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2.
Integr Biol (Camb) ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32195539

RESUMO

The blood-brain barrier plays a critical role in delivering oxygen and nutrients to the brain while preventing the transport of neurotoxins. Predicting the ability of potential therapeutics and neurotoxicants to modulate brain barrier function remains a challenge due to limited spatial resolution and geometric constraints offered by existing in vitro models. Using soft lithography to control the shape of microvascular tissues, we predicted blood-brain barrier permeability states based on structural changes in human brain endothelial cells. We quantified morphological differences in nuclear, junction, and cytoskeletal proteins that influence, or indicate, barrier permeability. We established a correlation between brain endothelial cell pair structure and permeability by treating cell pairs and tissues with known cytoskeleton-modulating agents, including a Rho activator, a Rho inhibitor, and a cyclic adenosine monophosphate analog. Using this approach, we found that high-permeability cell pairs showed nuclear elongation, loss of junction proteins, and increased actin stress fiber formation, which were indicative of increased contractility. We measured traction forces generated by high- and low-permeability pairs, finding that higher stress at the intercellular junction contributes to barrier leakiness. We further tested the applicability of this platform to predict modulations in brain endothelial permeability by exposing cell pairs to engineered nanomaterials, including gold, silver-silica, and cerium oxide nanoparticles, thereby uncovering new insights into the mechanism of nanoparticle-mediated barrier disruption. Overall, we confirm the utility of this platform to assess the multiscale impact of pharmacological agents or environmental toxicants on blood-brain barrier integrity.

3.
Small ; : e1907640, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196921

RESUMO

In the last decade, along with the increasing use of graphene oxide (GO) in various applications, there is also considerable interest in understanding its effects on human health. Only a few experimental approaches can simulate common routes of exposure, such as ingestion, due to the inherent complexity of the digestive tract. This study presents the synthesis of size-sorted GO of sub-micrometer- or micrometer-sized lateral dimensions, its physicochemical transformations across mouth, gastric, and small intestinal simulated digestions, and its toxicological assessment against a physiologically relevant, in vitro cellular model of the human intestinal epithelium. Results from real-time characterization of the simulated digestas of the gastrointestinal tract using multi-angle laser diffraction and field-emission scanning electron microscopy show that GO agglomerates in the gastric and small intestinal phase. Extensive morphological changes, such as folding, are also observed on GO following simulated digestion. Furthermore, X-ray photoelectron spectroscopy reveals that GO presents covalently bound N-containing groups on its surface. It is shown that the GO employed in this study undergoes reduction. Toxicological assessment of the GO small intestinal digesta over 24 h does not point to acute cytotoxicity, and examination of the intestinal epithelium under electron microscopy does not reveal histological alterations. Both sub-micrometer- and micrometer-sized GO variants elicit a 20% statistically significant increase in reactive oxygen species generation compared to the untreated control after a 6 h exposure.

4.
Environ Sci Technol ; 54(4): 2389-2400, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-31967798

RESUMO

Laser printers emit high levels of nanoparticles (PM0.1) during operation. Although it is well established that toners contain multiple engineered nanomaterials (ENMs), little is known about inhalation exposures to these nanoparticles and work practices in printing centers. In this report, we present a comprehensive inhalation exposure assessment of indoor microenvironments at six commercial printing centers in Singapore, the first such assessment outside of the United States, using real-time personal and stationary monitors, time-integrated instrumentation, and multiple analytical methods. Extensive presence of ENMs, including titanium dioxide, iron oxide, and silica, was detected in toners and in airborne particles collected from all six centers studied. We document high transient exposures to emitted nanoparticles (peaks of ∼500 000 particles/cm3, lung-deposited surface area of up to 220 µm2/cm3, and PM0.1 up to 16 µg/m3) with complex PM0.1 chemistry that included 40-60 wt % organic carbon, 10-15 wt % elemental carbon, and 14 wt % trace elements. We also record 271.6-474.9 pmol/mg of Environmental Protection Agency-priority polycyclic aromatic hydrocarbons. These findings highlight the potentially high occupational inhalation exposures to nanoparticles with complex compositions resulting from widespread usage of nano-enabled toners in the printing industry, as well as inadequate ENM-specific exposure control measures in these settings.


