects. Implications of species differences in respiratory tract anatomy, breathing pattern and brain anatomy for extrapolation to humans of NP effects observed in rodents need to be considered. Although there are anecdotal data indicating a causal relationship between long-term ultrafine particle exposures in ambient air (e.g., traffic related) or at the workplace (e.g., metal fumes) and resultant neurotoxic effects in humans, more studies are needed to test the hypothesis that inhaled nanoparticles cause neurodegenerative effects. Some but probably not the majority of NPs will have a significant toxicity (hazard) potential, and this will pose a significant risk if there is a sufficient exposure. The challenge is to identify such hazardous NPs and take appropriate measures to prevent exposure.
... Two lines of study have been influential in causing people to think that the associations reported in epidemiological studies and the early work on the dogs might be important. The first was the appreciation that ultrafine particles could reach the olfactory bulbs of the brain via the olfactory nerves (Oberdörster et al, 2009). The second concerned the protection of the brain by the blood-brain barrier. ...
... Whether small particles that form part of the ambient aerosol can cross the BBB has been debated at length (Oberdörster et al, 2009). ...
... A non-specific endocytotic process also exists and is thought to be involved in the transport of fluid and small peptides. Nano-sized particulate material has been found in the brains of both humans and experimental animals (Maher et al, 2016;Oberdörster et al, 2009;Elder et al 2006). ...
Dementia is an umbrella term for a range of conditions that affect how the brain works and, in particular, the ability to remember, think and reason. It mainly affects older people, both men and women, and gets worse over time. In recent years, there has been growing interest in the possibility that exposure to outdoor air pollution could increase the risk of dementia. COMEAP reviewed epidemiological and experimental studies and concluded that it is likely that air pollution contributes to a decline in mental ability and dementia in older people. The most likely way this occurs is through effects on the circulatory system. It is known that air pollutants, particularly fine particles, can affect the heart and blood vessels, including those of the brain. These effects are linked to vascular dementia, which is caused by damage to the blood vessels in the brain. Experimental studies suggest that air pollution may also stimulate immune cells in the brain, which can then damage nerve cells. It is also likely that some nano-sized (ultrafine) particles can enter the brain, either by transport along the olfactory nerve or by entering the circulation and crossing the blood-brain barrier. These particles may cause direct damage. Nonetheless, based on the available evidence, it does not seem likely that this is an important mechanism for the development of dementia. Recommendations were made for further research which would help develop the evidence on this important topic.
... As for other metallic NPs that can reach the central nervous system in mice and humans via the olfactory and/or trigeminal nerves, as well as the systemic circulation [21][22][23], TiO 2 -NPs can cross the blood-brain barrier and accumulate in the brain [24,25], notably in the hippocampus [26], a brain structure involved in memory processes and affected early and severely in AD [27]. In the hippocampus, different forms of TiO 2 -NPs were shown to exert some adverse effects such as oxidative stress, mitochondrial dysfunction, gliosis, and to provoke neuronal lesions [1,[28][29][30]. Exploiting reconstructed neuronal networks, TiO 2 -NPs were also reported to severely impair the electrical activity of neurons [31]. ...
... Because nanoparticle exposure elicits oxidative stress conditions in epithelial cells [17] and triggers oxidative lesions in the brain of mice [28,30], we examined whether nanoparticle interaction with full-length PrP C would disturb the PrP C -NADPH oxidase functional relationship [38] and promote ROS accumulation. ...
... Acute exposure of neuronal cells to TiO 2 -or CB-NPs provokes transient activation of NADPH oxidase and subsequent production of ROS. In the 1C11 cell line, the nanoparticle-induced ROS production does not promote oxidative stress conditions, which contrasts with oxidative lesions in the brain of animals exposed to TiO 2 -NPs [28,30]. These discrepancies may firstly reflect the acute versus chronic exposure of neurons to nanoparticles. ...
Background
Epidemiological emerging evidence shows that human exposure to some nanosized materials present in the environment would contribute to the onset and/or progression of Alzheimer’s disease (AD). The cellular and molecular mechanisms whereby nanoparticles would exert some adverse effects towards neurons and take part in AD pathology are nevertheless unknown.
Results
Here, we provide the prime evidence that titanium dioxide (TiO 2 ) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrP C ), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO 2 - or CB-NPs and PrP C at the surface of neuronal cells grown in culture corrupts PrP C signaling function. This triggers PrP C -dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrP C interaction, NPs also promote the activation of 3-phosphoinositide-dependent kinase 1 (PDK1), which in turn provokes the internalization of the neuroprotective TACE α-secretase. This diverts TACE cleavage activity away from (i) TNFα receptors (TNFR), whose accumulation at the plasma membrane augments the vulnerability of NP-exposed neuronal cells to TNFα -associated inflammation, and (ii) the amyloid precursor protein APP, leading to overproduction of neurotoxic amyloid Aβ40/42 peptides. The silencing of PrP C or the pharmacological inhibition of PDK1 protects neuronal cells from TiO 2 - and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrP C -PDK1-TACE pathway likely occurs in the brain of mice injected with TiO 2 -NPs by the intra-cerebro-ventricular route as we monitor a rise of TNFR at the cell surface of several groups of neurons located in distinct brain areas.
Conclusion
Our in vitro and in vivo study thus posits for the first time normal cellular prion protein PrP C as being a neuronal receptor of TiO 2 - and CB-NPs and identifies PrP C -coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ peptides. By identifying signaling cascades dysregulated by TiO 2 - and CB-NPs in neurons, our data shed light on how human exposure to some NPs might be related to AD.
... The importance of toxicology research on ENM has been substantiated by studies that support a role of ambient ultrafine particles (UFP) in air pollution-associated diseases (3). Similarly, increased attention has been given to the potential neurotoxicity of ENM (4)(5)(6). A pioneering inhalation study by Oberdoerster and co-workers (7), demonstrated that insoluble carbon particles in the nano size range can rapidly translocate to the brain upon deposition in the nasal mucosa in rats. ...
... Adverse effects on the brain have been shown nowadays in various studies. Investigations with diesel engine exhaust (DEE), collected diesel exhaust particles (DEP) or ambient particulate matter (PM) (6,8) as well as on-site-exposure studies with concentrated ambient PM (CAPs) have provided important support for the growing number of epidemiological studies that link air pollution to neurological diseases including dementia (9,10). Neurotoxicological studies with ENM in rodents have been performed with the most widely produced and used materials like Ag, SiO 2 , TiO 2 , CeO 2 , ZnO and carbon black. ...
... In general, as with other effects and associated disease outcomes (e.g., in the respiratory or cardiovascular system), oxidative stress and inflammation are also considered key processes of potential neurotoxic and neurological consequences following ENM exposure (5,6). Oxidative stress in ENM exposed cells, can cause activation of redox-sensitive signaling cascades involved in activation of pro-inflammatory cytokines and chemokines, proliferation, apoptosis and DNA damage induction (18), representing mediators or processes that all have been implicated in neurological and neurodegenerative diseases (5,19). ...
As with toxicology in general, major challenges have emerged in its subfield neurotoxicology regarding the testing of engineered nanomaterials (ENM). This is on the one hand due to their complex physicochemical properties, like size, specific surface area, chemical composition as well as agglomeration and dissolution behavior in biological environments. On the other hand, toxicological risk assessment has faced an increasing demand for the development and implementation of non-animal alternative approaches. Regarding the investigation and interpretation of the potential adverse effects of ENM on the brain, toxicokinetic data are relatively scarce and thus hampers dose selection for in vitro neurotoxicity testing. Moreover, recent in vivo studies indicate that ENM can induce neurotoxic and behavioral effects in an indirect manner, depending on their physicochemical properties and route of exposure. Such indirect effects on the brain may proceed through the activation and spill-over of inflammatory mediators by ENM in the respiratory tract and other peripheral organs as well via ENM induced disturbance of the gut microbiome and intestinal mucus barrier. These ENM specific aspects should be incorporated into the ongoing developments of advanced in vitro neurotoxicity testing methods and strategies.
... 6 Alternatively, it is hypothesized that air pollutant particles can also enter the brain by traveling across the olfactory nerve, which carries information about the sense of smell from the nose to the brain. 7 Once in the brain, these particles can trigger an immune response that leads to inflammation and oxidative stress, which in turn can cause damage to neurons and may lead to neurodegeneration. 8,9 Previously, we found that ambient black carbon particles can cross the human placenta into the fetal circulation and fetal brain. ...
... in the translocation of black carbon particles within the brain, as it is hypothesized that air pollutant nanoparticles can travel along the axonal path of the brain. 7 However, we can only speculate about the intratissue translocation of black carbon in the brain with the available data. Biokinetic studies are needed to investigate further the distribution of these black carbon particles in the human brain. ...
Importance
Ambient air pollution is a worldwide problem, not only related to respiratory and cardiovascular diseases but also to neurodegenerative disorders. Different pathways on how air pollutants could affect the brain are already known, but direct evidence of the presence of ambient particles (or nanoparticles) in the human adult brain is limited.
Objective
To examine whether ambient black carbon particles can translocate to the brain and observe their biodistribution within the different brain regions.
Design, Setting, and Participants
In this case series a label-free and biocompatible detection technique of nonincandescence-related white light generation was used to screen different regions of biobanked brains of 4 individuals from Belgium with neuropathologically confirmed Alzheimer disease for the presence of black carbon particles. The selected biological specimens were acquired and subsequently stored in a biorepository between April 2013 and April 2017. Black carbon measurements and data analysis were conducted between June 2020 and December 2022.
Main Outcomes and Measures
The black carbon load was measured in various human brain regions. A Kruskal-Wallis test was used to compare black carbon loads across these regions, followed by Dunn multiple comparison tests.
Results
Black carbon particles were directly visualized in the human brain of 4 individuals (3 women [75%]; mean [SD] age, 86 [13] years). Screening of the postmortem brain regions showed a significantly higher median (IQR) number of black carbon particles present in the thalamus (433.6 [289.5-540.2] particles per mm ³ ), the prefrontal cortex including the olfactory bulb (420.8 [306.6-486.8] particles per mm ³ ), and the hippocampus (364.7 [342.0-448.7] particles per mm ³ ) compared with the cingulate cortex (192.3 [164.2-277.5] particles per mm ³ ), amygdala (217.5 [147.3-244.5] particles per mm ³ ), and the superior temporal gyrus (204.9 [167.9-236.8] particles per mm ³ ).
Conclusions and Relevance
This case series provides evidence that ambient air pollution particles are able to translocate to the human brain and accumulate in multiple brain regions involved in cognitive functioning. This phenomenon may contribute to the onset and development of neurodegenerative disorders.
... For example, in our study, the majority of sampling occurred inside the participants home, indicating individual home exposures may be more indicative of health-related effects, compared to concentrations captured outside by stationary monitors. Though we did not find similar results with respect to depression and anxiety outcomes, it is possible UFPs activate different pathways than those of PM2.5 or interact directly with tissues, thereby eliciting differing symptoms of mental health [31,32]. The epidemiological literature on mental health effects of UFPs in children is lacking, therefore further research in this area is needed to confirm these relationships. ...
... Though we did not find similar results with respect to depression and anxiety outcomes, it is possible UFPs activate different pathways than those of PM 2 . 5 or interact directly with tissues, thereby eliciting differing symptoms of mental health [31,32]. The epidemiological literature on mental health effects of UFPs in children is lacking, therefore further research in this area is needed to confirm these relationships. ...
Incidence rates of mental health disorders among adolescents is increasing, indicating a strong need for effective prevention efforts at a population level. The etiology of mental health disorders includes genetic, social, and environmental factors. Ultrafine particles (UFPs; particles less than 0.1 μm in diameter) have been shown to exert neurotoxic effects on the brain; however, epidemiologic evidence on the relationship between UFPs and childhood mental health outcomes is unclear. The objective of this study was to determine if exposure to UFPs was associated with symptoms of mental health in adolescents. Adolescents completed personal UFP monitoring for one week as well as a series of validated Patient-Reported Outcomes Measurement Information System (PROMIS) assessments to measure five domains of mental and physical stress symptoms. Multivariable linear regression models were used to estimate the association between PROMIS domain T-scores and median weekly personal UFP exposure with the inclusion of interactions to explore sex differences. We observed that median weekly UFP exposure was significantly associated with physical stress symptoms (β: 5.92 per 10-fold increase in UFPs, 95% CI [0.72, 11.13]) but no other measured domains. Further, we did not find effect modification by sex on any of the PROMIS outcomes. The results of this study indicate UFPs are associated with physical symptoms of stress response among adolescents, potentially contributing to mental health disorders in this population.
... Air pollution negatively affects the nervous system (Genc et al. 2012), digestive system (Kaplan et al. 2013), and even urinary system (Calderon-Garciduenas et al. 2004) in humans. Air pollution is the cause and aggravating factor of many respiratory diseases such as chronic obstructive pulmonary disease (COPD) (Calderón-Garcidueñas et al. 2008;Oberdörster et al. 2009), asthma (Peters et al. 2006;Oberdörster et al. 2009), and lung cancer (Watson 2006;Craig et al. 2008;MohanKumar et al. 2008;Gold and Samet 2013). ...
... Air pollution negatively affects the nervous system (Genc et al. 2012), digestive system (Kaplan et al. 2013), and even urinary system (Calderon-Garciduenas et al. 2004) in humans. Air pollution is the cause and aggravating factor of many respiratory diseases such as chronic obstructive pulmonary disease (COPD) (Calderón-Garcidueñas et al. 2008;Oberdörster et al. 2009), asthma (Peters et al. 2006;Oberdörster et al. 2009), and lung cancer (Watson 2006;Craig et al. 2008;MohanKumar et al. 2008;Gold and Samet 2013). ...
