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1.
Part Fibre Toxicol ; 20(1): 15, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37085867

RESUMO

BACKGROUND: Microbial dysbiosis is a potential mediator of air pollution-induced adverse outcomes. However, a systemic comparison of the lung and gut microbiome alterations and lung-gut axis following air pollution exposure is scant. In this study, we exposed male C57BL/6J mice to inhaled air, CB (10 mg/m3), O3 (2 ppm) or CB + O3 mixture for 3 h/day for either one day or four consecutive days and were euthanized 24 h post last exposure. The lung and gut microbiome were quantified by 16 s sequencing. RESULTS: Multiple CB + O3 exposures induced an increase in the lung inflammatory cells (neutrophils, eosinophils and B lymphocytes), reduced absolute bacterial load in the lungs and increased load in the gut. CB + O3 exposure was more potent as it decreased lung microbiome alpha diversity just after a single exposure. CB + O3 co-exposure uniquely increased Clostridiaceae and Prevotellaceae in the lungs. Serum short chain fatty acids (SCFA) (acetate and propionate) were increased significantly only after CB + O3 co-exposure. A significant increase in SCFA producing bacterial families (Ruminococcaceae, Lachnospiraceae, and Eubacterium) were also observed in the gut after multiple exposures. Co-exposure induced significant alterations in the gut derived metabolite receptors/mediator (Gcg, Glp-1r, Cck) mRNA expression. Oxidative stress related mRNA expression in lungs, and oxidant levels in the BALF, serum and gut significantly increased after CB + O3 exposures. CONCLUSION: Our study confirms distinct gut and lung microbiome alterations after CB + O3 inhalation co-exposure and indicate a potential homeostatic shift in the gut microbiome to counter deleterious impacts of environmental exposures on metabolic system.


Assuntos
Microbiota , Ozônio , Camundongos , Animais , Masculino , Ozônio/toxicidade , Fuligem/toxicidade , Camundongos Endogâmicos C57BL , Pulmão/metabolismo , RNA Mensageiro/metabolismo
2.
J Toxicol Environ Health A ; 86(1): 1-22, 2023 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-36444639

RESUMO

The measurement of fine (diameter: 100 nanometers-2.5 micrometers) and ultrafine (UF: < 100 nanometers) titanium dioxide (TiO2) particles is instrument dependent. Differences in measurements exist between toxicological and field investigations for the same exposure metric such as mass, number, or surface area because of variations in instruments used, operating parameters, or particle-size measurement ranges. Without appropriate comparison, instrument measurements create a disconnect between toxicological and field investigations for a given exposure metric. Our objective was to compare a variety of instruments including multiple metrics including mass, number, and surface area (SA) concentrations for assessing different concentrations of separately aerosolized fine and UF TiO2 particles. The instruments studied were (1) DustTrak™ DRX, (2) personal DataRAMs™ (PDR), (3) GRIMMTM, and (4) diffusion charger (DC). Two devices of each field-study instrument (DRX, PDR, GRIMM, and DC) were used to measure various metrics while adjusting for gravimetric mass concentrations of fine and UF TiO2 particles in controlled chamber tests. An analysis of variance (ANOVA) was used to apportion the variance to inter-instrument (between different instrument-types), inter-device (within instrument), and intra-device components. Performance of each instrument-device was calculated using root mean squared error compared to reference methods: close-faced cassette and gravimetric analysis for mass and scanning mobility particle sizer (SMPS) real-time monitoring for number and SA concentrations. Generally, inter-instrument variability accounted for the greatest (62.6% or more) source of variance for mass, and SA-based concentrations of fine and UF TiO2 particles. However, higher intra-device variability (53.7%) was observed for number concentrations measurements with fine particles compared to inter-instrument variability (40.8%). Inter-device variance range(0.5-5.5%) was similar for all exposure metrics. DRX performed better in measuring mass closer to gravimetric than PDRs for fine and UF TiO2. Number concentrations measured by GRIMMs and SA measurements by DCs were considerably (40.8-86.9%) different from the reference (SMPS) method for comparable size ranges of fine and UF TiO2. This information may serve to aid in interpreting assessments in risk models, epidemiologic studies, and development of occupational exposure limits, relating to health effect endpoints identified in toxicological studies considering similar instruments evaluated in this study.