Assuntos
Nanopartículas , Exposição Ocupacional , Monitoramento Ambiental , Exposição por Inalação , Tamanho da Partícula , Impressão Tridimensional , Singapura , Estados Unidos
5.
Part Fibre Toxicol ; 17(1): 7, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996220

RESUMO

BACKGROUND: Using engineered nanomaterial-based toners, laser printers generate aerosols with alarming levels of nanoparticles that bear high bioactivity and potential health risks. Yet, the cardiac impacts of printer-emitted particles (PEPs) are unknown. Inhalation of particulate matter (PM) promotes cardiovascular morbidity and mortality, and ultra-fine particulates (< 0.1 µm aerodynamic diameter) may bear toxicity unique from larger particles. Toxicological studies suggest that PM impairs left ventricular (LV) performance; however, such investigations have heretofore required animal restraint, anesthesia, or ex vivo preparations that can confound physiologic endpoints and/or prohibit LV mechanical assessments during exposure. To assess the acute and chronic effects of PEPs on cardiac physiology, male Sprague Dawley rats were exposed to PEPs (21 days, 5 h/day) while monitoring LV pressure (LVP) and electrocardiogram (ECG) via conscious telemetry, analyzing LVP and heart rate variability (HRV) in four-day increments from exposure days 1 to 21, as well as ECG and baroreflex sensitivity. At 2, 35, and 70 days after PEPs exposure ceased, rats received stress tests. RESULTS: On day 21 of exposure, PEPs significantly (P < 0.05 vs. Air) increased LV end systolic pressure (LVESP, + 18 mmHg) and rate-pressure-product (+ 19%), and decreased HRV indicating sympathetic dominance (root means squared of successive differences [RMSSD], - 21%). Overall, PEPs decreased LV ejection time (- 9%), relaxation time (- 3%), tau (- 5%), RMSSD (- 21%), and P-wave duration (- 9%). PEPs increased QTc interval (+ 5%) and low:high frequency HRV (+ 24%; all P < 0.05 vs. Air), while tending to decrease baroreflex sensitivity and contractility index (- 15% and - 3%, P < 0.10 vs. Air). Relative to Air, at both 2 and 35 days after PEPs, ventricular arrhythmias increased, and at 70 days post-exposure LVESP increased. PEPs impaired ventricular repolarization at 2 and 35 days post-exposure, but only during stress tests. At 72 days post-exposure, PEPs increased urinary dopamine 5-fold and protein expression of ventricular repolarizing channels, Kv1.5, Kv4.2, and Kv7.1, by 50%. CONCLUSIONS: Our findings suggest exposure to PEPs increases cardiovascular risk by augmenting sympathetic influence, impairing ventricular performance and repolarization, and inducing hypertension and arrhythmia. PEPs may present significant health risks through adverse cardiovascular effects, especially in occupational settings, among susceptible individuals, and with long-term exposure.

6.
J Agric Food Chem ; 68(1): 358-368, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31815446

RESUMO

Nanoscale chitosan materials exhibit size-specific properties that make them useful in agri-food and biomedical applications. Chitosan nanoparticles (Chnps) are being explored as nanocarrier platforms to increase oral bioavailability of drugs and nutraceuticals, but little is known of their fate and transformations in the gastrointestinal tract (GIT) or of their potential toxicity. Here, the GIT fate and cytotoxicity of Chnps, soluble starch-coated Chnps (SS-Chnps), and bulk chitosan powder (Chp), were assessed using a 3-phase simulated digestion and an in vitro cellular small intestinal epithelium model. Physico-chemical characterization revealed dissolution of Chp, but not of Chnps or SS-Chnps, during the gastric phase of digestion, stability of the starch coating of SS-Chnps in the oral and gastric phases, and agglomeration of all materials during the small intestinal phase. A slight but significant (10%, p < 0.01) increase in cytotoxicity (LDH release) was observed with exposure to digested Chnps but not Chp or SS-Chnps.