The objective of this study is to statistically examine the variation of PM10 values measured at three stations in the center of Sivas between the years 2016 and 2020. Hourly PM10 measurement values were taken from three different stations (İstasyon Kavşağı, Meteoroloji, and Başöğretmen AQMSs) in the city center. Then the mean values of the measurements obtained between 2016 and 2020 were compared according to the years and the stations, as well as with the limit values given in the Regulation on Air Quality Assessment and Management(RAQAM). Analyses of variance were conducted to determine any differences between PM10 levels and 24-h limit values of PM10 for Turkey and between PM10 values of stations over the years. Considering the 5-year mean values, the mean value of all PM10 concentrations measured in the city center was calculated as 56.36 µg/m 3. No statistical difference was found between the PM10 values measured in 2017 and 2018 at the İstasyon Kavşağı AQMS, and the comparisons of PM10 between stations over the years showed no difference between the Meteoroloji AQMS and the Başöğretmen AQMS in 2019 and 2020. The Spearman's rank-order correlation results of PM10 over the years among the stations in the city showed that the strongest relationship was a moderate one between the years 2019 and 2020 with regard to the İstasyon Kavşağı AQMS. Probable dust transports were examined for the days when PM10 was at its highest, and the conclusion was that desert dust coming from the continent of Africa (south) to the center of Sivas had been effective.
... 31 The need to disperse nanomaterials in a balanced electrolyte solution that can be instilled intranasally is important in toxicity studies because some nanomaterials have recently demonstrated the ability to enter the brain through the olfactory pathway from the nose to the brain. [15][16][17][32][33][34][35][36] The olfactory pathway bypasses the bloodbrain barrier because olfactory neurons have direct contact with the lumen of the nose and their first synapse is in the olfactory bulb of the brain. This allows entry into the brain for some particles that cannot cross the blood-brain barrier. ...
... Thus, the dispersion of nanomaterials within biocompatible aqueous liquids is essential to evaluating the toxicity of such nanomaterials in short-term toxicology studies. 34,67 Dispersion media for such studies have similarities to some drug delivery systems developed for nose-to-brain transport of pharmaceuticals, which is an area of active research. 68-71 For short-term testing of neurotoxicity of occupational and environment nanoparticles using intranasal instillation, dispersion solutions, like pharmaceutical drug delivery systems, should be both biocompatible and compatible with olfactory transport. ...
With advances in nanotechnology, engineered nanomaterial applications are a rapidly growing sector of the economy. Some nanomaterials can reach the brain through nose-to-brain transport. This transport creates concern for potential neurotoxicity of insoluble nanomaterials and a need for toxicity screening tests that detect nose-to-brain transport. Such tests can involve intranasal instillation of aqueous suspensions of nanomaterials in dispersion media that limit particle agglomeration. Unfortunately, protein and some elements in existing dispersion media are suboptimal for potential nose-to-brain transport of nanomaterials because olfactory transport has size- and ion-composition requirements. Therefore, we designed a protein-free dispersion media containing phospholipids and amino acids in an isotonic balanced electrolyte solution, a solution for nasal and olfactory transport (SNOT). SNOT disperses hexagonal boron nitride nanomaterials with a peak particle diameter below 100 nm. In addition, multiwalled carbon nanotubes (MWCNTs) in an established dispersion medium, when diluted with SNOT, maintain dispersion with reduced albumin concentration. Using stereomicroscopy and microscopic examination of plastic sections, dextran dyes dispersed in SNOT are demonstrated in the neuroepithelium of the nose and olfactory bulb of B6;129P2- Omp tm3Mom /MomJ mice after intranasal instillation in SNOT. These findings support the potential for SNOT to disperse nanomaterials in a manner permitting nose-to-brain transport for neurotoxicity studies.
... The gastrointestinal and respiratory systems are the most well-known exposure routes for NPs in consumer products or from occupational exposure (Bergin and Witzmann 2013;Raftis and Miller 2019). NPs then distribute to the blood stream and may pass the blood-brain barrier (BBB) (Oberdörster et al. 2009), similar to ultrafine particles (UFPs) (Wang et al. 2017;Oberdörster et al. 2004). ...
... Exposure routes affect the biodistribution of NPs. After NI, NPs are absorbed into nerve fiber ends in the nasal cavity and then transported within and between neurons (Oberdörster et al. 2009;Hanada et al. 2014); after oral ingestion or injection, NPs first circulate in the blood stream and then cross the BBB to reach the brain (Sawicki et al. 2019). ...
Systemic exposure to nanoparticles (NPs) adversely affects different organs, including the nervous system. We systematically extracted data from publication on PubMed and Embase database up to the year 2020, and analyzed in vitro and in vivo neurotoxicity of 4 of the most well studied NPs (silver NPs, carbon-based NPs, iron NPs and silica NPs). A relatively good correlation was observed between in vitro and in vivo effects, including genotoxicity, oxidative stress, apoptosis and pro-inflammatory effects. However, crucial knowledge gap exists in current understanding of the underlying mechanisms. Some of the critical knowledge gaps and research needs identified in relation to neurotoxicity of nanoparticles include (1) lack of physio-chemical characteristics of NPs used, (2) cellular/tissue uptake of NP, (3) NP translocation across the blood-brain barrier (BBB), (4) Effect of exposure routes.
... These findings initially established the relationship between air pollution exposure and the hastening of pathological features common to neurodegenerative diseases. Even if the translocation rate of air pollutants from their entry site to secondary organs is low, chronic exposure to air pollution can lead to the accumulation of toxic substances in the brain and other secondary target organs over time [41,42]. ...
Air pollution, a growing concern for public health, has been linked to various respiratory and cardiovascular diseases. Emerging evidence also suggests a link between exposure to air pollutants and neurodegenerative diseases, particularly Alzheimer’s disease (AD). This review explores the composition and sources of air pollutants, including particulate matter, gases, persistent organic pollutants, and heavy metals. The pathophysiology of AD is briefly discussed, highlighting the role of beta-amyloid plaques, neurofibrillary tangles, and genetic factors. This article also examines how air pollutants reach the brain and exert their detrimental effects, delving into the neurotoxicity of air pollutants. The molecular mechanisms linking air pollution to neurodegeneration are explored in detail, focusing on oxidative stress, neuroinflammation, and protein aggregation. Preclinical studies, including in vitro experiments and animal models, provide evidence for the direct effects of pollutants on neuronal cells, glial cells, and the blood–brain barrier. Epidemiological studies have reported associations between exposure to air pollution and an increased risk of AD and cognitive decline. The growing body of evidence supporting air pollution as a modifiable risk factor for AD underscores the importance of considering environmental factors in the etiology and progression of neurodegenerative diseases, in the face of worsening global air quality.
... Despite the lack of fenestrations in endothelial cells, vectors still manage to penetrate into the brain. The latest theory is that these vectors pass through poorly developed or damaged areas or using dendrites and neuronal axons to penetrate the BBB (Oberdorster et al., 2009;Lankveld et al., 2010). Damage to the BBB by HIV-1 infection has been studied more so than other tissue barriers given the importance of the CNS as a reservoir. ...
Human immunodeficiency virus type 1 (HIV-1) infection is well known as one of the most complex and difficult viral infections to cure. The difficulty in developing curative strategies arises in large part from the development of latent viral reservoirs (LVRs) within anatomical and cellular compartments of a host. The clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9 (CRISPR/Cas9) system shows remarkable potential for the inactivation and/or elimination of integrated proviral DNA within host cells, however, delivery of the CRISPR/Cas9 system to infected cells is still a challenge. In this review, the main factors impacting delivery, the challenges for delivery to each of the LVRs, and the current successes for delivery to each reservoir will be discussed.
... Owing to their small size, nanomaterials can sorb various pollutants on their surface (for example, metals), cross biological barriers and reach the brain and exert neurotoxicity [51][52][53] . Finally, besides xenobiotics, there are many natural chemical compounds in the chemical exposome, such as microbial-derived compounds, that are known to regulate multiple aspects of brain health. ...
Over the past few decades, numerous environmental chemicals from solvents to pesticides have been suggested to be involved in the development and progression of neurodegenerative diseases. Most of the evidence has accumulated from occupational or cohort studies in humans or laboratory research in animal models, with a range of chemicals being implicated. What has been missing is a systematic approach analogous to genome-wide association studies, which have identified dozens of genes involved in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. Fortunately, it is now possible to study hundreds to thousands of chemical features under the exposome framework. This Perspective explores how advances in mass spectrometry make it possible to generate exposomic data to complement genomic data and thereby better understand neurodegenerative diseases.
... NPs are materials with a zero-dimensional structure and can be classified into organic, inorganic, and composite NPs (Oberdörster et al., 2009). Metal NPs have garnered significant attention because of their common use in medical, consumer, industrial, and military sectors. ...
Ensuring human health safety necessitates rigorous biosafety evaluations of substances and materials, particularly in the context of in-vivo exposure. Biodegradable materials, known for their natural decomposition capabilities through biological mechanisms, may exhibit toxicological profiles differing from non-biodegradable substances. Prior to their application in medical devices such as stents and implants, it is imperative to conduct thorough testing to ascertain their safety. This chapter aims to provide a comprehensive assessment of the in-vivo biosafety of various biodegradable materials. The authors employ an integrative approach, combining in-vitro ion-tolerance assays with in-vivo microanalysis techniques. This dual methodology allows for a detailed evaluation of the materials' biocompatibility and potential toxicity, particularly focusing on nanomaterial-induced toxicity in neural tissues. These findings offer critical insights into the safe application of biodegradable biomedical materials, underpinning informed decision-making in their usage for medical applications.
... UFP is considered to have a greater toxicity than particles in larger size categories due to its physical characteristics, including a size that allows penetration into the alveoli of the lungs and transport to the bloodstream [25]. While growing evidence implicates the ultrafine PM fraction in a range of adverse health effects including stroke, brain cancer, and childhood respiratory illness, accurately estimating UFP exposure remains a barrier in distinguishing its effects from total PM 2.5 [25][26][27][28][29]. ...
Background
National-scale linear regression-based modeling may mischaracterize localized patterns, including hyperlocal peaks and neighborhood- to regional-scale gradients. For studies focused on within-city differences, this mischaracterization poses a risk of exposure misclassification, affecting epidemiological and environmental justice conclusions.
Objective
Characterize the difference between intraurban pollution patterns predicted by national-scale land use regression modeling and observation-based estimates within a localized domain and examine the relationship between that difference and urban infrastructure and demographics.
Methods
We compare highly resolved (0.01 km²) observations of NO2 mixing ratio and ultrafine particle (UFP) count obtained via mobile monitoring with national model predictions in thirteen neighborhoods in the San Francisco Bay Area. Grid cell-level divergence between modeled and observed concentrations is termed “localized difference.” We use a flexible machine learning modeling technique, Bayesian Additive Regression Trees, to investigate potentially nonlinear relationships between discrepancy between localized difference and known local emission sources as well as census block group racial/ethnic composition.
Results
We find that observed local pollution extremes are not represented by land use regression predictions and that observed UFP count significantly exceeds regression predictions. Machine learning models show significant nonlinear relationships among localized differences between predictions and observations and the density of several types of pollution-related infrastructure (roadways, commercial and industrial operations). In addition, localized difference was greater in areas with higher population density and a lower share of white non-Hispanic residents, indicating that exposure misclassification by national models differs among subpopulations.
Impact
Comparing national-scale pollution predictions with hyperlocal observations in the San Francisco Bay Area, we find greater discrepancies near major roadways and food service locations and systematic underestimation of concentrations in neighborhoods with a lower share of non-Hispanic white residents. These findings carry implications for using national-scale models in intraurban epidemiological and environmental justice applications and establish the potential utility of supplementing large-scale estimates with publicly available urban infrastructure and pollution source information.
... Recently it was demonstrated by various researchers by using transmission electron microscopy that extremely small NPs (>100 nm), contact the nasal mucosa, and then go through it to the olfactory bulb. Recently scientist have confirmed that NP below 500 nm did not transcytosis by olfactory and forebrain neurons but they were primarily endocytosed by olfactory and cortical microglia [8,43]. Fig. 11.4 explains different strategies for targeting PLGA NPs to brain. ...
Alzheimer's disease (AD) is an incessant neurodegenerative disorder, the cases of which are estimated by WHO to cross 130 million by the year 2050. The high levels of β-amyloid (Aβ) peptides and the aggregation of the same is estimated to elicit AD symptoms leading to gradual loss of higher cognitive abilities. The prevalence of unconquerable Blood Brain Barrier (BBB) is one of the biggest challenges preventing therapeutic agents to reach AD site. Clinical uses of nanoparticles (NPs) have exhibited substantial benefits for targeting and drug delivery, notably in the management of AD. In this regard, the FDA approved native PLGA, due to its ability to attenuate memory deficit, finds unique potential in AD pathology. PLGA is advantageous over other polymers that are used in drug and gene delivery, imparting unique biodegradability, biocompatibility, and approval for human use granted by the FDA. Formulations made of PLGA have been studied extensively as delivery carriers for a variety of drugs, proteins and other macromolecules. In fact, some earlier studies have shown that PLGA-encapsulated drugs like donepezil, memantine etc., had beneficial effects on cellular and/or animal models of AD with satisfactory biocompatibility. This chapter highlights the challenges in AD treatment, therapeutic strategies to combat the disease, PLGA for treating AD, and current formulations of PLGA in the pipeline for the same.
... The association of nanotoxicology with neurology in a new discipline, with its specific tools and methods of investigation, should make it possible to answer questions still pending (Bencsik et al., 2018). The challenge is to identify these dangerous NPs for the nervous system and to take the appropriate measures to prevent exposure (Oberdorster et al., 2009). ...