Assuntos
Monitoramento Ambiental , Exposição Ocupacional , Monitoramento Ambiental/métodos , Exposição Ocupacional/análise , Titânio , Tamanho da Partícula , Aerossóis
3.
J Toxicol Environ Health A ; 86(8): 246-262, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-36859793

RESUMO

Despite the perception that e-cigarettes are safer than conventional cigarettes, numerous findings demonstrated that e-cigarette aerosol (EC) exposure induced compromised immune functionality, vascular changes even after acute exposure, and lung injury. Notably, altered neutrophil functionality and platelet hemodynamics have been observed post-EC exposure. It was hypothesized that EC exposure initiates an inflammatory response resulting in altered neutrophil behavior and increased neutrophil-platelet interaction in the pulmonary microvasculature. Neutrophil and platelet responses were examined up to 48 hrs following whole-body, short-term EC exposure without flavorants or nicotine in a murine model, which most closely modeled secondhand exposure. This study is the first to investigate the impact of EC exposure through lung intravital imaging. Compared to room air-exposed mice, EC-exposed mice displayed significantly increased 1.7‒1.9-fold number of neutrophils in the pulmonary microvasculature associated with no marked change in neutrophils within whole blood or bronchoalveolar lavage fluid (BALF). Neutrophil-platelet interactions were also significantly elevated 1.9‒2.5-fold in exposed mice. Plasma concentration of myeloperoxidase was markedly reduced 1.5-fold 48 hr following exposure cessation, suggesting suppressed neutrophil antimicrobial activity. Cytokine expression exhibited changes indicating vascular damage. Effects persisted for 48 hr post-EC exposure. Data demonstrated that EC exposure repeated for 3 consecutive days in 2.5 hr intervals in the absence of flavorants or nicotine resulted in modified pulmonary vasculature hemodynamics, altered immune functionality, and a pro-inflammatory state in female BALB/cJ mice.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Neutrófilos , Feminino , Camundongos , Animais , Neutrófilos/metabolismo , Agregação Plaquetária , Nicotina/metabolismo , Infiltração de Neutrófilos , Aerossóis e Gotículas Respiratórios , Pulmão/metabolismo , Microvasos
4.
Part Fibre Toxicol ; 19(1): 18, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35260159

RESUMO

BACKGROUND: Pregnancy is associated with many rapid biological adaptations that support healthy development of the growing fetus. One of which is critical to fetal health and development is the coordination between maternal liver derived substrates and vascular delivery. This crucial adaptation can be potentially derailed by inhalation of toxicants. Engineered nanomaterials (ENM) are commonly used in household and industrial products as well as in medicinal applications. As such, the potential risk of exposure remains a concern, especially during pregnancy. We have previously reported that ENM inhalation leads to upregulation in the production of oxidative species. Therefore, we aimed to determine if F0 dam maternal nano-TiO2 inhalation exposure (exclusively) resulted in altered H2O2 production capacity and changes in downstream redox pathways in the F0 dams and subsequent F1 pups. Additionally, we investigated whether this persisted into adulthood within the F1 generation and how this impacted F1 gestational outcomes and F2 fetal health and development. We hypothesized that maternal nano-TiO2 inhalation exposure during gestation in the F0 dams would result in upregulated H2O2 production in the F0 dams as well as her F1 offspring. Additionally, this toxicological insult would result in gestational vascular dysfunction in the F1 dams yielding smaller F2 generation pups. RESULTS: Our results indicate upregulation of hepatic H2O2 production capacity in F0 dams, F1 offspring at 8 weeks and F1 females at gestational day 20. H2O2 production capacity was accompanied by a twofold increase in phosphorylation of the redox sensitive transcription factor NF-κB. In cell culture, naïve hepatocytes exposed to F1-nano-TiO2 plasma increased H2O2 production. Overnight exposure of these hepatocytes to F1 plasma increased H2O2 production capacity in a partially NF-κB dependent manner. Pregnant F1- nano-TiO2 females exhibited estrogen disruption (12.12 ± 3.1 pg/ml vs. 29.81 ± 8.8 pg/ml sham-control) and vascular dysfunction similar to their directly exposed mothers. F1-nano-TiO2 uterine artery H2O2 production capacity was also elevated twofold. Dysfunctional gestational outcomes in the F1-nano-TiO2 dams resulted in smaller F1 (10.22 ± 0.6 pups vs. sham-controls 12.71 ± 0.96 pups) and F2 pups (4.93 ± 0.47 g vs. 5.78 ± 0.09 g sham-control pups), and fewer F1 male pups (4.38 ± 0.3 pups vs. 6.83 ± 0.84 sham-control pups). CONCLUSION: In conclusion, this manuscript provides critical evidence of redox dysregulation across generations following maternal ENM inhalation. Furthermore, dysfunctional gestational outcomes are observed in the F1-nano-TiO2 generation and impact the development of F2 offspring. In total, this data provides strong initial evidence that maternal ENM exposure has robust biological impacts that persists in at least two generations.