Assuntos
Quitosana/química , Quitosana/metabolismo , Epitélio/metabolismo , Intestino Delgado/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Disponibilidade Biológica , Células CACO-2 , Quitosana/toxicidade , Trato Gastrointestinal/metabolismo , Humanos , Cinética , Modelos Biológicos , Nanopartículas/toxicidade , Tamanho da Partícula
7.
Part Fibre Toxicol ; 16(1): 40, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665028

RESUMO

BACKGROUND: Amorphous silica nanoparticles (SiO2 NPs) have been regarded as relatively benign nanomaterials, however, this widely held opinion has been questioned in recent years by several reports on in vitro and in vivo toxicity. Surface chemistry, more specifically the surface silanol content, has been identified as an important toxicity modulator for SiO2 NPs. Here, quantitative relationships between the silanol content on SiO2 NPs, free radical generation and toxicity have been identified, with the purpose of synthesizing safer-by-design fumed silica nanoparticles. RESULTS: Consistent and statistically significant trends were seen between the total silanol content, cell membrane damage, and cell viability, but not with intracellular reactive oxygen species (ROS), in the macrophages RAW264.7. SiO2 NPs with lower total silanol content exhibited larger adverse cellular effects. The SAEC epithelial cell line did not show any sign of toxicity by any of the nanoparticles. Free radical generation and surface reactivity of these nanoparticles were also influenced by the temperature of combustion and total silanol content. CONCLUSION: Surface silanol content plays an important role in cellular toxicity and surface reactivity, although it might not be the sole factor influencing fumed silica NP toxicity. It was demonstrated that synthesis conditions for SiO2 NPs influence the type and quantity of free radicals, oxidative stress, nanoparticle interaction with the biological milieu they come in contact with, and determine the specific mechanisms of toxicity. We demonstrate here that it is possible to produce much less toxic fumed silicas by modulating the synthesis conditions.

8.
Chem Res Toxicol ; 32(12): 2382-2397, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31657553

RESUMO

Iron oxide nanoparticles (IONP) have recently surged in production and use in a wide variety of biomedical and environmental applications. However, their potential long-term health effects, including carcinogenesis, are unknown. Limited research suggests IONP can induce genotoxicity and neoplastic transformation associated with particle dissolution and release of free iron ions. "Safe by design" strategies involve the modification of particle physicochemical properties to affect subsequent adverse outcomes, such as an amorphous silica coating to reduce IONP dissolution and direct interaction with cells. We hypothesized that long-term exposure to a specific IONP (nFe2O3) would induce neoplastic-like cell transformation, which could be prevented with an amorphous silica coating (SiO2-nFe2O3). To test this hypothesis, human bronchial epithelial cells (Beas-2B) were continuously exposed to a 0.6 µg/cm2 administered a dose of nFe2O3 (∼0.58 µg/cm2 delivered dose), SiO2-nFe2O3 (∼0.55 µg/cm2 delivered dose), or gas metal arc mild steel welding fumes (GMA-MS, ∼0.58 µg/cm2 delivered dose) for 6.5 months. GMA-MS are composed of roughly 80% iron/iron oxide and were recently classified as a total human carcinogen. Our results showed that low-dose/long-term in vitro exposure to nFe2O3 induced a time-dependent neoplastic-like cell transformation, as indicated by increased cell proliferation and attachment-independent colony formation, which closely matched that induced by GMA-MS. This transformation was associated with decreases in intracellular iron, minimal changes in reactive oxygen species (ROS) production, and the induction of double-stranded DNA damage. An amorphous silica-coated but otherwise identical particle (SiO2-nFe2O3) did not induce this neoplastic-like phenotype or changes in the parameters mentioned above. Overall, the presented data suggest the carcinogenic potential of long-term nFe2O3 exposure and the utility of an amorphous silica coating in a "safe by design" hazard reduction strategy, within the context of a physiologically relevant exposure scenario (low-dose/long-term), with model validation using GMA-MS.