Nanoparticles (NPs) are widely used in the manufacture of common consumer products, namely cosmetics, food and beverages, food packaging, household appliances, automobiles, textiles, toys, etc. which raise questions about their toxic effects on human health. These effects are studied in the field of nanotoxicology. The present review synthesized current knowledge concerning metallic nanoparticles (NPs) used in the food sector and their potential health effects. Experimental studies published in the scientific literature have shown that nanoparticles
used in food sector, such as titanium dioxide (TiO2), silicium dioxide (SiO2), zinc oxide (ZnO), gold nanoparticles (Au NPs), silver nanoparticles (Ag NPs), etc.), could have long-term toxic health effects. Indeed, they cause cancers, nephrotoxicity, hepatotoxicity, pneumotoxicity, immunotoxicity and cytotoxicity, endocrine disruption as well as uterine malformations. Research in nanotoxicology should continue in this field in order establish a regulatory arsenal protecting the general population’s health ____ Keywords: Nanoparticles; Nanotoxicology; Long-term toxicity; Health effects; Food safety.
... Due to their very small size range (1-100 nm), engineered nanoparticles (NP) are used as additives in many applications (Oberdörster et al., 2009;Teleanu et al., 2018). The unique physicochemical properties and reactivity of NP are determined by size, but also by their shape, surface characteristics, and inner structure (for details see Shi et al., 2013). ...
In vivo toxicokinetic studies provide evidence for the translocation and accumulation of nanoparticles (NP) in the brain, thereby causing concern for adverse health effects, particularly for effects following chronic exposure. To date, only few studies investigated the effects of NP exposure on neuronal function in vitro, primarily focusing on short-term effects. The aim of this study was therefore to investigate the effects of two common types of NP, titanium dioxide NP (TiO2NP) and silver NP (AgNP), on neuronal function following acute (0.5 h), sub-chronic (24 h and 48 h) and chronic (14 days) exposure in vitro. Effects of NP exposure on intracellular calcium homeostasis, spontaneous neuronal (network) activity and neuronal network morphology were investigated in rat primary cortical cells using respectively, single-cell microscopy calcium imaging, micro-electrode array (MEA) recordings and immunohistochemistry.
Our data demonstrate that high doses of AgNP (≥ 30 µg/mL) decrease calcium influx after 24 h exposure, although neuronal activity is not affected following acute and sub-chronic exposure. However, chronic exposure to non-cytotoxic doses of AgNP (1-10 µg/mL) potently decreases spontaneous neuronal (network) activity, without affecting network morphology and viability. Exposure to higher doses (≥ 30 µg/mL) affects network morphology and is also associated with cytotoxicity. In contrast, acute and sub-chronic exposure to TiO2NP is without effects, whereas chronic exposure only modestly reduces neuronal function without affecting morphology.
Our combined findings indicate that TiO2NP exposure is of limited hazard for neuronal function whereas AgNP, in particularly during chronic exposure, has profound effects on neuronal (network) function and morphology.
... The appearance of lipid-NP clusters at surface pressures below the monolayer-multilayer transition of lung surfactant indicates that key factors consider for NP drug delivery design such as the material's biodegradability, biocompatibility, and particle size limit 49,[90][91][92][93] are not sufficient to assess the safety of the drug delivery application as shown here for materials considered as safe. ...
Biocompatible materials are increasingly used for pulmonary drug delivery, and it is essential to understand their potential impact on the respiratory system, notably their effect on lung surfactant, a monolayer of lipids and proteins, responsible for preventing alveolar collapse during breathing cycles. We have developed a complex mimic of lung surfactant composed of eight lipids mixed in ratios reported for native lung surfactant. A synthetic peptide based on surfactant protein B was added to better mimic the biological system. This model was used to evaluate the impact of biocompatible gelatin and poly(lactic-co-glycolic acid) nanoparticles. Surface pressure-area isotherms were used to assess lipid packing, film compressibility and stability, whereas the lateral organization was visualized by Brewster angle microscopy. Nanoparticles increased film fluidity and altered the monolayer collapse pressure. Bright protruding clusters formed in their presence indicate a significant impact on the lateral organization of the surfactant film. Altogether, this work indicates that biocompatible materials considered to be safe for drug delivery still need to be assessed for their potential detrimental impact before use in therapeutic applications
... Just as an example, recently it has been reported that plastics with submicron size were found in the bloodstream of healthy donors [10]. This finding is not surprising considering that the translocation of particles in that size range was reported in experimental studies in 2002 [11], and since then many other studies have shown that particulate matter can translocate to the circulation [12] and can reach different tissues including the brain [13], even in a fetal stage [14]. The difference between the plastics in blood study and previous reports, is that the plastics report comes in a time when the discussion related to microplastics in the oceans [15] has reached the mass media [16], therefore giving big mediatic attention to this report [17]. ...
The use of nanomaterials has been increasing in recent times, and they are widely used in industries such as cosmetics, drug, food, water treatment and agriculture. The rapid development of new nanomaterials demands a set of approaches to evaluate the potential toxicity and risks related to them. In this regard, nanosafety has been using and adapting already existing methods (toxicological approach), but the unique characteristics of nanomaterials demand new approaches (nanotoxicology) to fully understand the potential toxicity, immunotoxicity and (epi)genotoxicity. Also, new technologies, such as organ-on-chip and sophisticated sensors, are under development and/or adaptation. All the information generated is used to develop new in silico approaches trying to predict the potential effects of newly developed materials. The overall evaluation of how from the production to final disposition chain of nanomaterials is evaluated under Life Cycle Assessment (LCA), which is becoming an important element of nanosafety considering sustainability and environmental impact. In this review we give an overview of all these elements of nanosafety.
... Ce transport direct de certaines substances inhalées via l'épithélium olfactif peut ainsi entraîner une distribution supplémentaire dans le SNC avec la présence potentielle d'un gradient de distribution antéropostérieure du contaminant [133]. Il a été observé, pour des particules ultrafines déposées sur l'épithélium olfactif, une distribution à l'intégralité du cerveau attribuée au transport olfactif [134,135]. Ces voies de transport ne sont pas disponibles pour tout contaminant [137] et semblent dépendre de la taille, de la nature chimique et de la biodisponibilité des composés. Concernant les métaux et en plus du tungstène, divers contaminants métalliques (manganèse, fer, cadmium, thallium, mercure, cobalt, zinc) ainsi que des particules de carbone semblent pouvoir passer dans le cerveau après des expositions par inhalation ou par instillation intranasale/trachéale [132]. ...
L’exposition à des aérosols particulaires est la principale cause de contamination dans les installations nucléaires, et le cerveau peut en être une cible directe. Ce projet de thèse a étudié les effets biologiques induits par l’inhalation de particules de tungstène, présenté comme un contaminant émergent. Pourtant peu de connaissance sont disponibles concernant ses effets sur le cerveau. Du fait de son usage pour ses propriétés physico-chimiques remarquables, les situations d’exposition sont principalement professionnelles, notamment en lien avec les activités nucléaires (démantèlement, réacteurs de fusion nucléaire). Des travaux préalables de métrologie ont été réalisés pour maitriser la génération de l’aérosol à des concentrations de l’ordre de la Valeur Limite Moyenne d’Exposition Professionnelle, et caractériser sa granulométrie. L’extrême densité de ces particules leur confère des propriétés particulières, notamment une grande différence entre les diamètres aérodynamiques et de mobilité électrique qui dictent leur comportement dans les voies aériennes. Des campagnes d’exposition par inhalation ont été réalisées à deux concentrations différentes (5 et 80 mg.m-3) en mode aigu et répété sur 1 semaine chez le rat adulte. L’étude de processus impliqués en toxicologie cérébrale a été entreprise 24 heures après exposition. Des modifications régionalisées d’un point de vue anatomique et dépendantes de la concentration d’exposition pour les acteurs impliqués dans ces processus cibles ont été observées. Au niveau du bulbe olfactif, les résultats suggèrent un potentiel effet précoce sur la survie et la morphologie des cellules microgliales qui pourrait témoigner d’une réactivité au contaminant. Selon les modes d’exposition, ces cellules présentent une diminution de leur densité associée à une augmentation de marqueur apoptotique. Un phénotype anormal des noyaux de certains neurones matures, potentiellement signe d’une souffrance neuronale, a également été observé au niveau du cortex frontal et serait en potentiellement lié avec l’implication du stress oxydant. Les effets différentiels observés selon les schémas d’exposition pourraient impliquer plusieurs composantes : locale (propre au cerveau) et/ou systémique. En effet, le tungstène, en plus d’être retrouvé dans les poumons et les reins, est présent dans le cerveau des animaux exposés à la forte concentration, et semble modifier les processus inflammatoires au niveau du plasma. Nos données questionnent la relative innocuité du tungstène et soulèvent plusieurs hypothèses concernant de possibles mécanismes adaptatifs ou neurotoxiques qui pourraient finalement altérer l’intégrité neuronale selon les schémas d’exposition.
... Mechanistically, air contaminants have the potential to reach the brain directly via olfactory nerve axons following inhalation. On the other hand, air contaminants have been shown to indirectly affect the brain through systemic route as well (Peters et al., 2006;Oberdörster et al., 2009). ...
Increased incidences of neuro-inflammatory diseases in the mid-western United States of America (USA) have been linked to exposure to agriculture contaminants. Organic dust (OD) is a major contaminant in the animal production industry and is central to the respiratory symptoms in the exposed individuals. However, the exposure effects on the brain remain largely unknown. OD exposure is known to induce a pro-inflammatory phenotype in microglial cells. Further, blocking cytoplasmic NOX-2 using mitoapocynin (MA) partially curtail the OD exposure effects. Therefore, using a mouse model, we tested a hypothesis that inhaled OD induces neuroinflammation and sensory-motor deficits. Mice were administered with either saline, fluorescent lipopolysaccharides (LPSs), or OD extract intranasally daily for 5 days a week for 5 weeks. The saline or OD extract-exposed mice received either a vehicle or MA (3 mg/kg) orally for 3 days/week for 5 weeks. We quantified inflammatory changes in the upper respiratory tract and brain, assessed sensory-motor changes using rotarod, open-field, and olfactory test, and quantified neurochemicals in the brain. Inhaled fluorescent LPS (FL-LPS) was detected in the nasal turbinates and olfactory bulbs. OD extract exposure induced atrophy of the olfactory epithelium with reduction in the number of nerve bundles in the nasopharyngeal meatus, loss of cilia in the upper respiratory epithelium with an increase in the number of goblet cells, and increase in the thickness of the nasal epithelium. Interestingly, OD exposure increased the expression of HMGB1, 3- nitrotyrosine (NT), IBA1, glial fibrillary acidic protein (GFAP), hyperphosphorylated Tau (p-Tau), and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL)-positive cells in the brain. Further, OD exposure decreased time to fall (rotarod), total distance traveled (open-field test), and olfactory ability (novel scent test). Oral MA partially rescued olfactory epithelial changes and gross congestion of the brain tissue. MA treatment also decreased the expression of HMGB1, 3-NT, IBA1, GFAP, and p-Tau, and significantly reversed exposure induced sensory-motor deficits. Neurochemical analysis provided an early indication of depressive behavior. Collectively, our results demonstrate that inhalation exposure to OD can cause sustained neuroinflammation and behavior deficits through lung-brain axis and that MA treatment can dampen the OD-induced inflammatory response at the level of lung and brain.
... The exposure of neuronal cells to NPs can then lead to a direct alteration of the CNS structure and/or functioning, which may result in subsequent effects due to glial stimulation and glial-neuronal interactions. In this way, the neurotoxic effect of NPs that occur through various mechanisms, including oxidative stress, immune responses and neuroinflammation, could permanently damage the CNS or trigger irreversible alterations to the barrier that control its access [211,212]. ...
Nanotechnology represents a novel powerful technology with the potential to overcome some of the problems related to brain research. In particular, nanoparticles can be used as platforms for drug delivery, contrast agents for imaging diagnosis, or therapeutic probes. The small scale of these materials can be exploited to interact with individual neurons and even with target-specific molecules of the neuron. Moreover, some nanoparticles can be transcranially activated with external stimuli such as infrared light, ultrasounds, or magnetic fields. Nanoparticles are able to transduce such stimuli in a variety of physicochemical responses such as mechanical forces, local heat, catalytic activity, and drug release that modify the internal physiology of the neurons. Despite the enormous potential of nanoparticles, some issues still need to be solved such as the biodistribution through the blood–brain barrier and the minimization of potential toxicological hazards.
The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson’s disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson’s disease and open the door toward the ultimate goal –prevention.
Aerotoxic Syndrome may develop as a result of chronic, low-level exposure to organophosphates (OPs) and volatile organic compounds in the airplane cabin air, caused by engine oil leaking past wet seals. Additionally, acute high-level exposures, so-called "fume events," may occur. However, air quality monitoring studies concluded that levels of inhaled chemicals might be too low to cause adverse effects. The presence of aerosols of nanoparticles (NPs) in bleed air has often been described. The specific hypothesis is a relation between NPs acting as a vector for toxic compounds in the etiology of the Aerotoxic Syndrome. These NPs function as carriers for toxic engine oil compounds leaking into the cabin air. Inhaled by aircrew NPs carrying soluble and insoluble components deposit in the alveolar region, where they are absorbed into the bloodstream. Subsequently, they may cross the blood-brain barrier and release their toxic compounds in the central nervous system. Olfactory absorption is another route for NPs with access to the brain. To study the hypothesis, all published in-flight measurement studies (2003–2023) of airborne volatile (and low-volatile) organic pollutants in cabin air were reviewed, including NPs (10–100 nm). Twelve studies providing data for a total of 387 flights in 16 different large-passenger jet aircraft types were selected. Maximum particle number concentrations (PNC) varied from 104 to 2.8x106 #/cm3 and maximum mass concentrations from 9 to 29 lg/m3. NP-peaks occurred after full-power take-off, in tailwind condition, after auxiliary power unit (APU) bleed air introduction, and after air conditioning pack failure. Chemical characterization of the NPs showed aliphatic hydrocarbons, black carbon, and metallic core particles. An aerosol mass-spectrometry pattern was consistent with aircraft engine oil. It is concluded that chronic exposure of aircrew to NP-aerosols, carrying oil derivatives, maybe a significant feature in the etiology of Aerotoxic Syndrome. Mobile NP measuring equipment should be made available in the cockpit for long-term monitoring of bleed air. Consequently, risk assessment of bleed air should include monitoring and analysis of NPs, studied in a prospective cohort design.