Assuntos
Exposição por Inalação , NF-kappa B , Feminino , Humanos , Peróxido de Hidrogênio , Exposição por Inalação/efeitos adversos , Masculino , Oxirredução , Gravidez , Titânio
5.
Anal Chem ; 93(3): 1489-1497, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33326204

RESUMO

Enzyme-linked immunosorbent assay (ELISA) is the gold standard method for protein biomarkers. However, scaling up ELISA for multiplexed biomarker analysis is not a trivial task due to the lengthy procedures for fluid manipulation and high reagent/sample consumption. Herein, we present a highly scalable multiplexed ELISA that achieves a similar level of performance to commercial single-target ELISA kits as well as shorter assay time, less consumption, and simpler procedures. This ELISA is enabled by a novel microscale fluid manipulation method, composable microfluidic plates (cPlate), which are comprised of miniaturized 96-well plates and their corresponding channel plates. By assembling and disassembling the plates, all of the fluid manipulations for 96 independent ELISA reactions can be achieved simultaneously without any external fluid manipulation equipment. Simultaneous quantification of four protein biomarkers in serum samples is demonstrated with the cPlate system, achieving high sensitivity and specificity (∼ pg/mL), short assay time (∼1 h), low consumption (∼5 µL/well), high scalability, and ease of use. This platform is further applied to probe the levels of three protein biomarkers related to vascular dysfunction under pulmonary nanoparticle exposure in rat's plasma. Because of the low cost, portability, and instrument-free nature of the cPlate system, it will have great potential for multiplexed point-of-care testing in resource-limited regions.


Assuntos
Proteína C-Reativa/análise , Antígeno Carcinoembrionário/análise , Ensaio de Imunoadsorção Enzimática , Interleucina-6/análise , Técnicas Analíticas Microfluídicas , Antígeno Prostático Específico/análise , Biomarcadores/análise , Humanos
6.
Int J Mol Sci ; 22(22)2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34830344

RESUMO

Electronic cigarettes are frequently viewed as a safer alternative to conventional cigarettes; however, evidence to support this perspective has not materialized. Indeed, the current literature reports that electronic cigarette use is associated with both acute lung injury and subclinical dysfunction to the lung and vasculature that may result in pathology following chronic use. E-cigarettes can alter vascular dynamics, polarize innate immune populations towards a proinflammatory state, compromise barrier function in the pulmonary endothelium and epithelium, and promote pre-oncogenic phenomena. This review will summarize the variety of e-cigarette products available to users, discuss current challenges in e-cigarette study design, outline the range of pathologies occurring in cases of e-cigarette associated acute lung injury, highlight disease supporting tissue- and cellular-level changes resulting from e-cigarette exposure, and briefly examine how these changes may promote tumorigenesis. Continued research of the mechanisms by which e-cigarettes induce pathology benefit users and clinicians by resulting in increased regulation of vaping devices, informing treatments for emerging diseases e-cigarettes produce, and increasing public awareness to reduce e-cigarette use and the onset of preventable disease.


Assuntos
Lesão Pulmonar Aguda/patologia , Doenças Cardiovasculares/patologia , Sistemas Eletrônicos de Liberação de Nicotina , Neoplasias Pulmonares/patologia , Vaping/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/imunologia , Plaquetas/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Roedores , Vaping/imunologia
7.
Part Fibre Toxicol ; 17(1): 2, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924220

RESUMO

BACKGROUND: Previous studies have shown that inhalation of welding fumes may induce pulmonary and systemic inflammation and organ accumulation of metal, to which spermatogenesis and endocrine function may be sensitive. Also obesity may induce low-grade systemic inflammation. This study aimed to investigate the effects on sperm production of inhaled metal nanoparticles from stainless steel welding, and the potential exacerbation by intake of a high fat diet. Both the inbred Brown Norway and the outbred Sprague Dawley rat strains were included to study the influence of strain on the detection of toxicity. Rats were fed regular or high fat (HF) diet for 24 weeks and were exposed to 20 mg/m3 of gas metal arc-stainless steel (GMA-SS) welding fumes or filtered air for 3 h/day, 4 days/week for 5 weeks, during weeks 7-12. Outcomes were assessed upon termination of exposure (week 12) and after recovery (week 24). RESULTS: At week 12, the GMA-SS exposure induced pulmonary inflammation in both strains, without consistent changes in markers of systemic inflammation (CRP, MCP-1, IL-6 and TNFα). GMA-SS exposure lowered daily sperm production compared to air controls in Sprague Dawley rats, but only in GMA-SS Brown Norway rats also fed the HF diet. Overall, HF diet rats had lower serum testosterone levels compared to rats on regular diet. Metal content in the testes was assessed in a limited number of samples in Brown Norway rats, but no increase was obsedrved. At week 24, bronchoalveolar lavage cell counts had returned to background levels for GMA-SS exposed Sprague Dawley rats but remained elevated in Brown Norway rats. GMA-SS did not affect daily sperm production statistically significantly at this time point, but testicular weights were lowered in GMA-SS Sprague Dawley rats. Serum testosterone remained lowered in Sprague Dawley rats fed the HF diet. CONCLUSION: Exposure to GMA-SS welding fumes lowered sperm production in two strains of rats, whereas high fat diet lowered serum testosterone. The effect on sperm counts was likely not mediated by inflammation or lowered testosterone levels. The studied reproductive outcomes seemed more prone to disruption in the Sprague Dawley compared to the Brown Norway strain.