9.
Nanoscale ; 11(38): 17878-17893, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31553035

RESUMO

Engineered nanomaterials (ENMs) are increasingly used in consumer products due to their unique physicochemical properties, but the specific hazards they pose to the structural and functional integrity of endothelial barriers remain elusive. When assessing the effects of ENMs on vascular barrier function, endothelial cell monolayers are commonly used as in vitro models. Monolayer models, however, do not offer a granular understanding of how the structure-function relationships between endothelial cells and tissues are disrupted due to ENM exposure. To address this issue, we developed a micropatterned endothelial cell pair model to quantitatively evaluate the effects of 10 ENMs (8 metal/metal oxides and 2 organic ENMs) on multiple cellular parameters and determine how these parameters correlate to changes in vascular barrier function. This minimalistic approach showed concerted changes in endothelial cell morphology, intercellular junction formation, and cytoskeletal organization due to ENM exposure, which were then quantified and compared to unexposed pairs using a "similarity scoring" method. Using the cell pair model, this study revealed dose-dependent changes in actin organization and adherens junction formation following exposure to representative ENMs (Ag, TiO2 and cellulose nanocrystals), which exhibited trends that correlate with changes in tissue permeability measured using an endothelial monolayer assay. Together, these results demonstrate that we can quantitatively evaluate changes in endothelial architecture emergent from nucleo-cytoskeletal network remodeling using micropatterned cell pairs. The endothelial pair model therefore presents potential applicability as a standardized assay for systematically screening ENMs and other test agents for their cellular-level structural effects on vascular barriers.


Assuntos
Núcleo Celular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Modelos Biológicos , Nanopartículas/química , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos
10.
ACS Omega ; 4(7): 12049-12057, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31460318

RESUMO

Withania coagulans is an Indian medicinal herb, the natural extracts of which are purported to have health-benefiting properties. In this study, the extract was encapsulated in nature-derived polymers with the aim of enhancing its bioavailability. The aqueous extract obtained from the plant W. coagulans was found to elicit the glucose-lowering effect by means of promoting insulin secretion from pancreatic ß cells. The cells treated with the extract showed a nearly 2-fold increase in insulin secretion compared to untreated cells. A delivery system for the extract was developed based on electrosprayed chitosan nanoparticles coated with food-based starch. The enteric starch coating retarded (by 2.5 times) the release of the extract in the stomach. The bioactivity of the encapsulated extract was subsequently tested in vitro on mouse-derived pancreatic ß cells, whereby the delivery system was found to promote insulin secretion. Finally, the extract-encapsulated oral delivery system was tested on diabetic mice and was validated to decrease blood glucose levels by 60%. In summary, it could be inferred that food-grade enteric-coated polysaccharide-based particles increase the bioavailability of the extracted compounds from the plant W. coagulans.

11.
NanoImpact ; 13: 13-25, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31093583

RESUMO

Food matrix effects impact the bioavailability and toxicity of pharmaceuticals, nutraceuticals, pesticides, and engineered nanomaterials (ENMs). However, there are currently no standardized food models to test the impact of food matrix effects using in vitro gastrointestinal models. The purpose of this study was to establish a standardized food model (SFM) for evaluating the toxicity and fate of ingested ENMs and then to assess its efficacy by examining the impact of food matrix effects on the toxicity of TiO2 nanoparticles. The formulation of the SFM was based on the average composition of the US diet: 3.4% protein (sodium caseinate); 4.6% sugar (sucrose); 5.2% digestible carbohydrates (modified corn starch); 0.7% dietary fiber (pectin); 3.4% fat (corn oil); and, 0.5% minerals (sodium chloride). The SFM consisted of an oil-in-water emulsion suitable for use in both wet and dried forms. The dried form was produced by spray drying the emulsion to improve its handling and extend its shelf-life. The particle size (D32 = 135 nm), surface charge (-37.8 mV), viscosity, color (L*, a,* b* = 82.1, -2.5, 1.3), and microstructure of the wet SFM were characterized. The hydration properties, flowability (repose angle ≈ 27.9°; slide angle ≈ 28.2°), and moisture sorption isotherms of the dry SFM were comparable to commercial food powders. The potential gastrointestinal fate of the SFM was determined using a simulated gastrointestinal tract, including mouth, stomach, and small intestine steps. Conversion of the SFM into a powdered form did not impact its gastrointestinal fate. A nanotoxicology case study with TiO2 nanoparticles exposed to a tri-culture epithelial cell model showed that food matrix effects reduced ENM cytotoxicity more than 5-fold. The SFM developed in the current study could facilitate studies of the impact of food matrix effects on the gastrointestinal fate and toxicity of various types of food NPs.