Given the rapid growth of nanotechnology, it is essential to know the hazardous effects of metal oxide nanoparticles (MeOx NPs) posed to the living organisms within the ecosystem. With the...
Taiwan is located downwind of a variety of regional sources of air pollutants transported particularly during the seasons of East Asian winter monsoon. In addition, western Taiwan is a highly populated and urbanized/industrialized area, where the air quality is subject to the influences of local air pollution. To mitigate the impacts of air pollution, a series of control strategies have been developed and enforced during the last couple of decades, which evolved conceptually from being technically oriented in the 1970s to being cost-benefit oriented since 2003. Along with the efforts in controlling air pollutants emitted from various sources, a significant improvement in air quality has been evidenced by monitoring data. Here, the time series of the ambient levels of respective criteria air pollutants in Taiwan for the period of 1996–2020 are presented. It is noteworthy that the ambient levels of O3 in all air quality districts in Taiwan have almost leveled off in the past 25 years, while all the other criteria air pollutants (PM10, PM2.5, CO, NOx, and SO2) exhibited consistently a declining trend. Moreover, the data on the chemical speciation of PM2.5 shows that the secondary aerosols (i.e., ammonium, sulfate, nitrate, and organic matter) remained the major constituents of PM2.5, which did not change significantly in the last two decades. Given the observed facts, it is inferred that the air quality in Taiwan is strongly subject to the impacts of photochemical reactions. As a result, in addition to the elevated ozone level, the production of secondary organic aerosols and ultrafine particles, as well as their impacts on atmospheric visibility, are expected to be major challenges in the near future.
Diversified nanosystems with tunable physicochemical attributes have emerged as potential solution to globally devastating cancer by offering novel possibilities for improving the techniques of cancer detection, imaging, therapies, diagnosis, drug delivery and treatment. Drug delivery systems based on nanoparticles (NPs) with ability of crossing different biological barriers are becoming increasingly popular. Besides, NPs are utilized in pharmaceutical sciences to mitigate the toxicity of conventional cancer therapeutics. However, significant NPs-associated toxicity, off-targeted activities, and low biocompatibility limit their utilization for cancer theranostics and can be hazardous to cancer patients up to life-threatening conditions. NPs interact with the biomolecules and disturb their regular function by aggregating inside cells and forming a protein corona, and the formulation turns ineffective in controlling cancer cell growth. The adverse interactions between NPs and biological entities can lead to life-threatening toxicities. This review focuses on the widespread use of various NPs including zinc oxide, titanium oxide, silver, and gold, which serve as efficient nano-vehicles and demonstrate notable pharmacokinetic and pharmacodynamic advantages in cancer therapy. Subsequently, the mechanism of nanotoxicity attached with these NPs, alternate solutions and their prospect to revolutionize cancer theranostics are highlighted. This review will serve as guide for future developments associated with high-performance NPs with controlled toxicity for establishing them as modern-age nanotools to manage cancer in tailored manner.
Exposure to particulate matter (PM) has been associated with a wide range of adverse health effects, but it is still unclear how particles from various transport modes differ in terms of toxicity and associations with different human health outcomes. This literature review aims to summarize toxicological and epidemiological studies of the effect of ultrafine particles (UFPs), also called nanoparticles (NPs, <100 nm), from different transport modes with a focus on vehicle exhaust (particularly comparing diesel and biodiesel) and non-exhaust as well as particles from shipping (harbor), aviation (airport) and rail (mainly subway/underground). The review includes both particles collected in laboratory tests and the field (intense traffic environments or collected close to harbor, airport, and in subway). In addition, epidemiological studies on UFPs are reviewed with special attention to studies aimed at distinguishing the effects of different transport modes. Results from toxicological studies indicate that both fossil and biodiesel NPs show toxic effects. Several in vivo studies show that inhalation of NPs collected in traffic environments not only impacts the lung, but also triggers cardiovascular effects as well as negative impacts on the brain, although few studies compared NPs from different sources. Few studies were found on aviation (airport) NPs, but the available results suggest similar toxic effects as traffic-related particles. There is still little data related to the toxic effects linked to several sources (shipping, road and tire wear, subway NPs), but in vitro results highlighted the role of metals in the toxicity of subway and brake wear particles. Finally, the epidemiological studies emphasized the current limited knowledge of the health impacts of source-specific UFPs related to different transport modes. This review discusses the necessity of future research for a better understanding of the relative potencies of NPs from different transport modes and their use in health risk assessment.
An increasing number of studies have shown that particulate matter (PM) exposure can produce damaging effects on respiratory and cardiovascular systems, however, whether PM can enter the brain and produce neurotoxicity has been an important research question for PM health effects in recent years. In this review, we discuss the health risks of PM (mainly PM2.5) on the central nervous system (CNS) in age-specific cohorts, exposure pathways and molecular mechanisms by reviewing the latest in vivo and in vitro evidence from relevant experimental and epidemiological studies. The sensitivity and vulnerability to PM2.5 exposure varied across different cohorts, especially in the children, the elderly groups and occupational populations working in dusty environments. PM2.5 may affect the CNS directly or indirectly through the blood–brain barrier, olfactory nerve, optic nerve, microbiota-gut-brain axis, and nasal microbes. They exert neurotoxicological effects by inducing oxidative stress, inflammation, mitochondrial dysfunction, neuronal apoptosis, synaptic damage, DNA methylation, cellular autophagy, blood homeostasis imbalance and metabolic disturbance. This review presents the requirements for further research on the neurotoxicological effects of PM2.5 exposure, points out future research orientations in this field and provides a theoretical basis and prevention strategies for alleviating the adverse effects of PM2.5 exposure to the CNS.
The study aimed to develop a strategy and methodology for neuroprotection during long-term space missions, which is based on a comprehensive study of the impact of therapeutic hypothermia combined with the action of neuroactive drugs on the key characteristics of synaptic transmission in brain nerve terminals, which change under the influence of planetary dust and conditions of altered gravity. Development of neurotoxicity under conditions of altered gravity may result from excess extracellular glutamate caused by the reverse functioning of glutamate transporters. Under conditions of moderate and deep hypothermia, a gradual decrease in the transporter-mediated release of L-[14C]glutamate from nerve terminals was demonstrated, which is stimulated by plasma membrane depolarization with KCl and dissipation of the proton gradient of synaptic vesicles by the protonophore FCCP. This fact indicates a neuroprotective effect, which increases when hypothermia changes from moderate to deep. The possible risks of using hypothermia in space medicine have been determined. Hypothermia is not able to reduce the extracellular level of L-[14C]glutamate and [3H]GABA, which increases under the conditions of exposure to carbon-containing planetary dust. Hypothermia can lead to a further decrease in the rate of accumulation of neurotransmitters in the presence of carbon-containing planetary dust and to contribute to the development of neurotoxicity, which is a possible risk of using hypothermia in space medicine. In this context, it is important to choose the optimal individual temperature regime for each astronaut.
Taiwan is located downwind of a variety of regional sources of air pollutants transported particularly during the seasons of East Asian winter monsoon. In addition, western Taiwan is a highly populated and urbanized/industrialized area, where the air quality is subject to the influences of local air pollution. To mitigate the impacts of air pollution, a series of control strategies have been developed and enforced during the last couple of decades, which evolved conceptually from being technically oriented in the 1970s to being cost-benefit oriented since 2003. Along with the efforts in controlling air pollutants emitted from various sources, a significant improvement in air quality has been evidenced by monitoring data. Here, the time series of the ambient levels of respective criteria air pollutants in Taiwan for the period of 1996–2020 are presented. It is noteworthy that the ambient levels of O3 in all air quality districts in Taiwan have almost leveled off in the past 25 years, while all the other criteria air pollutants (PM10, PM2.5, CO, NOx, and SO2) exhibited consistently a declining trend. Moreover, the data on the chemical speciation of PM2.5 shows that the secondary aerosols (i.e., ammonium, sulfate, nitrate, and organic matter) remained the major constituents of PM2.5, which did not change significantly in the last two decades. Given the observed facts, it is inferred that the air quality in Taiwan is strongly subject to the impacts of photochemical reactions. As a result, in addition to the elevated ozone level, the production of secondary organic aerosols and ultrafine particles, as well as their impacts on atmospheric visibility, are expected to be major challenges in the near future.
Versatile nature of copper oxide nanoparticles (CuO NPs) has made them an imperative nanomaterial being employed in nanomedicine. Various physical, chemical, and biological methodologies are in use for the preparation of CuO NPs. The physicochemical and biological properties of CuO NPs are primarily affected by their method of fabrication; therefore, selectivity of a synthetic technique is immensely important that makes these NPs appropriate for a specific biomedical application. The deliberate use of CuO NPs in biomedicine questions their biocompatible nature. For this reason, the present review has been designed to focus on the approaches employed for the synthesis of CuO NPs; their biomedical applications highlighting antimicrobial, anticancer, and antioxidant studies; and most importantly, the in vitro and in vivo toxicity associated with these NPs. This comprehensive overview of CuO NPs is unique and novel as it emphasizes on biomedical applications of CuO NPs along with its toxicological assessments which would be useful in providing core knowledge to researchers working in these domains for planning and conducting futuristic studies.
Key Points
• The recent methods for fabrication of CuO nanoparticles have been discussed with emphasis on green synthesis methods for different biomedical approaches.
• Antibacterial, antioxidant, anticancer, antiparasitic, antidiabetic, and antiviral properties of CuO nanoparticles have been explained.
• In vitro and in vivo toxicological studies of CuO nanoparticles exploited along with their respective mechanisms.
Graphical Abstract
Particulate matter (PM) concentration levels in the London Underground (LU) are higher than London background levels and beyond World Health Organization (WHO) defined limits. Wheel, track, and brake abrasion are the primary sources of particulate matter, producing predominantly Fe-rich particles that make the LU microenvironment particularly well suited to study using environmental magnetism. Here we combine magnetic properties, high-resolution electron microscopy, and electron tomography to characterize the structure, chemistry, and morphometric properties of LU particles in three dimensions with nanoscale resolution. Our findings show that LU PM is dominated by 5–500 nm particles of maghemite, occurring as 0.1–2 μm aggregated clusters, skewing the size-fractioned concentration of PM artificially to larger sizes when measured with traditional monitors. Magnetic properties are largely independent of the PM filter size (PM10, PM4, and PM2.5), and demonstrate the presence of superparamagnetic (< 30 nm), single-domain (30–70 nm), and vortex/pseudo-single domain (70–700 nm) signals only (i.e., no multi-domain particles > 1 µm). The oxidized nature of the particles suggests that PM exposure in the LU is dominated by resuspension of aged dust particles relative to freshly abraded, metallic particles from the wheel/track/brake system, suggesting that periodic removal of accumulated dust from underground tunnels might provide a cost-effective strategy for reducing exposure. The abundance of ultrafine particles identified here could have particularly adverse health impacts as their smaller size makes it possible to pass from lungs to the blood stream. Magnetic methods are shown to provide an accurate assessment of ultrafine PM characteristics, providing a robust route to monitoring, and potentially mitigating this hazard.
Air pollution (AP) is becoming recognized as a major threat to neurological health across the lifespan with increased risk of both neurodevelopmental and neurodegenerative disorders. AP is a complex mixture of gases and particulate matter, with adsorbed contaminants including metals and trace elements, which may differentially contribute to its neurodevelopmental impacts. Iron (Fe) is one of the most abundant metals found in AP, and Fe concentrations may drive some behavioral deficits observed in children. Furthermore, brains of neonate mice exposed to concentrated ambient ultrafine particulate matter (UFP) show significant brain accumulation of Fe and sulfur (S) supporting the hypothesis that AP exposure may lead to brain metal dyshomeostasis. The current study determined the extent to which behavioral effects of UFP, namely memory deficits and impulsive-like behavior, could be recapitulated with exposure to Fe aerosols with or without concomitant SO2. Male and female neonate mice were either exposed to filtered air or spark discharge-generated ultrafine Fe particles with or without SO2 gas (n = 12/exposure/sex). Inhalation exposures occurred from postnatal day (PND) 4-7 and 10-13 for 4hr/day, mirroring our previous UFP exposures. Mice were aged to adulthood prior to behavioral testing. While Fe or Fe + SO2 exposure did not affect gross locomotor behavior, Fe + SO2-exposed females displayed consistent thigmotaxis during locomotor testing. Neither exposure affected novel object memory. Fe or Fe + SO2 exposure produced differential outcomes on a fixed-interval reinforcement schedule with males showing higher (Fe-only) or lower (Fe + SO2) response rates and postreinforcement pauses (PRP) and females showing higher (Fe-only) PRP. Lastly, Fe-exposed, but not Fe + SO2-exposed, males showed increased impulsive-like behavior in tasks requiring response inhibition with no such effects in female mice. These findings suggest that: 1) exposure to realistic concentrations of Fe aerosols can recapitulate behavioral effects of UFP exposure, 2) the presence of SO2 can modulate behavioral effects of Fe inhalation, and 3) brain metal dyshomeostasis may be an important factor in AP neurotoxicity.