Assuntos
Poluentes Atmosféricos/toxicidade , Dieta Hiperlipídica/efeitos adversos , Exposição por Inalação/efeitos adversos , Espermatogênese/efeitos dos fármacos , Testosterona/sangue , Soldagem , Animais , Biomarcadores/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Ratos Sprague-Dawley , Especificidade da Espécie , Contagem de Espermatozoides , Aço Inoxidável
8.
Toxicol Appl Pharmacol ; 367: 51-61, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30711534

RESUMO

The fetal consequences of gestational engineered nanomaterial (ENM) exposure are unclear. The placenta is a barrier protecting the fetus and allowing transfer of substances from the maternal circulation. The purpose of this study was to determine the effects of maternal pulmonary titanium dioxide nanoparticle (nano-TiO2) exposure on the placenta and umbilical vascular reactivity. We hypothesized that pulmonary nano-TiO2 inhalation exposure increases placental vascular resistance and impairs umbilical vascular responsiveness. Pregnant Sprague-Dawley rats were exposed via whole-body inhalation to nano-TiO2 with an aerodynamic diameter of 188 ±â€¯0.36 nm. On gestational day (GD) 11, rats began inhalation exposures (6 h/exposure). Daily lung deposition was 87.5 ±â€¯2.7 µg. Animals were exposed for 6 days for a cumulative lung burden of 525 ±â€¯16 µg. On GD 20, placentas, umbilical artery and vein were isolated, cannulated, and treated with acetylcholine (ACh), angiotensin II (ANGII), S-nitroso-N-acetyl-DL-penicillamine (SNAP), or calcium-free superfusate (Ca2+-free). Mean outflow pressure was measured in placental units. ACh increased outflow pressure to 53 ±â€¯5 mmHg in sham-controls but only to 35 ±â€¯4 mmHg in exposed subjects. ANGII decreased outflow pressure in placentas from exposed animals (17 ±â€¯7 mmHg) compared to sham-controls (31 ±â€¯6 mmHg). Ca2+-free superfusate yielded maximal outflow pressures in sham-control (63 ±â€¯5 mmHg) and exposed (30 ±â€¯10 mmHg) rats. Umbilical artery endothelium-dependent dilation was decreased in nano-TiO2 exposed fetuses (30 ±â€¯9%) compared to sham-controls (58 ±â€¯6%), but ANGII sensitivity was increased (-79 ±â€¯20% vs -36 ±â€¯10%). These results indicate that maternal gestational pulmonary nano-TiO2 exposure increases placental vascular resistance and impairs umbilical vascular reactivity.


Assuntos
Hemodinâmica/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Placenta/irrigação sanguínea , Titânio/toxicidade , Animais , Feminino , Exposição por Inalação , Exposição Materna , Gravidez , Ratos Sprague-Dawley
9.
Part Fibre Toxicol ; 16(1): 24, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215478