12.
Environ Sci Technol ; 53(13): 7574-7583, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31120250

RESUMO

Inhalation exposure to nanoparticles from toner-based laser printer and photocopier emissions (LPEs) induces airway inflammation and systemic oxidative stress, cytotoxicity, and genotoxicity (such as DNA damage). Recent evidence from human and in vitro studies suggests a strong role for oxidative stress caused by free radicals, such as reactive oxygen species (ROS), in the toxicity of laser printer emissions. However, the amount of ROS generated from laser printer nanoparticle emissions and the relative contribution of various fractions (vapors, organics, metals, and metal oxides) have not been investigated to-date. In this study, we aim to quantify short-lived ROS and H2O2 laser printer emissions, as well as the relative contribution of various fractions of LPEs in ROS generation. An aerosol chamber with HEPA filtered air was used to generate LPE emissions from one representative printer. In separate experiments, size fractionated LPEs were collected on filters (particles) or impingers (particles and vapors). The nanoscale fraction of LPEs (PM0.1) was further separated into the organic fraction and inorganic (transition metals/metal oxides) following a sequence of extraction with solvents and centrifugation. The short-lived ROS and H2O2 generated from each fraction were quantified with an acellular Trolox-based liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) method recently developed in our lab. The particulate fraction of LPEs PM0.1 generated 2.68 times more total ROS (sum of short-lived ROS and H2O2) than the vapor fraction. In tested LPEs, transition metal oxides, which constituted 3% by mass, produced 69× and 202× times more short-lived ROS and H2O2, respectively, on a mass basis, than the organic fraction. Furthermore, fresh PM0.1 generated 282× and 32× times more short-lived ROS and H2O2, respectively, than aged and processed PM0.1. We conclude that transition metal oxides, albeit a minor constituent of the LPE PM0.1 emissions, are the species responsible for the majority of acellular ROS in this printer. A larger range of printers should be tested in the future. Because transition metal oxides in toners originate primarily from engineering nanomaterials (ENMs) in printer toner powder, reformulation of toner powders to contain less of these ROS active metals is recommended.


Assuntos
Peróxido de Hidrogênio , Espectrometria de Massas em Tandem , Humanos , Metais , Óxidos , Material Particulado , Espécies Reativas de Oxigênio
13.
Nanomedicine ; 18: 234-242, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30904585

RESUMO

Infectious diseases represent a major public health challenge worldwide. There are various modes for the transmission of these diseases, with surface and airborne transmission being two of the most important ones. The inefficiencies of current intervention methods have resulted in the emergence of nosocomial infections. Here, we report the use of a nanotechnology based antimicrobial platform using Engineered Water Nanostructures (EWNS) generated using a combined electrospray and ionization of an aqueous suspension of various active ingredients (AIs). These EWNS based nano-sanitizers were tested in terms of their ability to efficiently deliver AI and inactivate Acinetobacter baumannii and influenza H1N1/PR/8 on both surfaces and air. Results indicate a significant reduction in the concertation of the pathogens, while the delivered to pathogen AI doses required for inactivation were miniscule (nanogram level), indicating the viability of such nano-carrier platform as an intervention technology against infectious microorganisms.


Assuntos
Anti-Infecciosos/farmacologia , Hospitais , Viabilidade Microbiana/efeitos dos fármacos , Nanoestruturas/química , Nanotecnologia , Água , Ar , Propriedades de Superfície
14.
Nano Lett ; 19(2): 793-804, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30616354

RESUMO

Understanding the uptake and transport dynamics of engineered nanomaterials (ENMs) by mammalian cells is an important step in designing next-generation drug delivery systems. However, to track these materials and their cellular interactions, current studies often depend on surface-bound fluorescent labels, which have the potential to alter native cellular recognition events. As a result, there is still a need to develop methods capable of monitoring ENM-cell interactions independent of surface modification. Addressing these concerns, here we show how scatter enhanced phase contrast (SEPC) microscopy can be extended to work as a generalized label-free approach for monitoring nanoparticle uptake and transport dynamics. To determine which materials can be studied using SEPC, we turn to Lorenz-Mie theory, which predicts that individual particles down to ∼35 nm can be observed. We confirm this experimentally, demonstrating that SEPC works for a variety of metal and metal oxides, including Au, Ag, TiO2, CeO2, Al2O3, and Fe2O3 nanoparticles. We then demonstrate that SEPC microscopy can be used in a quantitative, time-dependent fashion to discriminate between distinct modes of active cellular transport, including intracellular transport and membrane-assisted transport. Finally, we combine this technique with microcontact printing to normalize transport dynamics across multiple cells, allowing for a careful study of ensemble TiO2 nanoparticle uptake. This revealed three distinct regions of particle transport across the cell, indicating that membrane dynamics play an important role in regulating particle flow. By avoiding fluorescent labels, SEPC allows for a rational exploration of the surface properties of nanomaterials in their native state and their role in endocytosis and cellular transport.