Silver nanoparticles (AgNPs) are important and widely used as antimicrobials and nanodrug carriers. The increased use of AgNPs in consumer products has raised concerns about nanosafety; for instance, AgNPs may be inhaled and translocated to the brain via olfactory neural stem cells/progenitors. While the biological effects of nanoparticle size have been widely investigated, there are little data on the effects of particle shape on cellular phenotype. Therefore, here we investigated the interactions between AgNP spheres, rods, cubes, and triangles and human plasma proteins as well as their effects on the viability of NE‐4C neural stem cells. Nanoparticles were synthesized by wet chemistry methods and characterized by UV‐vis spectroscopy, dynamic light scattering, zeta potential measurement, transmission electron microscopy, nanoparticle tracking analysis, and differential centrifugal sedimentation. NE‐4C cell viability was assessed using the MTT reduction assay, and the cellular uptake of differently shaped nanoparticles was monitored by electron microscopy. All 50 nm (in at least one dimension) AgNPs exerted toxic effects, with rods and cubes displaying greater toxicity than spheres and triangles. These cellular and physicochemical results indicate that edges on the AgNPs increase toxicity, presumably due to enhanced ion dissolution from the edges.
Major source of carbon-contacting air born particular matter that significantly pollutes environment and provokes development of neuropathology is forest fires and wood combustion. Here, water-suspended smoke particulate matter preparations (SPs) were synthesized from birch, pine, poplar wood, and also birch bark and pine needles. Taking into account importance of the gut-brain communication system, SP properties were compared regarding their capability to modulate functioning of nerve terminals and gut cells/preparations. In cortex nerve terminals, poplar wood SP was more effective in decreasing uptake and increasing the extracellular levels of excitatory and inhibitory neurotransmitters L-[14C]glutamate and [3H]GABA, respectively. Spontaneous and H2O2-stimulated ROS generation in nerve terminals decreased by SPs, the most efficient one was from poplar wood. SPs from birch, pine and poplar wood caused membrane depolarization, poplar wood SP effect was 5-fold higher vs. birch and pine wood ones. Functional characteristics of gut cells/preparations, which tightly related to nerve terminal experiments, were assessed. SPs increased paracellular permeability of proximal colon mucosal-submucosal preparations monitored in Ussing chamber system (FITC-dextran, 4kDa), where the most prominent effect had poplar wood SP. The latter demonstrated more considerable influence on COLO 205 cell causing 30% loss of cell viability. PM emitted to the environment during combustion of various wood caused similar unidirectional harmful effects on brain and gut cell functioning, thereby triggering development of pathologies in gut and brain and gut-brain communication system.
Particulate matter (PM) concentration levels in the London Underground (LU) are higher than Londonbackground levels, and beyond World Health Organization defined limits. Wheel, track, and brakeabrasion are the primary sources of particulate matter, producing predominantly Fe-rich particles thatmake the LU microenvironment particularly well suited to study using environmental magnetism. Here we combine magnetic properties, high-resolution electron microscopy, and electron tomography to characterize the structure, chemistry, and morphometric properties of LU particles in three dimension with nanoscale resolution. Our findings show that LU PM is dominated by 5-500 nm particles of oxidized magnetite, occurring as 0.1-2 μm aggregated clusters, skewing the size-fractioned concentration of PM artificially to larger sizes when measured with traditional monitors. Magnetic properties are largely independent of the PM filter size (PM10, PM4, and PM2.5), and demonstrate the presence of superparamagnetic, single-domain, and vortex/pseudo-single domain signals only (i.e., no multi-domainparticles > 1 μm). The oxidized state of the particles suggests that PM exposure in the LU is dominated byresuspension of aged dust particles relative to freshly abraded, metallic particles from thewheel/track/brake system, suggesting that periodic removal of accumulated dust from undergroundtunnels might provide a cost-effective strategy for reducing exposure. The abundance of ultra-fine particles identified here could have particularly adverse health impacts as their smaller size makes it possible to pass from lungs to the blood stream. Magnetic methods are shown to provide an accurate assessment of ultra-fine PM characteristics, providing a robust route to monitoring, and potentially mitigating this hazard
Epidemiological studies increasingly associate air pollution with neurodevelopmental disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia, all male‐biased disorders, with such effects reported in different cohorts and in different countries. Studies in animal models are providing biological plausibility for these reported associations. Multiple mechanisms may underlie these impairments, such as microglial activation, inflammation, and alterations in brain neurochemistry, including excitatory/inhibitory balance. Future studies of air pollution exposures, specifically ambient exposures, will be critical to further understanding how critical periods of brain development influence outcome, as well as the basis for sex differences in the neurotoxicity produced by developmental exposures. Such studies may be assisted by assessment of the role of specific contaminants of air pollution, e.g., metals and trace elements, in producing neurotoxicity.
The use of nanomaterials has been increasing in recent times, and they are widely used in industries such as cosmetics, drugs, food, water treatment, and agriculture. The rapid development of new nanomaterials demands a set of approaches to evaluate the potential toxicity and risks related to them. In this regard, nanosafety has been using and adapting already existing methods (toxicological approach), but the unique characteristics of nanomaterials demand new approaches (nanotoxicology) to fully understand the potential toxicity, immunotoxicity, and (epi)genotoxicity. In addition, new technologies, such as organs-on-chips and sophisticated sensors, are under development and/or adaptation. All the information generated is used to develop new in silico approaches trying to predict the potential effects of newly developed materials. The overall evaluation of nanomaterials from their production to their final disposal chain is completed using the life cycle assessment (LCA), which is becoming an important element of nanosafety considering sustainability and environmental impact. In this review, we give an overview of all these elements of nanosafety.
Silver nanoparticles have many medical and commercial applications, but their effects on human health are poorly understood. They are used extensively in products of daily use, but little is known about their potential neurotoxic effects. A xenobiotic metal, silver has no known physiological significance in the human body as a trace metal. Biokinetics of silver nanoparticles indicates its elimination from the body via urine and faeces route. However, a substantial amount of evidence from both in‐vitro and in‐vivo experimental research unequivocally establish the fact of easier penetration of smaller nanoparticles across the Blood‐Brain Barrier to enter in brain and thereby interaction with cellular components to induce neurotoxic effects. Toxicological effects of silver nanoparticles rely on the degree of exposure, particle size, surface coating, and agglomeration state as well as the type of cell or organism used to evaluate its toxicity. This review covers pertinent facts and the present state of knowledge about the neurotoxicity of silver nanoparticles reviewing the impacts on oxidative stress, neuroinflammation, mitochondrial function, neurodegeneration, apoptosis and necrosis. The effect of silver nanoparticles on the central nervous system is a topic of growing interest and concern that requires immediate consideration.
Exposure to air pollution is associated with neuroinflammation in healthy children and dogs in Mexico City. Comparative studies were carried out in healthy children and young dogs similarly exposed to ambient pollution in Mexico City. Children from Mexico City (n: 55) and a low polluted city (n:18) underwent psychometric testing and brain magnetic resonance imaging MRI. Seven healthy young dogs with similar exposure to Mexico City air pollution had brain MRI, measurement of mRNA abundance of two inflammatory genes cyclooxygenase-2, and interleukin 1 β in target brain areas, and histopathological evaluation of brain tissue. Children with no known risk factors for neurological or cognitive disorders residing in a polluted urban environment exhibited significant deficits in a combination of fluid and crystallized cognition tasks. Fifty-six percent of Mexico City children tested showed prefrontal white matter hyperintense lesions and similar lesions were observed in dogs (57%). Exposed dogs had frontal lesions with vascular subcortical pathology associated with neuroinflammation, enlarged Virchow–Robin spaces, gliosis, and ultrafine particulate matter deposition. Based on the MRI findings, the prefrontal cortex was a target anatomical region in Mexico City children and its damage could have contributed to their cognitive dysfunction. The present work presents a groundbreaking, interdisciplinary methodology for addressing relationships between environmental pollution, structural brain alterations by MRI, and cognitive deficits/delays in healthy children.
Air pollution is a complex mixture of gases (e.g., ozone), particulate matter, and organic compounds present in outdoor and indoor air. Dogs exposed to severe air pollution exhibit chronic inflammation and acceleration of Alzheimer's-like pathology, suggesting that the brain is adversely affected by pollutants. We investigated whether residency in cities with high levels of air pollution is associated with human brain inflammation. Expression of cyclooxygenase-2 (COX2), an inflammatory mediator, and accumulation of the 42-amino acid form of beta-amyloid (Abeta42), a cause of neuronal dysfunction, were measured in autopsy brain tissues of cognitively and neurologically intact lifelong residents of cities having low (n:9) or high (n:10) levels of air pollution. Genomic DNA apurinic/apyrimidinic sites, nuclear factor-kappaB activation and apolipoprotein E genotype were also evaluated. Residents of cities with severe air pollution had significantly higher COX2 expression in frontal cortex and hippocampus and greater neuronal and astrocytic accumulation of Abeta42 compared to residents in low air pollution cities. Increased COX2 expression and Abeta42 accumulation were also observed in the olfactory bulb. These findings suggest that exposure to severe air pollution is associated with brain inflammation and Abeta42 accumulation, two causes of neuronal dysfunction that precede the appearance of neuritic plaques and neurofibrillary tangles, hallmarks of Alzheimer's disease.
A method to investigate the dependence of the physicochemical properties of nanoparticles (e.g. size, surface area and crystal phase) on their oxidant generating capacity is proposed and demonstrated for TiO(2) nanoparticles. Gas phase synthesis methods that allow for strict control of size and crystal phase were used to prepare TiO(2) nanoparticles. The reactive oxygen species (ROS) generating capacity of these particles was then measured. The size dependent ROS activity was established using TiO(2) nanoparticles of 9 different sizes (4 - 195 nm) but the same crystal phase. For a fixed total surface area, an S-shaped curve for ROS generation per unit surface area was observed as a function of particle size. The highest ROS activity per unit area was observed for 30 nm particles, and observed to be constant above 30 nm. There was a decrease in activity per unit area as size decreased from 30 nm to 10 nm; and again constant for particles smaller than 10 nm. The correlation between crystal phase and oxidant capacity was established using TiO(2) nanoparticles of 11 different crystal phase combinations but similar size. The ability of different crystal phases of TiO(2) nanoparticles to generate ROS was highest for amorphous, followed by anatase, and then anatase/rutile mixtures, and lowest for rutile samples. Based on evaluation of the entire dataset, important dose metrics for ROS generation are established. Their implications of these ROS studies on biological and toxicological studies using nanomaterials are discussed.
Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.
There is increasing concern about the neurodegenerative and behavioral consequences of ozone pollution in industrialized urban centers throughout the world and that women may be more susceptible to brain neurodegenerative disorders. In the present study we have investigated the effects of chronic (30 or 60 days) exposure to ozone on olfactory perception and memory and on levels of lipid peroxidation, alpha and beta estrogen receptors and dopamine beta-hydroxylase in the olfactory bulb in ovariectomized female rats. The ability of 17beta-estradiol to prevent these effects was then assessed. Results showed that ozone exposure for 30 or 60 days impaired formation/retention of a selective olfactory recognition memory 120 min after exposure to a juvenile stimulus animal with the effect at 60 days being significantly greater than at 30 days. They also showed impaired speed in locating a buried chocolate reward after 60 days of ozone exposure indicating some loss of olfactory perception. These functional impairments could all be prevented by coincident estradiol treatment. In the olfactory bulb, levels of lipid peroxidation were increased at both 30- and 60-day time-points and numbers of cells with immunohistochemical staining for alpha and beta estrogen receptors, and dopamine beta-hydroxylase were reduced as were alpha and beta estrogen receptor protein levels. These effects were prevented by estradiol treatment. Oxidative stress damage caused by chronic exposure to ozone does therefore impair olfactory perception and social recognition memory and may do so by reducing noradrenergic and estrogen receptor activity in the olfactory bulb. That these effects can be prevented by estradiol treatment suggests increased susceptibility to neurodegenerative disorders in aging women may be contributed to by reduced estrogen levels post-menopause.
Exposure to excess levels of the essential trace element manganese produces cognitive, psychiatric, and motor abnormalities. The understanding of Mn neurotoxicology is heavily governed by pathologic and neurochemical observations derived from rodent studies that often employ acute Mn exposures. The comparatively sparse studies incorporating in vivo neuroimaging in nonhuman primates provide invaluable insights on the effects of Mn on brain chemistry.
The purpose of this review is to discuss important aspects of Mn neurotoxicology and to synthesize recent findings from one of the largest cohorts of nonhuman primates used to study the neurologic effects of chronic Mn exposure.
We reviewed our recent in vivo and ex vivo studies that have significantly advanced the understanding of Mn-induced neurotoxicity. In those studies, we administered weekly doses of 3.3-5.0 (n=4), 5.0-6.7 (n=5), or 8.3-10.0 mg Mn/kg (n=3) for 7-59 weeks to cynomolgus macaque monkeys. Animals expressed subtle deficits in cognition and motor function and decreases in the N-acetylaspartate-to-creatine ratio in the parietal cortex measured by magnetic resonance spectroscopy reflective of neuronal dysfunction. Impaired striatal dopamine release measured by positron emission tomography was observed in the absence of changes in markers of dopamine neuron degeneration. Neuropathology indicated decreased glutamine synthetase expression in the globus pallidus with otherwise normal markers of glutamatergic and GABAergic neurotransmission. Increased amyloid beta (A4) precursor-like protein 1 gene expression with multiple markers of neurodegeneration and glial cell activation was observed in the frontal cortex.
These findings provide new information on mechanisms by which Mn affects behavior, neurotransmitter function, and neuropathology in nonhuman primates.