RESUMO

BACKGROUND: Nano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). However, little is known regarding the consequences maternal ENM inhalation exposure has on growing progeny during gestation. ENM inhalation exposure has been reported to decrease mitochondrial bioenergetics and cardiac function, though the mechanisms responsible are poorly understood. Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling. RESULTS: Pregnant FVB dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.09 ± 0.26 mg/m3 starting at gestational day five (GD 5), for 6 h over 6 non-consecutive days. Aerosol size distribution measurements indicated an aerodynamic count median diameter (CMD) of 156 nm with a geometric standard deviation (GSD) of 1.70. Echocardiographic imaging was used to assess cardiac function in maternal, fetal (GD 15), and young adult (11 weeks) animals. Electron transport chain (ETC) complex activities, mitochondrial size, complexity, and respiration were evaluated, along with 5-methylcytosine, Dnmt1 protein expression, and Hif1α activity. Cardiac functional analyses revealed a 43% increase in left ventricular mass and 25% decrease in cardiac output (fetal), with an 18% decrease in fractional shortening (young adult). In fetal pups, hydrogen peroxide (H2O2) levels were significantly increased (~ 10 fold) with a subsequent decrease in expression of the antioxidant enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx4). ETC complex activity IV was decreased by 68 and 46% in fetal and young adult cardiac mitochondria, respectively. DNA methylation was significantly increased in fetal pups following exposure, along with increased Hif1α activity and Dnmt1 protein expression. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure. CONCLUSIONS: Maternal inhalation exposure to nano-TiO2 results in adverse effects on cardiac function that are associated with increased H2O2 levels and dysregulation of the Hif1α/Dnmt1 regulatory axis in fetal offspring. Our findings suggest a distinct interplay between ROS and epigenetic remodeling that leads to sustained cardiac contractile dysfunction in growing and young adult offspring following maternal ENM inhalation exposure.


Assuntos
Epigênese Genética/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Exposição Materna/efeitos adversos , Nanopartículas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Titânio/toxicidade , Animais , Feminino , Coração Fetal/citologia , Coração Fetal/efeitos dos fármacos , Coração Fetal/metabolismo , Cardiopatias/embriologia , Cardiopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nanopartículas/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Titânio/administração & dosagem
10.
Inhal Toxicol ; 31(13-14): 432-445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31874579

RESUMO

Objective: Fused filament fabrication "3-dimensional (3-D)" printing has expanded beyond the workplace to 3-D printers and pens for use by children as toys to create objects.Materials and methods: Emissions from two brands of toy 3-D pens and one brand of toy 3-D printer were characterized in a 0.6 m3 chamber (particle number, size, elemental composition; concentrations of individual and total volatile organic compounds (TVOC)). The effects of print parameters on these emission metrics were evaluated using mixed-effects models. Emissions data were used to model particle lung deposition and TVOC exposure potential.Results: Geometric mean particle yields (106-1010 particles/g printed) and sizes (30-300 nm) and TVOC yields (

Assuntos
Poluição do Ar em Ambientes Fechados/análise , Monitoramento Ambiental/métodos , Material Particulado/análise , Jogos e Brinquedos , Impressão Tridimensional , Compostos Orgânicos Voláteis/análise , Criança , Humanos , Tamanho da Partícula
11.
Am J Physiol Heart Circ Physiol ; 312(3): H446-H458, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011589

RESUMO

Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7-8 nonconsecutive days, beginning at gestational day 5-6 Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4-10 days), and young adult (6-12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle-tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E-to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano-exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction.NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Coração/diagnóstico por imagem , Miocárdio/patologia , Nanoestruturas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/patologia , Envelhecimento , Animais , Ecocardiografia , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Cardiopatias/induzido quimicamente , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Testes de Função Cardíaca , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Titânio/toxicidade
12.
J Toxicol Environ Health A ; 79(11): 447-52, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27092594

RESUMO

It is generally accepted that gestational xenobiotic exposures result in systemic consequences in the adult F1 generation. However, data on detailed behavioral and cognitive consequences remain limited. Using our whole-body nanoparticle inhalation facility, pregnant Sprague-Dawley rats (gestational day [GD] 7) were exposed 4 d/wk to either filtered air (control) or nano-titanium dioxide aerosols (nano-TiO2; count median aerodynamic diameter of 170.9 ± 6.4 nm, 10.4 ± 0.4 mg/m(3), 5 h/d) for 7.8 ± 0.5 d of the remaining gestational period. All rats received their final exposure on GD 20 prior to delivery. The calculated daily maternal deposition was 13.9 ± 0.5 µg. Subsequently, at 5 mo of age, behavior and cognitive functions of these pups were evaluated employing a standard battery of locomotion, learning, and anxiety tests. These assessments revealed significant working impairments, especially under maximal mnemonic challenge, and possible deficits in initial motivation in male F1 adults. Evidence indicates that maternal engineered nanomaterial exposure during gestation produces psychological deficits that persist into adulthood in male rats.