Assuntos
Microscopia de Contraste de Fase/instrumentação , Nanopartículas/metabolismo , Transporte Biológico , Endocitose , Desenho de Equipamento , Células Endoteliais da Veia Umbilical Humana , Humanos , Metais/análise , Metais/metabolismo , Microscopia de Contraste de Fase/métodos , Nanopartículas/análise , Óxidos/análise , Óxidos/metabolismo , Propriedades de Superfície
15.
Int J Mol Sci ; 20(24)2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31888290

RESUMO

Laser printer-emitted nanoparticles (PEPs) generated from toners during printing represent one of the most common types of life cycle released particulate matter from nano-enabled products. Toxicological assessment of PEPs is therefore important for occupational and consumer health protection. Our group recently reported exposure to PEPs induces adverse cardiovascular responses including hypertension and arrythmia via monitoring left ventricular pressure and electrocardiogram in rats. This study employed genome-wide mRNA and miRNA profiling in rat lung and blood integrated with metabolomics and lipidomics profiling in rat serum to identify biomarkers for assessing PEPs-induced disease risks. Whole-body inhalation of PEPs perturbed transcriptional activities associated with cardiovascular dysfunction, metabolic syndrome, and neural disorders at every observed time point in both rat lung and blood during the 21 days of exposure. Furthermore, the systematic analysis revealed PEPs-induced transcriptomic changes linking to other disease risks in rats, including diabetes, congenital defects, auto-recessive disorders, physical deformation, and carcinogenesis. The results were also confirmed with global metabolomics profiling in rat serum. Among the validated metabolites and lipids, linoleic acid, arachidonic acid, docosahexanoic acid, and histidine showed significant variation in PEPs-exposed rat serum. Overall, the identified PEPs-induced dysregulated genes, molecular pathways and functions, and miRNA-mediated transcriptional activities provide important insights into the disease mechanisms. The discovered important mRNAs, miRNAs, lipids and metabolites may serve as candidate biomarkers for future occupational and medical surveillance studies. To the best of our knowledge, this is the first study systematically integrating in vivo, transcriptomics, metabolomics, and lipidomics to assess PEPs inhalation exposure-induced disease risks using a rat model.

16.
Part Fibre Toxicol ; 15(1): 29, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29970114

RESUMO

BACKGROUND: Engineered nanomaterials (ENM) are used extensively in food products to fulfill a number of roles, including enhancement of color and texture, for nutritional fortification, enhanced bioavailability, improved barrier properties of packaging, and enhanced food preservation. Safety assessment of ingested engineered nanomaterials (iENM) has gained interest in the nanotoxicology community in recent years. A variety of test systems and approaches have been used for such evaluations, with in vitro monoculture cell models being the most common test systems, owing to their low cost and ease-of-use. The goal of this review is to systematically assess the current state of science in toxicological testing of iENM, with particular emphasis on model test systems, their physiological relevance, methodological strengths and challenges, realistic doses (ranges and rates), and then to identify future research needs and priorities based on these assessments. METHODS: Extensive searches were conducted in Google Scholar, PubMed and Web of Science to identify peer-reviewed literature on safety assessment of iENM over the last decade, using keywords such as "nanoparticle", "food", "toxicity", and combinations thereof. Relevant literature was assessed based on a set of criteria that included the relevance of nanomaterials tested; ENM physicochemical and morphological characterization; dispersion and dosimetry in an in vitro system; dose ranges employed, the rationale and dose realism; dissolution behavior of iENM; endpoints tested, and the main findings of each study. Observations were entered into an excel spreadsheet, transferred to Origin, from where summary statistics were calculated to assess patterns, trends, and research gaps. RESULTS: A total of 650 peer-reviewed publications were identified from 2007 to 2017, of which 39 were deemed relevant. Only 21% of the studies used food grade nanomaterials for testing; adequate physicochemical and morphological characterization was performed in 53% of the studies. All in vitro studies lacked dosimetry and 60% of them did not provide a rationale for the doses tested and their relevance. Only 12% of the studies attempted to consider the dissolution kinetics of nanomaterials. Moreover, only 1 study attempted to prepare and characterize standardized nanoparticle dispersions. CONCLUSION: We identified 5 clusters of factors deemed relevant to nanotoxicology of food-grade iENM: (i) using food-grade nanomaterials for toxicity testing; (ii) performing comprehensive physicochemical and morphological characterization of iENM in the dry state, (iii) establishing standard NP dispersions and their characterization in cell culture medium, (iv) employing realistic dose ranges and standardized in vitro dosimetry models, and (v) investigating dissolution kinetics and biotransformation behavior of iENM in synthetic media representative of the gastrointestinal (GI) tract fluids, including analyses in a fasted state and in the presence of a food matrix. We discussed how these factors, when not considered thoughtfully, could influence the results and generalizability of in vitro and in vivo testing. We conclude with a set of recommendations to guide future iENM toxicity studies and to develop/adopt more relevant in vitro model systems representative of in vivo animal and human iENM exposure scenarios.