Air pollution has been considered a hazard to human health. In the past decades, many studies highlighted the role of ambient airborne particulate matter (PM) as an important environmental pollutant for many different cardiopulmonary diseases and lung cancer. Numerous epidemiological studies in the past 30 years found a strong exposure-response relationship between PM for short-term effects (premature mortality, hospital admissions) and long-term or cumulative health effects (morbidity, lung cancer, cardiovascular and cardiopulmonary diseases, etc). Current research on airborne particle-induced health effects investigates the critical characteristics of particulate matter that determine their biological effects. Several independent groups of investigators have shown that the size of the airborne particles and their surface area determine the potential to elicit inflammatory injury, oxidative damage, and other biological effects. These effects are stronger for fine and ultrafine particles because they can penetrate deeper into the airways of the respiratory tract and can reach the alveoli in which 50% are retained in the lung parenchyma. Composition of the PM varies greatly and depends on many factors. The major components of PM are transition metals, ions (sulfate, nitrate), organic compound, quinoid stable radicals of carbonaceous material, minerals, reactive gases, and materials of biologic origin. Results from toxicological research have shown that PM have several mechanisms of adverse cellular effects, such as cytotoxicity through oxidative stress mechanisms, oxygen-free radical-generating activity, DNA oxidative damage, mutagenicity, and stimulation of proinflammatory factors. In this review, the results of the most recent epidemiological and toxicological studies are summarized. In general, the evaluation of most of these studies shows that the smaller the size of PM the higher the toxicity through mechanisms of oxidative stress and inflammation. Some studies showed that the extractable organic compounds (a variety of chemicals with mutagenic and cytotoxic properties) contribute to various mechanisms of cytotoxicity; in addition, the water-soluble faction (mainly transition metals with redox potential) play an important role in the initiation of oxidative DNA damage and membrane lipid peroxidation. Associations between chemical compositions and particle toxicity tend to be stronger for the fine and ultrafine PM size fractions. Vehicular exhaust particles are found to be most responsible for small-sized airborne PM air pollution in urban areas. With these aspects in mind, future research should aim at establishing a cleared picture of the cytotoxic and carcinogenic mechanisms of PM in the lungs, as well as mechanisms of formation during internal engine combustion processes and other sources of airborne fine particles of air pollution.
Air pollution is increasingly recognized as an important and modifiable determinant of cardiovascular disease in urban communities. Acute exposure has been linked to a range of adverse cardiovascular events including hospital admissions with angina, myocardial infarction, and heart failure. Long-term exposure increases an individual's lifetime risk of death from coronary heart disease. The main arbiter of these adverse health effects seems to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Inhalation of this particulate matter leads to pulmonary inflammation with secondary systemic effects or, after translocation from the lung into the circulation, to direct toxic cardiovascular effects. Through the induction of cellular oxidative stress and proinflammatory pathways, particulate matter augments the development and progression of atherosclerosis via detrimental effects on platelets, vascular tissue, and the myocardium. These effects seem to underpin the atherothrombotic consequences of acute and chronic exposure to air pollution. An increased understanding of the mediators and mechanisms of these processes is necessary if we are to develop strategies to protect individuals at risk and reduce the effect of air pollution on cardiovascular disease.
Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are "primed" to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]).
Here, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n = 9) and central nervous system (CNS) inflammatory (n = 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n = 34-35).
Injection of LPS (100 microg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-beta (IFN-beta) transcription and microglial IL-1beta translation in prion-diseased animals relative to control animals. This inflammation caused exaggerated impairments in burrowing and locomotor activity, and induced hypothermia and cognitive changes in prion-diseased animals that were absent in LPS-treated control animals. At 15 weeks PI, LPS (500 microg/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. After recovery, these animals also showed earlier onset of disease-associated impairments on these parameters.
These data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression. These deleterious effects of systemic inflammation have implications for the treatment of chronic neurodegeneration and associated delirium.
The evaluation of respiratory tract toxicity from airborne materials frequently involves exposure of animals via inhalation. This provides a natural route of entry into the host and, as such, is the preferred method for the introduction of toxicants into the lungs. However, for various reasons, this technique cannot always be used, and the direct instillation of a test material into the lungs via the trachea has been employed in many studies as an alternative exposure procedure. Intratracheal instillation has become sufficiently widely used that the Inhalation Specialty Section of the Society of Toxicology elected to develop this document to summarize some key issues concerning the use of this exposure procedure. Although there are distinct differences in the distribution, clearance, and retention of materials when administered by instillation compared to inhalation, the former can be a useful and cost-effective procedure for addressing specific questions regarding the respiratory toxicity of chemicals, as long as certain caveats are clearly understood and certain guidelines are carefully followed.
The impact of global air pollution on climate and the environment is a new focus in atmospheric science. Intercontinental
transport and hemispheric air pollution by ozone jeopardize agricultural and natural ecosystems worldwide and have a strong
effect on climate. Aerosols, which are spread globally but have a strong regional imbalance, change global climate through
their direct and indirect effects on radiative forcing. In the 1990s, nitrogen oxide emissions from Asia surpassed those from
North America and Europe and should continue to exceed them for decades. International initiatives to mitigate global air
pollution require participation from both developed and developing countries.
The prevalence of parkinsonian syndromes was studied in the province of Brescia (Northern Italy), in order to verify its possible increase in the surroundings of ferroalloy plants located in a valley of the pre-Alps. A case-list of subjects affected by these disturbances was identified using four different sources of information: a) registers from local medical clinics; b) admission charts from local hospitals; c) consumption of levodopa; d) NHS list of exemption from prescription payment, due to the illness. Exploratory data show a frequency of parkinsonian disturbances among the residents in the surroundings of the ferroalloy plants and downwind (crude prevalence = 358/100,000 population, standardized for age and sex = 438) significantly higher (s.m.r, = 1.58; C.I. = 1.41-1.76) than the entire Province (crude prevalence 246/100,000). This preliminary result could indicate the interaction of prolonged environmental exposure to heavy metals, such as manganese, and genetic factors, potentially relevant in this mountain population.
Ultrafine particles (UFP, particles <100 nm) are ubiquitous in ambient urban and indoor air from multiple sources and may contribute to adverse respiratory and cardiovascular effects of particulate matter (PM). Depending on their particle size, inhaled UFP are efficiently deposited in nasal, tracheobronchial, and alveolar regions due to diffusion. Our previous rat studies have shown that UFP can translocate to interstitial sites in the respiratory tract as well as to extrapulmonary organs such as liver within 4 to 24 h postexposure. There were also indications that the olfactory bulb of the brain was targeted. Our objective in this follow-up study, therefore, was to determine whether translocation of inhaled ultrafine solid particles to regions of the brain takes place, hypothesizing that UFP depositing on the olfactory mucosa of the nasal region will translocate along the olfactory nerve into the olfactory bulb. This should result in significant increases in that region on the days following the exposure as opposed to other areas of the central nervous system (CNS). We generated ultrafine elemental (13)C particles (CMD = 36 nm; GSD = 1.66) from [(13)C] graphite rods by electric spark discharge in an argon atmosphere at a concentration of 160 microg/m(3). Rats were exposed for 6 h, and lungs, cerebrum, cerebellum and olfactory bulbs were removed 1, 3, 5, and 7 days after exposure. (13)C concentrations were determined by isotope ratio mass spectroscopy and compared to background (13)C levels of sham-exposed controls (day 0). The background corrected pulmonary (13)C added as ultrafine (13)C particles on day 1 postexposure was 1.34 microg/lung. Lung (13)C concentration decreased from 1.39 microg/g (day 1) to 0.59 microg/g by 7 days postexposure. There was a significant and persistent increase in added (13)C in the olfactory bulb of 0.35 microg/g on day 1, which increased to 0.43 microg/g by day 7. Day 1 (13)C concentrations of cerebrum and cerebellum were also significantly increased but the increase was inconsistent, significant only on one additional day of the postexposure period, possibly reflecting translocation across the blood-brain barrier in certain brain regions. The increases in olfactory bulbs are consistent with earlier studies in nonhuman primates and rodents that demonstrated that intranasally instilled solid UFP translocate along axons of the olfactory nerve into the CNS. We conclude from our study that the CNS can be targeted by airborne solid ultrafine particles and that the most likely mechanism is from deposits on the olfactory mucosa of the nasopharyngeal region of the respiratory tract and subsequent translocation via the olfactory nerve. Depending on particle size, >50% of inhaled UFP can be depositing in the nasopharyngeal region during nasal breathing. Preliminary estimates from the present results show that approximately 20% of the UFP deposited on the olfactory mucosa of the rat can be translocated to the olfactory bulb. Such neuronal translocation constitutes an additional not generally recognized clearance pathway for inhaled solid UFP, whose significance for humans, however, still needs to be established. It could provide a portal of entry into the CNS for solid UFP, circumventing the tight blood-brain barrier. Whether this translocation of inhaled UFP can cause CNS effects needs to be determined in future studies.
The contributing role of environmental factors to the development of Parkinson's disease has become increasingly evident. We report that mesencephalic neuron-glia cultures treated with diesel exhaust particles (DEP; 0.22 microM) (5-50 microg/ml) resulted in a dose-dependent decrease in dopaminergic (DA) neurons, as determined by DA-uptake assay and tyrosine-hydroxylase immunocytochemistry (ICC). The selective toxicity of DEP for DA neurons was demonstrated by the lack of DEP effect on both GABA uptake and Neu-N immunoreactive cell number. The critical role of microglia was demonstrated by the failure of neuron-enriched cultures to exhibit DEP-induced DA neurotoxicity, where DEP-induced DA neuron death was reinstated with the addition of microglia to neuron-enriched cultures. OX-42 ICC staining of DEP treated neuron-glia cultures revealed changes in microglia morphology indicative of activation. Intracellular reactive oxygen species and superoxide were produced from enriched-microglia cultures in response to DEP. Neuron-glia cultures from NADPH oxidase deficient (PHOX-/-) mice were insensitive to DEP neurotoxicity when compared with control mice (PHOX+/+). Cytochalasin D inhibited DEP-induced superoxide production in enriched-microglia cultures, implying that DEP must be phagocytized by microglia to produce superoxide. Together, these in vitro data indicate that DEP selectively damages DA neurons through the phagocytic activation of microglial NADPH oxidase and consequent oxidative insult.
Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.
Ozone exposure, depending on the dose, is a noninvasive model of oxidative stress. The purpose of this work was to study striatal damage and cell death induced by oxidative stress. Sixty-three male Wistar rats were divided into two groups--Group 1: animals were exposed to an air stream free of ozone for 4 h; and Group 2: animals were exposed to 1 ppm of ozone for 4 h. Four subgroups in each treatment group were then tested 3 h after control or ozone exposure for: (1) exploratory and freezing behavior; (2) lipid peroxidation levels; (3) in vivo release of amino acid and monoamine transmitters, and metabolites and nitric oxide; and (4) striatal ultrastructural changes. Results showed that the ozone decreased exploratory and increased freezing behaviors. It also increased striatal lipoperoxidation levels and basal dopamine, glutamate, and nitric oxide (arginine, citrulline, and nitrate used as indices) concentrations and decreased those of 5-HT. Concentrations of GABA were initially decreased 3 h after ozone but then were increased 3 and 5 days afterwards. Increased lipofucsine, neuronal cytoplasm and dendrite vacuolation, and dilation of rough endoplasmic reticulum cisterns and dark cells were observed in striatal medium spiny neurons in ozone-exposed rats. These alterations suggest a neurodegenerative process caused by oxidative stress after acute ozone exposure.
Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in Parkinson's disease. The incidence of Parkinson's disease is higher in men than in women, and estrogen may provide neuroprotection against oxidative damage. We examined the protective effects of estrogen on rat nigral death after chronic ozone inhalation. Ozone inhalation produced impaired nigral cell morphology and loss of dopamine neurons in ovariectomized rats. This was counteracted after 60 days of 17β-estradiol treatment, when blood levels were highest. These results indicate that ozone exposure may be a useful Parkinson's disease model and neuroprotection afforded by 17β-estradiol is dependent on the high levels achieved after its prolonged administration.
This study was carried out to test the hypothesis that nanogold particles can accumulate in the olfactory bulb, and translocate from the lung to other organs after inhalation exposure. Gold nanoparticles were aerosolized and introduced through an exposure chamber. The number concentration of airborne nano-sized particles was 2×106 #NSPs/cm3 with >75% of particulates between 30 and 110 nm. Exposure for 5 days resulted in significant increase of Au in the lung and olfactory bulb as detected by ICP-MS, but after 15 days, significant accumulation of gold was detected in the lung, esophagus, tongue, kidney, aorta, spleen, septum, heart and blood. Microarray analysis showed downregulation of many genes related to muscle in the nanogold-exposed lung. Lipidomic analysis of the lung showed a specific decrease in phosphatidylserine 36:1 species. We conclude that nanogold is able to translocate from the lung to other organs with time, and causes significant effects in exposed tissues.
Materials and Methods
ObservationsSummaryDiscussionReferences
Multi-walled carbon nanotubes functionalized with diethylentriaminepentaacetic dianhydride (DTPA-MWNT) and radiolabeled with Indium-111, having therapeutic and diagnostic applications, were tracked in the systemic blood circulation and the excretory system using a microSingle Photon Emission Tomography (microSPECT) scanner. Quantitative Kaiser test was used to determine the number of free amino groups on the DTPA-MWNT. A suspension of PBS and DTPA-MWNT was intravenously injected by tail vein in the Wistar rats and the urine production, water consumption and body weight were observed for 24 hours. The rat was necropised and tissues of various organs were fixed and observed with a Nikon Microphot-FXA microscope coupled with digital camera. The Length of DTPA-MWNT used in the study is larger than the dimensions of the glomerular capillary wall, so it was excreted through urine after 24 hours post-administration.