Assuntos
Cognição/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Titânio/toxicidade , Animais , Feminino , Masculino , Exposição Materna , Gravidez , Ratos , Ratos Sprague-Dawley
13.
Am J Physiol Heart Circ Physiol ; 309(10): H1609-20, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26386111

RESUMO

The cardiovascular response to xenobiotic particle exposure has been increasingly studied over the last two decades, producing an extraordinary scope and depth of research findings. With the flourishing of nanotechnology, the term "xenobiotic particles" has expanded to encompass not only air pollution particulate matter (PM) but also anthropogenic particles, such as engineered nanomaterials (ENMs). Historically, the majority of research in these fields has focused on pulmonary exposure and the adverse physiological effects associated with a host inflammatory response or direct particle-tissue interactions. Because these hypotheses can neither account entirely for the deleterious cardiovascular effects of xenobiotic particle exposure nor their time course, the case for substantial neurological involvement is apparent. Indeed, considerable evidence suggests that not only is neural involvement a significant contributor but also a reality that needs to be investigated more thoroughly when assessing xenobiotic particle toxicities. Therefore, the scope of this review is several-fold. First, we provide a brief overview of the major anatomical components of the central and peripheral nervous systems, giving consideration to the potential biologic targets affected by inhaled particles. Second, the autonomic arcs and mechanisms that may be involved are reviewed. Third, the cardiovascular outcomes following neurological responses are discussed. Lastly, unique problems, future risks, and hurdles associated with xenobiotic particle exposure are discussed. A better understanding of these neural issues may facilitate research that in conjunction with existing research, will ultimately prevent the untoward cardiovascular outcomes associated with PM exposures and/or identify safe ENMs for the advancement of human health.


Assuntos
Poluentes Atmosféricos/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Exposição por Inalação , Pulmão/efeitos dos fármacos , Nanoestruturas , Material Particulado/farmacologia , Xenobióticos/farmacologia , Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/inervação , Sistema Cardiovascular/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Humanos , Inflamação , Pulmão/inervação , Pulmão/fisiopatologia
14.
Am J Physiol Heart Circ Physiol ; 309(12): H2017-30, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26497962

RESUMO

Throughout the United States, air pollution correlates with adverse health outcomes, and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM), a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its roles in PM-related cardiovascular effects are not realized. In this study, we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PM MTM). To address this question, we exposed male Sprague-Dawley rats to PM MTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty-four hours following exposure, we evaluated cardiac function, apoptotic indices, and mitochondrial function. PM MTM exposure elicited a significant decrease in ejection fraction and fractional shortening compared with controls. Investigation into the cellular impacts of PM MTM exposure identified a significant increase in mitochondrial-induced apoptotic signaling, as reflected by an increase in TUNEL-positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PM MTM increases cardiac mitochondrial-associated apoptotic signaling and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptotic signaling and decreased mitochondrial function.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Poluição do Ar/efeitos adversos , Cardiopatias/induzido quimicamente , Doenças Mitocondriais/induzido quimicamente , Material Particulado/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Ecocardiografia , Exposição Ambiental , Monitoramento Ambiental , Cardiopatias/diagnóstico por imagem , Marcação In Situ das Extremidades Cortadas , Injeções Espinhais , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/diagnóstico por imagem , Contração Miocárdica/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
15.
Anal Chem ; 86(16): 8121-8, 2014 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-25068446

RESUMO

A new instrument that couples a low-pressure drift tube with a linear ion trap mass spectrometer is demonstrated for complex mixture analysis. The combination of the low-pressure separation with the ion trapping capabilities provides several benefits for complex mixture analysis. These include high sensitivity, unique ion fragmentation capabilities, and high reproducibility. Even though the gas-phase separation and the mass measurement steps are each conducted in an ion filtering mode, detection limits for mobility-selected peptide ions are in the tens of attomole range. In addition to ion separation, the low-pressure drift tube can be used as an ion fragmentation cell yielding mobility-resolved fragment ions that can be subsequently analyzed by multistage tandem mass spectrometry (MS(n)) methods in the ion trap. Because of the ion trap configuration, these methods can be comprised of any number (limited by ion signal) of collision-induced dissociation (CID) and electron transfer dissociation (ETD) processes. The high reproducibility of the gas-phase separation allows for comparison of two-dimensional ion mobility spectrometry (IMS)-MS data sets in a pixel-by-pixel fashion without the need for data set alignment. These advantages are presented in model analyses representing mixtures encountered in proteomics and metabolomics experiments.