Assuntos
Aditivos Alimentares/toxicidade , Nanoestruturas/toxicidade , Testes de Toxicidade/métodos , Animais , Disponibilidade Biológica , Aditivos Alimentares/química , Aditivos Alimentares/farmacocinética , Inocuidade dos Alimentos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Humanos , Nanoestruturas/química , Tamanho da Partícula , Propriedades de Superfície
17.
ACS Nano ; 12(8): 8115-8128, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30021067

RESUMO

Engineered nanomaterials (ENM) are extensively used as food additives in numerous food products, and at present, little is known about the fate of ingested ENM (iENM) in the gastrointestinal (GI) environment. Here, we investigated the dissolution behavior, biodurability, and persistence of four major iENM (TiO2, SiO2, ZnO, and two Fe2O3) in individual simulated GI fluids (saliva, gastric, and intestinal) and a physiologically relevant digestion cascade (saliva → gastric → intestinal) in the fasted state over physiologically relevant time frames. TiO2 was found to be the most biodurable and persistent iENM in simulated GI fluids with a maximum of only 0.42% (4 µM Ti4+ ion release) dissolution in cascade digestion, followed by iron oxides, of which the rod-like morphology was more biodurable and persistent (0.7% maximum dissolution, 8.7 µM Fe3+) than the acicular one (2.27% maximum dissolution, 16.7 µM Fe3+) in the cascade digestion, respectively. SiO2 and ZnO were less biodurable than Fe2O3, with 65.5% (416 µM Si4+) and 100% (1718.1 µM Zn2+) dissolution in the gastric phase, respectively. In the intestinal phase, however, Si4+ ions reprecipitated, possibly due to sudden pH changes, while ZnO remained completely dissolved. These observations were also confirmed using high-resolution particle size and concentration, and electron microscopy, time-dependent analysis. In terms of decreasing biodurability and persistence in the simulated GI environment, the tested nanomaterials can be ranked as follows: TiO2 ≫ rod-like Fe2O3 > acicular Fe2O3 ≫ SiO2 > ZnO, which is in agreement with limited animal biokinetics data. Chronic uptake of these iENM as particles or ions by the GI tract, especially in the presence of a food matrix and authentic digestive media, and associated implications for human health warrants further investigation.


Assuntos
Suco Gástrico/química , Trato Gastrointestinal/química , Nanoestruturas/química , Compostos Férricos/química , Compostos Férricos/metabolismo , Suco Gástrico/metabolismo , Trato Gastrointestinal/metabolismo , Humanos , Dióxido de Silício/química , Dióxido de Silício/metabolismo , Titânio/química , Titânio/metabolismo , Óxido de Zinco/química , Óxido de Zinco/metabolismo
18.
Small ; 14(30): e1800922, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29968352