Characterizing the state of nanoparticles (such as size, surface charge, and degree of agglomeration) in aqueous suspensions
and understanding the parameters that affect this state are imperative for toxicity investigations. In this study, the role
of important factors such as solution ionic strength, pH, and particle surface chemistry that control nanoparticle dispersion
was examined. The size and zeta potential of four TiO2 and three quantum dot samples dispersed in different solutions (including one physiological medium) were characterized. For
15nm TiO2 dispersions, the increase of ionic strength from 0.001M to 0.1M led to a 50-fold increase in the hydrodynamic diameter,
and the variation of pH resulted in significant change of particle surface charge and the hydrodynamic size. It was shown
that both adsorbing multiply charged ions (e.g., pyrophosphate ions) onto the TiO2 nanoparticle surface and coating quantum dot nanocrystals with polymers (e.g., polyethylene glycol) suppressed agglomeration
and stabilized the dispersions. DLVO theory was used to qualitatively understand nanoparticle dispersion stability. A methodology
using different ultrasonication techniques (bath and probe) was developed to distinguish agglomerates from aggregates (strong
bonds), and to estimate the extent of particle agglomeration. Probe ultrasonication performed better than bath ultrasonication
in dispersing TiO2 agglomerates when the stabilizing agent sodium pyrophosphate was used. Commercially available Degussa P25 and in-house synthesized
TiO2 nanoparticles were used to demonstrate identification of aggregated and agglomerated samples.
Ozone is known to cause radicals to be formed in biological systems; for example, it initiates lipid peroxidation and vitamin E protects in vitro model systems, cells, and animals against the effects of ozone. Ozone is not itself a radical, and we have asked: With what molecules does ozone react in the lung and how are radicals produced?Ozone reacts by two quite different mechanisms to produce radicals; one involves an ozone—olefin reaction and the other a reaction with electron donors such as glutathione (GSH). The first mechanism splits an R⋅ radical out of an olefin with the structure RCHCH2. The R⋅ then reacts with dioxygen to become a peroxyl radical (ROO⋅), and both carbon- and oxygen- centered radicals can be detected by the electron spin resonance spin trap method. From the effects of temperature, metal chelators, and water, it is concluded that ozone reacts by the Criegee ozonation pathway to give the classical 1,2,3-trioxolane, which then undergoes OO bond homolysis to form a diradical. This diradical then either undergoes β-scission to split out the R⋅ radical or forms the more usual carbonyl oxide and a carbonyl compound. (See Figure 3 in the text.) The low yield of Criegee ozonide that is generally obtained probably is due in part to the reactions forming radicals from the 1,2,3-trioxolane that compete with production of the Criegee ozonide.The second mechanism for radical production involves the reaction of ozone with electron donors. If the electron donor is, for example, GSH or its ion (GS−), this reaction produces the thiyl GS⋅ and O3⋅. The ozone radical anion then reacts reacts with a proton to form the hydroxyl radical and dioxygen: O3⋅ + H+ → HO⋅ + O2. Using 5,5-dimethyl-1-pyrroline-N-oxide, the spin adduct of the hydroxyl radical is detected. Similar reactions are observed with catechol.
The rapid transport of optically detectable organelles in axons has been well documented, although its molecular mechanism remains unknown. Here we report that synthetic particles microinjected into the giant axons of the shore crab, Carcinus maenas, are also transported, moving as though they were endogenous organelles. Polystyrene beads, polyacrolein beads, paraffin droplets and glass fragments, of sizes up to 0.5 micron in diameter, have been tested. Many of these foreign particles move rapidly and for long distances along the axon in the anterograde direction, travelling in a saltatory fashion, within a well defined velocity range. In many respects the movements are indistinguishable from those of anterogradely moving endogenous organelles seen by phase-contrast in these axons. Our results indicate that there is a transport system in axons capable of carrying almost any particle of suitable physical properties in an anterograde direction.
Determinations of the activity of the cerebrospinal fluid in 32 rabbits were made after administering the isotope 198Au under the mucous membrane of the olfactory region of the nose. Such activity indicates the direct penetration of 198Au from this membrane into the cerebrospinal fluid of the anterior cranial fossa.
Vascular disease recurrence following stroke is the main cause of morbidity and mortality. The MITICO study was designed to assess the prognostic value of markers of inflammation in relation to the risk of recurrence of vascular disease.
Multi-centered prospective observational study, in patients with ischemic stroke not receiving anti-coagulation therapy and who were recruited within 1-3 months from stroke onset. Blood samples were obtained at baseline and follow- up for the determination of high-sensitive C reactive protein (CRP), IL-6, IL-10, ICAM-1, VCAM- 1, MMP-9 and cellular fibronectin. Four follow-up visits within the first year were to rule out recurrence.
Of 965 patients from 65 hospitals, 780 (aged 67.5+/-11.2 years, 33.6 % female) were valid for main analysis. One-hundred and three patients (13.2 %) had a new adverse vascular event and 116 patients (14.9 %) a vascular event or vascular death (66.4 % stroke, 21.5 % coronary and 12.1 % peripheral). Levels of IL-6 > 5 pg/mL and VCAM-1 > 1350 ng/mL (ROC curve analyses) were associated with vascular disease recurrence risk (OR: 28.7; 95 % CI: 14.2-58.0 vs. OR: 4.1; 95 % CI: 2.4-7.1, respectively) following adjustment for confounding variables. Risk of adverse vascular event or death from vascular disease were associated with IL-6 (OR: 21.2; 95 % CI: 11.6-38.7) and VCAM-1 (OR: 3.8; 95 % CI: 2.3-6.4).
Baseline values of IL-6 > 5 pg/mL and VCAM-1 > 1350 ng/mL increase 21-fold and 4-fold, respectively, the risk of new vascular disease event or death from vascular disease in patients with ischemic stroke not receiving anti-coagulation treatment.
It is well established that several infectious diseases can directly lead to ischemic or hemorrhagic stroke during their course. It appears possible that common viral and bacterial infections can increase the susceptibility to stroke by promoting atherosclerosis, inflammation, and local thrombosis. Stroke commonly leads to disruption of protective mechanisms against infection and induces a cascade of anti-inflammatory and immunosuppressive reactions, which greatly increases the risk of infection. The social and economic costs of post-stroke infections and their impact on stroke morbidity and outcome are dramatic. Understanding the pathophysiologic links between stroke and infection is therefore of paramount importance, and effective preventive strategies to reduce the risk of infection are needed. This article summarizes current clinical and experimental data regarding the interactions between stroke and infection and outlines possible targets for therapeutic intervention.
Nanoscale titanium dioxide (TiO(2)) is massively produced and widely used in living environment, which hence make the potential risk to human health. Central nervous system (CNS) is the potential susceptible target of inhaled nanoparticles, but the studies on this aspect are limited so far. We report the accumulation and toxicity results in vivo of two crystalline phases of TiO(2) nanoparticles (80nm, rutile and 155nm, anatase; purity >99%). The female mice were intranasally instilled with 500microg of TiO(2) nanoparticles suspension every other day for 30 days. Synchrotron radiation X-ray fluorescence analysis (SRXRF) and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine the contents of titanium in murine brain. Then, the pathological examination of brain tissue, oxidative stress-mediated responses, and levels of neurochemicals in the brain of exposed mice were also analyzed. The obvious morphological changes of hippocampal neurons and increased GFAP-positive astrocytes in the CA4 region were observed, which were in good agreements with higher Ti contents in the hippocampus region. Oxidative stress occurred obviously in whole brain of exposed mice such as lipid peroxidation, protein oxidation and increased activities of catalase, as well as the excessive release of glutamic acid and nitric oxide. These findings indicate anatase TiO(2) nanoparticles exhibited higher concern on some tested biological effects. To summarize, results provided the preliminary evidence that nasal instilled TiO(2) nanoparticles could be translocated into the central nervous system and cause potential lesion of brain, and the hippocampus would be the main target within brain.
Nanoparticles can be administered via nasal, oral, intraocular, intratracheal (pulmonary toxicity), tail vein and other routes. Here, we focus on the time-dependent translocation and potential damage of TiO(2) nanoparticles on central nervous system (CNS) through intranasal instillation. Size and structural properties are important to assess biological effects of TiO(2) nanoparticles. In present study, female mice were intranasally instilled with two types of well-characterized TiO(2) nanoparticles (i.e. 80 nm, rutile and 155 nm, anatase; purity>99%) every other day. Pure water instilled mice were served as controls. The brain tissues were collected and evaluated for accumulation and distribution of TiO(2), histopathology, oxidative stress, and inflammatory markers at post-instillation time points of 2, 10, 20 and 30 days. The titanium contents in the sub-brain regions including olfactory bulb, cerebral cortex, hippocampus, and cerebellum were determined by inductively coupled plasma mass spectrometry (ICP-MS). Results indicated that the instilled TiO(2) directly entered the brain through olfactory bulb in the whole exposure period, especially deposited in the hippocampus region. After exposure for 30 days, the pathological changes were observed in the hippocampus and olfactory bulb using Nissl staining and transmission electron microscope. The oxidative damage expressed as lipid peroxidation increased significantly, in particular in the exposed group of anatase TiO(2) particles at 30 days postexposure. Exposure to anatase TiO(2) particles also produced higher inflammation responses, in association with the significantly increased tumor necrosis factor alpha (TNF-alpha) and interleukin (IL-1 beta) levels. We conclude that subtle differences in responses to anatase TiO(2) particles versus the rutile ones could be related to crystal structure. Thus, based on these results, rutile ultrafine-TiO(2) particles are expected to have a little lower risk potential for producing adverse effects on central nervous system. Although understanding the mechanisms requires further investigation, the present results suggest that we should pay attention to potential risk of occupational exposure for large-scaled production of TiO(2) nanoparticles.
Ozone, a major photochemical pollutant, produces rapid damages in the pulmonary airway tract and in the central nervous system. This study focused on the neural mechanisms underlying the adaptive responses to an acute ozone exposure. Vascular endothelial growth factor (VEGF) is a factor associated with cellular recovery following brain injury. The aim of this study was to assess and localize the cellular expression of VEGF, since the central respiratory areas show a neuroplasticity in response to ozone. Adult rats were subjected to 0.5ppm ozone for 3h and then recovered for further 3h. The expression of VEGF was evaluated by immunocytochemistry in the central respiratory areas, i.e., the nucleus tractus solitarius (NTS) and the ventrolateral medulla (VLM). The data show a VEGF overexpression at the end of ozone exposure, which persisted during the 3-h recovery. Interestingly, using confocal analysis the bulk of VEGF labeling was observed in astroglial cell bodies and branches, while neuronal labeling was hardly noticed. Moreover, VEGF colocalized with IL-6 and TNFalpha in astrocytes closely apposed to blood vessel walls. The vasculature area was markedly increased (+58%) during post-ozone recovery. The data show that an acute ozone exposure affects primarily glial cells in the central nervous system. The VEGF up-regulation which persists after ozone exposure may contribute to brain repair and consecutive functional adaptations.
Extensive evidence implicates inflammation in multiple phases of stroke etiology and pathology. In particular, there is growing awareness that inflammatory events outside the brain have an important impact on stroke susceptibility and outcome. Numerous conditions, including infection and chronic non-infectious diseases, that are established risk factors for stroke are associated with an elevated systemic inflammatory profile. Recent clinical and pre-clinical studies support the concept that the systemic inflammatory status prior to and at the time of stroke is a key determinant of acute outcome and long-term prognosis. Here, we provide an overview of the impact of systemic inflammation on stroke susceptibility and outcome. We discuss potential mechanisms underlying the impact on ischemic brain injury and highlight the implications for stroke prevention, therapy and modeling.
This article reviews recent studies which involve, or impact on, the condition of dust overloading in the lungs of several species, especially the Fischer 344 rat. Its main purpose is to provide an update of the overload concept and new information of possible mechanistic relevance. At present, the most likely general explanation for the suppression of particle transport by the alveolar macrophage (AM) and the development of concurrent events, e.g., increased interstitial dust uptake and prolonged inflammatory response, is the persistent, possibly excessive, elaboration of chemotactic and chemokinetic factors by the AM. The induction of these interrelated events is hypothesized as related to the volume of dust phagocytized by the AM pool. The review concludes, inter alia, that information is badly needed on dust overload in nonrodent species and on the normal role of the AM in dust removal from the human lungs.
A variety of silicotic lesions derived from thoracic silicosis via lymphohematogenous spread to the liver, spleen, bone marrow, and extrathoracic lymph nodes are described. The morphologic features of these lesions depend on the extent of macrophage aggregation, the occurrence of fibrogenesis, and the development of necrosis and degradative changes in macrophages and adjacent extracellular matrix, presumably caused by lysosomal enzymes released from macrophages. Ultrastructurally, the degenerative alterations of matrix material include longitudinal splitting and breakage of collagen fibrils into segments one and three quarters the length of the original fibrils and deposition of flocculent electron-dense material either focally or diffusely around collagen fibrils. The corresponding changes viewed light microscopically are those of fibrinoid necrosis. The sclerohyaline nodule, the characteristic lesion of silicosis, includes all of these features as it evolves through nodular histiocytic and subsequent fibrohistiocytic phases. Its ultimate morphology appears to be determined by the reassembly of the degraded matrix into non-native, fibrous long-spacing collagen via a spiny collagen intermediary. The sclerohyaline nodule occurs infrequently in the spleen and liver, although less typical lesions caused by silica alone or admixed with other dusts seem to occur more commonly in these organs. These lesions appeared as loose or nodular histiocytic or fibrohistiocytic aggregates. Nonspecific fibrous nodules or more extensive fibrosis, as seen in portal triads, may represent advanced stages of such lesions. Acute or healed focal segmental glomerulonephritis occurred in 40 per cent of the cases, suggesting that it may be an important remote effect of silicosis. Continuous destruction of lymphocytes adjacent to silicotic nodules may be an antigenic source of the high concentration of autoimmune reactants described in silicosis.
Silica deposition and characteristic nodular silicotic lesions of the bone marrow, virtually unknown features of silicosis, are described in a case of severe lung silicosis with silicotic granulomas of the liver and spleen. Scanning electron microscopy and X-ray microanalysis confirmed the presence of quartz and feld-spars. The bone marrow lesions included inconspicuous accumulations of silica-containing macrophages, free silica, slight lymphocyte and plasma cell infiltration, and reticulin fibre formation; and development of slightly larger partly fibrous silicotic nodules, comparable to those of the lung, liver, and spleen. Silicosis must therefore be considered in the differential diagnosis of bone marrow granulomas.