Assuntos
Espectrometria de Massas/instrumentação , Metabolômica/instrumentação , Proteômica/instrumentação , Sequência de Aminoácidos , Animais , Proteínas Sanguíneas/análise , Misturas Complexas/análise , Desenho de Equipamento , Humanos , Íons/química , Dados de Sequência Molecular , Fosfopeptídeos/análise , Plasma/química , Pressão
16.
Adv Redox Res ; 102024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38562524

RESUMO

The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulation, and thus impacts fetal growth and development. We have previously shown that nano-titanium dioxide (nano-TiO2) inhalation exposure during gestation decreased fetal female pup and placenta mass [1], which persists in the following generation [2]. In utero exposed females, once mated, their offspring's placentas had increased capacity for H2O2 production. Generation of oxidants such as hydrogen peroxide (H2O2), have been shown to impact cyclooxygenase activity, specifically metabolites such as prostacyclin (PGI2) or thromboxane (TXA2). Therefore, we hypothesized that maternal nano-TiO2 inhalation exposure during gestation results in alterations in placental production of prostacyclin and thromboxane mediated by enhanced H2O2 production in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed to nano-TiO2 aerosols or filtered air (sham--control) from gestational day (GD) 10-19. Dams were euthanized on GD 20, and fetal serum and placental tissue were collected based on fetal sex. Fetal placental zones (junctional zone (JZ) and labyrinth zone (LZ)) were assessed for xanthine oxidoreductase (XOR) activity, H2O2, and catalase activity, as well as 6-keto-PGF1α and TXB2 levels. Nano-TiO2 exposed fetal female LZ demonstrated significantly greater XOR activity compared to exposed males. Exposed fetal female LZ also demonstrated significantly diminished catalase activity compared to sham-control females. Exposed fetal female LZ had significantly increased abundance of 6-keto-PGF1α compared to sham-control females and increased TXB2 compared to exposed males. In the aggregate these data indicate that maternal nano-TiO2 inhalation exposure has a greater impact on redox homeostasis and PGI2/TXA2 balance in the fetal female LZ. Future studies need to address if treatment with an XO inhibitor during gestation can prevent diminished fetal female growth during maternal nano-TiO2 inhalation exposure.

17.
Microcirculation ; 20(2): 158-69, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22963349

RESUMO

OBJECTIVE: Air pollution PM is associated with cardiovascular morbidity and mortality. In Appalachia, PM from mining may represent a health burden to this sensitive population that leads the nation in cardiovascular disease, among others. Cardiovascular consequences following inhalation of PM(MTM) are unclear, but must be identified to establish causal effects. METHODS: PM was collected within 1 mile of an active MTM site in southern WV. The PM was extracted and was primarily <10 µm in diameter (PM10), consisting largely of sulfur (38%) and silica (24%). Adult male rats were IT with 300 µg PM(MTM) . Twenty-four hours following exposure, rats were prepared for intravital microscopy, or isolated arteriole experiments. RESULTS: PM(MTM) exposure blunted endothelium-dependent dilation in mesenteric and coronary arterioles by 26%, and 25%, respectively, as well as endothelium-independent dilation. In vivo, PM(MTM) exposure inhibited endothelium-dependent arteriolar dilation (60% reduction). α-adrenergic receptor blockade inhibited PVNS-induced vasoconstriction in exposed animals compared with sham. CONCLUSIONS: These data suggest that PM(MTM) exposure impairs microvascular function in disparate microvascular beds, through alterations in NO-mediated dilation and sympathetic nerve influences. Microvascular dysfunction may contribute to cardiovascular disease in regions with MTM sites.


Assuntos
Poluentes Atmosféricos/toxicidade , Minas de Carvão , Microcirculação/fisiologia , Material Particulado/toxicidade , Doenças Vasculares/etiologia , Animais , Região dos Apalaches , Arteríolas/fisiopatologia , Circulação Coronária/fisiologia , Endotélio Vascular/fisiopatologia , Masculino , Metais/toxicidade , Microscopia/métodos , Ratos , Ratos Sprague-Dawley , Circulação Esplâncnica/fisiologia , Doenças Vasculares/fisiopatologia
18.
Am J Obstet Gynecol ; 209(3): 227.e1-11, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23643573

RESUMO

OBJECTIVE: The continued development and use of engineered nanomaterials (ENM) has given rise to concerns over the potential for human health effects. Although the understanding of cardiovascular ENM toxicity is improving, one of the most complex and acutely demanding "special" circulations is the enhanced maternal system to support fetal development. The Barker hypothesis proposes that fetal development within a hostile gestational environment may predispose/program future sensitivity. Therefore, the objective of this study was 2-fold: (1) to determine whether maternal ENM exposure alters uterine and/or fetal microvascular function and (2) test the Barker hypothesis at the microvascular level. STUDY DESIGN: Pregnant (gestation day 10) Sprague-Dawley rats were exposed to nano-titanium dioxide aerosols (11.3 ± 0.039 mg/m(3)/hr, 5 hr/d, 8.2 ± 0.85 days) to evaluate the maternal and fetal microvascular consequences of maternal exposure. Microvascular tissue isolation (gestation day 20) and arteriolar reactivity studies (<150 µm passive diameter) of the uterine premyometrial and fetal tail arteries were conducted. RESULTS: ENM exposures led to significant maternal and fetal microvascular dysfunction, which was seen as robustly compromised endothelium-dependent and -independent reactivity to pharmacologic and mechanical stimuli. Isolated maternal uterine arteriolar reactivity was consistent with a metabolically impaired profile and hostile gestational environment that impacted fetal weight. The fetal microvessels that were isolated from exposed dams demonstrated significant impairments to signals of vasodilation specific to mechanistic signaling and shear stress. CONCLUSION: To our knowledge, this is the first report to provide evidence that maternal ENM inhalation is capable of influencing fetal health and that the Barker hypothesis is applicable at the microvascular level.