RESUMO

The majority of cancer mortality is associated with cancer metastasis. Epithelial-to-mesenchymal transition (EMT) is a process by which cells attain migratory and invasive properties, eventually leading to cancer metastasis. Here, it is shown that titanium dioxide nanoparticles (nano-TiO2 ), a common food additive, can induce the EMT process in colorectal cancer cells. Nano-TiO2 exposure is observed to activate transforming growth factor-ß (TGF-ß)/mitogen-activated protein kinase (MAPK) and wingless (Wnt) pathways, and drive the EMT process. Similarly, silica nanoparticles (nano-SiO2 ) and hydroxyapatite nanoparticles (nano-HA), as food-based additives, can be ingested and accumulated in the stomach, and are found to be able to induce the EMT progression. The implication of this work can be profound for colorectal cancer patients where these food additives may unknowingly and unnecessarily hasten the progression of their cancers.


Assuntos
Neoplasias Colorretais/patologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Nanopartículas/toxicidade , Titânio/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Durapatita/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Modelos Biológicos , Invasividade Neoplásica , Dióxido de Silício/toxicidade , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
19.
NanoImpact ; 10: 26-37, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30035243

RESUMO

There is a growing need to develop and characterize reference metal and metal oxide engineered nanomaterials (ENMs) of high purity and tunable intrinsic properties suitable for nanotoxicology research. Here a high throughput (volume) and precision flame spray pyrolysis (FSP) approach coupled with state-of-the-art characterization techniques are utilized to generate such reference ENMs. The lab-based and industrially relevant FSP system, termed as Versatile Engineered Nanomaterials Generation System (VENGES), synthesizes the metals and metal oxides, at high throughput manner with controlled properties, such as primary particle size, aggregate diameter, shape, crystallinity, stoichiometry and surface chemistry. A nanopanel of nine reference ENMs (silica, silver, silver supported on silica, alumina, ceria and iron oxide) was synthesized and characterized using combined electron microscopy, advanced spectroscopic techniques and physical analyses (e.g., BET, XRD, TEM, pycnometry, XPS, ICP-MS and FTIR). ENMs show a high degree of chemical purity and stoichiometry, and low content of carbon residuals, and are sterile and free of bacteria and endotoxins. Further, their colloidal properties and their implication in in-vitro dosimetry have been also investigated in both environmental and test biological media. The suitability of reference ENMs and protocols developed in this study brings forth new arenas to generate reliable and reproducible toxicological data in an effort to reduce conflicting and contradicting inter-laboratory data on relative toxic effects of ENMs.

20.
ACS Nano ; 12(7): 6469-6479, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29874029

RESUMO

Engineered nanomaterials are increasingly added to foods to improve quality, safety, or nutrition. Here we report the ability of ingested nanocellulose (NC) materials to reduce digestion and absorption of ingested fat. In the small intestinal phase of an acellular simulated gastrointestinal tract, the hydrolysis of free fatty acids (FFA) from triglycerides (TG) in a high-fat food model was reduced by 48.4% when NC was added at 0.75% w/w to the food, as quantified by pH stat titration, and by 40.1% as assessed by fluorometric FFA assay. Furthermore, translocation of TG and FFA across an in vitro cellular model of the intestinal epithelium was significantly reduced by the presence of 0.75% w/w NC in the food (TG by 52% and FFA by 32%). Finally, in in vivo experiments, the postprandial rise in serum TG 1 h after gavage with the high fat food model was reduced by 36% when 1.0% w/w NC was administered with the food. Scanning electron microscopy and molecular dynamics studies suggest two primary mechanisms for this effect: (1) coalescence of fat droplets on fibrillar NC (CNF) fibers, resulting in a reduction of available surface area for lipase binding and (2) sequestration of bile salts, causing impaired interfacial displacement of proteins at the lipid droplet surface and impaired solubilization of lipid digestion products. Together these findings suggest a potential use for NC, as a food additive or supplement, to reduce absorption of ingested fat and thereby assist in weight loss and the management of obesity.


Assuntos
Celulose/metabolismo , Digestão , Gorduras/metabolismo , Aditivos Alimentares/metabolismo , Triglicerídeos/metabolismo , Animais , Celulose/química , Aditivos Alimentares/química , Humanos , Hidrólise , Absorção Intestinal , Intestinos/fisiologia , Masculino , Nanoestruturas/química , Ratos Wistar
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