Odor identification ability and detection threshold sensitivity were measured in 25 probands with Huntington's disease, 12 at-risk offspring, and 37 unrelated controls. Relative to controls and at-risk offspring, HD patients exhibited significant impairment on both measures of olfactory function. By contrast, at-risk offspring did not evidence any olfactory impairment relative to controls. Thus, impaired olfactory function does not aggregate in the family members of HD patients, and does not serve as an indicator of genetic vulnerability to the disorder.
1. The fluid homeostasis of the brain depends both on the endothelial blood–brain barrier and on the epithelial blood–cerebrospinal fluid (CSF) barrier located at the choroid plexuses and the outer arachnoid membrane.
2. The brain has two fluid environments: the brain interstitial fluid, which surrounds the neurons and glia, and the CSF, which fills the ventricles and external surfaces of the central nervous system.
3. CSF acts as a fluid cushion for the brain and as a drainage route for the waste products of cerebral metabolism.
4. Recent findings suggest that CSF may also act as a “third circulation” conveying substances secreted into the CSF rapidly to many brain regions.
PTFE (polytetrafluoroethylene) fumes consisting of large numbers of ultrafine (uf) particles and low concentrations of gas-phase compounds can cause severe acute lung injury. Our studies were designed to test three hypotheses: (i) uf PTFE fume particles are causally involved in the induction of acute lung injury, (ii) uf PTFE elicit greater pulmonary effects than larger sized PTFE accumulation mode particles, and (iii) preexposure to the uf PTFE fume particles will induce tolerance. We used uf Teflon (PTFE) fumes (count median particle size approximately 16 nm) generated by heating PTFE in a tube furnace to 486 degrees C to evaluate principles of ultrafine particle toxicity. Teflon fumes at ultrafine particle concentrations of 50 microg/m(3) were extremely toxic to rats when inhaled for only 15 min. We found that when generated in argon, the ultrafine Teflon particles alone are not toxic at these exposure conditions; neither were Teflon fume gas-phase constituents when generated in air. Only the combination of both phases when generated in air caused high toxicity, suggesting either the existence of radicals on the surface or a carrier mechanism of the ultrafine particles for adsorbed gas compounds. Aging of the fresh Teflon fumes for 3.5 min led to a predicted coagulation to >100 nm particles which no longer caused toxicity in exposed animals. This result is consistent with a greater toxicity of ultrafine particles compared to accumulation mode particles, although changes in particle surface chemistry during the aging process may have contributed to the diminished toxicity. Furthermore, the pulmonary toxicity of the ultrafine Teflon fumes could be prevented by adapting the animals with short 5-min exposures on 3 days prior to a 15-min exposure. Messages encoding antioxidants and chemokines were increased substantially in nonadapted animals, yet were unaltered in adapted animals. This study shows the importance of preexposure history for the susceptibility to acute ultrafine particle effects.
The physicochemical complexity of airborne particulate matter (PM) has hampered identifying a specific mechanism(s) for its toxicity. In this study, selected physicochemical characteristics (i.e., size, particle number, acidity, and surface charge) were measured on various field PM, derived from urban ambient (St. Louis, Ottawa, Canada), residential (Woodstove), volcanic dust from Mt. St. Helen (MSH), and industrial [oil fly ash (OFA) coal fly ash (CFA)] sources. Morphometric analysis of visible (< or = 2.0 to >10 microm) field particles indicated that the industrial PM (OFA, CFA) had the smallest diameter and lowest total number of particles per weight while Woodstove and Ottawa had the largest diameter and highest number of particles. All PM lowered the pH of an unbuffered 10 mM NaCl solution from pH 7.4 to pH 4.7-6.8 but did not change the neutral pH of the cell culture medium, keratinocyte growth media (KGM). The surface charge (i.e., zeta potential) of microscopically visible (> or = 2.0 microm) field particles, suspended in either a Hepes-buffered KCl solution or in KGM, was measured by microelectrophoresis. In KCl solution, the mean zeta potential of all tested PM ranged from -36 +/- 2 (Woodstove) to -27 +/- 4.3 mV (MSH). When measured in KGM medium, the mean zeta potential value of each PM was significantly less (p > 0.001) than those measured in KCl solution, with values ranging from -17 +/- 0.3 mV (St. Louis) to -9 +/- 0.6 mV (MSH). Suspensions of field PM, its soluble and washed particulate fractions, were next prepared from each PM. The biological effects (i.e., increases in intracellular calcium ([Ca2+]i), cytokine release) of their exposure were measured in human, immortalized, tracheal-bronchial epithelial cells (BEAS-2B). Exposure of BEAS-2B cells to each fraction produced an immediate, but differential increase in [Ca2+]i and the subsequent release of the inflammatory cytokine IL-6, 4 and 16 h later. Increases in [Ca2+]i by field PM significantly correlated with the IL-6 released by each fraction (r2 > or = 0.76) after both 4 and 16 h exposures. The biological effects of each PM were compared with their physicochemical characteristics. No correlation was found between increases in [Ca2+]i or cytokine release and a PM's acidity or the number or size of its visible (> or = 2.0 microm) particles. However, the surface charge of PM field particles, when measured in the KGM exposure medium, showed a high correlation (r2 > or = 0.94) with the IL-6 release by field PM after both 4 and 16 h exposure. Increases in [Ca2+]i also correlated (r2 = 0.85) with the surface charge of PM field particles when measured in KGM. These data indicate that the surface charge (i.e., zeta potential) carried on PM's visible field particles predicts their differential release of the inflammatory cytokine IL-6 in cultures of human respiratory epithelial cells.
Recently it was speculated that ultrafine particles may translocate from deposition sites in the lungs to systemic circulation. This could lead to accumulation and potentially adverse reactions in critical organs such as liver, heart, and even brain, consistent with the hypothesis that ultrafine insoluble particles may play a role in the onset of cardiovascular diseases, as growing evidence from epidemiological studies suggests. Ultrafine 192 Ir radio-labeled iridium particles (15 and 80 nm count median diameter) generated by spark discharging were inhaled by young adult, healthy, male WKY rats ventilated for 1 h via an endotracheal tube. After exposure, excreta were collected quantitatively. At time points ranging from 6 h to 7 d, rats were sacrificed, and a complete balance of 192 Ir activity retained in the body and cleared by excretion was determined gamma spectroscopically. Thoracic deposition fractions of inhaled 15- and 80-nm 192 Ir particles were 0.49 and 0.28, respectively. Both batches of ultrafine iridium particles proved to be insoluble (
The pathophysiology of neurogenic inflammation culminates in the overt symptoms of tissue inflammation through a series of events which are initiated by the activation of vanilloid receptors (VR1). This study was designed to test the hypothesis that a sufficiently negative, electrostatic charge carried on a particulate matter (PM) particle, could acquire a cloud of protons sufficient to activate proton-sensitive VR1 receptors and acid-sensitive ionic channels (ASICs) pathways. For this, nanometer-sized, synthetic polystyrene micells (SPM) or those charged with chemical groups (e.g. diamino, carboxyl) were used. These chemical groups imparted either a net positive (i.e. diamino) or negative (i.e. carboxyl) charge on the SPM when suspended in a neutral ionic medium. The zeta potential, a measure of the SPM's electronegativity, was taken in both cell culture nutrient medium and in ultraviolet light-distilled water (UV-DW). In both vehicles, the rank order of electronegativity (most to least negative) was carboxyl > polystyrene > diamino-SPM. Individual types of SPM were exposed to human, immortalized bronchial-tracheal epithelial cells (i.e. BEAS-2B) and endpoints of biological activation (i.e. membrane depolarization, increases in intracellular calcium (i.e. [Ca(2+)](i)) levels, IL-6 release) were measured. Cells loaded with a fluorescent probe for membrane depolarization (3,3'-dihexyloxacarbocyanine iodide, DiOC-6-3) showed a positive reaction when exposed to carboxyl-SPM but not to diamino-SPM. BEAS-2B cells exposed to carboxyl-SPM responded with significant increases in [Ca(2+)](i), and IL-6 release relative to uncharged SPM or diamino-SPM. This IL-6 release could be reduced by pretreatment with antagonists to the VR1 receptor (i.e. capsazepine) or to acid-sensitive ionc channels (i.e. amiloride). Although both diamino and carboxyl-SPM groups stimulated increases in IL-6 transcript, only the more electronegatively charged carboxyl-SPM stimulated mRNA-VR1 receptor. These data suggest that measurable inflammatory changes can be stimulated in human epithelial target cells by the electrostatic charge carried on an inert particle. Further, these changes appear to be mediated through acid-sensitive VR1 receptors and ASICs.
Although olfaction is the primal sense in animals, its importance in humans is underappreciated. Extensive literature demonstrates that aging is accompanied by olfactory loss and hyposmia/anosmia which is also a feature of several neurodegenerative disorders. Alzheimer's and Parkinson's diseases are characterized by severe olfactory deficits, while problems of olfactory discrimination are less prominent features in several other disorders. Olfactory loss is accompanied by structural abnormalities of the olfactory epithelium, the olfactory bulb and the central olfactory cortices. This review summarizes our present knowledge about the pathological changes in the olfactory system during aging and in various neurodegenerative diseases.
Recently it was speculated that ultrafine particles (UFP) may translocate from deposition sites in the lungs to systemic circulation and whether long-term clearance differs between ultrafine and micrometer-sized particles. We have studied lung retention and clearance kinetics in 12 healthy male adult WKY rats up to 6 mo after an inhalation of (192)Ir-radiolabeled, insoluble, ultrafine 15- to 20-nm iridium particles. Whole-body retention was followed by external gamma counting, and particle clearance kinetics were determined by excretion radioanalysis. Four rats each were sacrificed after 3 wk and 2 and 6 mo; all organs as well as tissues and the carcass were radioanalyzed to balance the entire deposited radioactivity of the particles. The most prominent fraction was retained in the lungs at each time point of sacrifice (26%, 15%, 6%, respectively), and clearance out of the body was solely via excretion. Extrapulmonary particle uptake did not continue to increase but decreased with time in liver, spleen, heart, and brain when compared to previous data obtained during the first 7 days after inhalation (Kreyling et al., 2002). UFP long-term lung retention derived from whole-body measurements was comparable to previously reported data using insoluble micrometer-sized particles (Bellmann et al., 1994; Lehnert et al., 1989). In addition, differential analysis including daily excretion data revealed a pattern of fractional particle clearance rate of the ultrafine iridium particles similar to that of micrometer-sized particles reported by Snipes et al. (1983) and Bailey et al. (1985).
Delivery of drugs to the brain is still a major challenge. Successful delivery across the bloodbrain barrier has only been achieved in some cases, e.g., using pro-drugs. The review describes the delivery to the brain using nanoparticulate drug carriers in combination with the novel targeting principle of "differential protein adsorption" (PathFinder technology). The PathFinder technology exploits proteins in the blood which adsorb onto the surface of intravenously injected carriers for targeting. Apolipoprotein E is the targeting moiety for the delivery of particles to the endothelials of the blood-brain barrier. To reach therapeutic drug level in the brain, nanoparticulate drug carriers with sufficiently high loading capacity are reviewed, including drug nanocrystals (nanosuspensions), lipid drug conjugate (LDC) nanoparticles and lipid nanoparticles (solid lipid nanoparticles-SLN, nanostructured lipid carriers-NLC). The features are described, including regulatory aspects and large scale production.
This study reports that subchronic exposure of Tuxedo, NY concentrated ambient particulates (CAPs) produces neuropathological damage in the brains of Apo E-deficient mice (Apo E-/-). These genetically modified mice are characterized by elevated levels of oxidative stress (OS) in the brain. Microscopic examination of coronal sections of the brain, immunocytochemically stained for dopamineric neurons, indicated that neurons from the substantia nigral nucleus compacta were significantly reduced by 29% in CAPs-exposed Apo E-/- mice relative to air-exposed Apo E-/- controls. In addition, statistically significant increases (p < .05) in immunocytochemically stained astrocytes were noted. The dopaminergic neurons of the nucleus compact are specifically targeted in Parkinson's disease. The present study expands the systems affected by particulate matter to include the brain, and supports an environmental role for the development of neurodegeneration in OS-susceptible individuals.
The influence of tumor necrosis factor alpha (TNF-alpha) on the processes of sphingomyelin cycle activation and intensity of peroxidation in animal brain in vivo has been studied. Alterations in activity of sphingomyelinase, a key sphingomyelin cycle enzyme and in sphingomyelin, ceramide content as well as accumulation of the products of lipid peroxidation (diene conjugates and diene ketons) were measured in the cortex, the cerebellum and the hippocampus of rats 5, 15, 30 min, 1, 2 and 5 hours after TNF-alpha intraperitoneal injection in dosage 100 mkg per animal. It is shown that 2 hours after the injection, TNF-alpha initiated an accumulation of the products of lipid peroxidation, which intensively developed in the cerebellum and the hippocampus. Sphingomyelinase activation was found in the same brain structures. At the initial stage of TNF-alpha action, an increase of lipid peroxidation products correlated with sphingomyelinase activation in the cerebellum and the hippocampus suggesting an interaction of two cell signal systems of sphingomyelin cycle and oxidative system.
See also Vermylen J, Nemmar A, Nemery B, Hoylaerts MF. Ambient air pollution and acute myocardial infarction. This issue, pp 1955-61. Blomberg A, Törnqvist H, Desmyter L, Deneys V, Hermans C. Exposure to diesel exhaust nanoparticles does not induce blood hypercoagulability in an at-risk population. This issue, pp 2103–5.