Assuntos
Feto/efeitos dos fármacos , Exposição Materna/efeitos adversos , Nanoestruturas/toxicidade , Animais , Endotélio Vascular/fisiologia , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Titânio/toxicidade , Contração Uterina/efeitos dos fármacos , Útero/irrigação sanguínea , Útero/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
19.
Toxicol Pathol ; 41(2): 395-409, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23389777

RESUMO

Nanotechnology involves technology, science, and engineering in dimensions less than 100 nm. A virtually infinite number of potential nanoscale products can be produced from many different molecules and their combinations. The exponentially increasing number of nanoscale products will solve critical needs in engineering, science, and medicine. However, the virtually infinite number of potential nanotechnology products is a challenge for toxicologic pathologists. Because of their size, nanoparticulates can have therapeutic and toxic effects distinct from micron-sized particulates of the same composition. In the nanoscale, distinct intercellular and intracellular translocation pathways may provide a different distribution than that obtained by micron-sized particulates. Nanoparticulates interact with subcellular structures including microtubules, actin filaments, centrosomes, and chromatin; interactions that may be facilitated in the nanoscale. Features that distinguish nanoparticulates from fine particulates include increased surface area per unit mass and quantum effects. In addition, some nanotechnology products, including the fullerenes, have a novel and reactive surface. Augmented microscopic procedures including enhanced dark-field imaging, immunofluorescence, field-emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy are useful when evaluating nanoparticulate toxicologic pathology. Thus, the pathology assessment is facilitated by understanding the unique features at the nanoscale and the tools that can assist in evaluating nanotoxicology studies.


Assuntos
Nanotecnologia , Patologia , Toxicologia , Animais , Humanos
20.
Toxicol Sci ; 191(1): 61-78, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36303316

RESUMO

Air pollution accounts for more than 7 million premature deaths worldwide. Using ultrafine carbon black (CB) and ozone (O3) as a model for an environmental co-exposure scenario, the dose response relationships in acute pulmonary injury and inflammation were determined by generating, characterizing, and comparing stable concentrations of CB aerosols (2.5, 5.0, 10.0 mg/m3), O3 (0.5, 1.0, 2.0 ppm) with mixture CB + O3 (2.5 + 0.5, 5.0 + 1.0, 10.0 + 2.0). C57BL6 male mice were exposed for 3 h by whole body inhalation and acute toxicity determined after 24 h. CB itself did not cause any alteration, however, a dose response in pulmonary injury/inflammation was observed with O3 and CB + O3. This increase in response with mixtures was not dependent on the uptake but was due to enhanced reactivity of the particles. Benchmark dose modeling showed several-fold increase in potency with CB + O3 compared with CB or O3 alone. Principal component analysis provided insight into response relationships between various doses and treatments. There was a significant correlation in lung responses with charge-based size distribution, total/alveolar deposition, oxidant generation, and antioxidant depletion potential. Lung tissue gene/protein response demonstrated distinct patterns that are better predicted by either particle dose/aerosol responses (interleukin-1ß, keratinocyte chemoattractant, transforming growth factor beta) or particle reactivity (thymic stromal lymphopoietin, interleukin-13, interleukin-6). Hierarchical clustering showed a distinct signature with high dose and a similarity in mRNA expression pattern of low and medium doses of CB + O3. In conclusion, we demonstrate that the biological outcomes from CB + O3 co-exposure are significantly greater than individual exposures over a range of aerosol concentrations and aerosol characteristics can predict biological outcome.


Assuntos
Poluentes Atmosféricos , Pneumopatias , Lesão Pulmonar , Ozônio , Pneumonia , Camundongos , Animais , Masculino , Ozônio/toxicidade , Fuligem/toxicidade , Lesão Pulmonar/metabolismo , Aerossóis e Gotículas Respiratórios , Pneumopatias/induzido quimicamente , Pulmão , Pneumonia/metabolismo , Inflamação/metabolismo , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/metabolismo
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