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1.
Ecotoxicol Environ Saf ; 191: 110154, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954217

RESUMO

Limited evidence is available for the associations between fine particulate matter (PM2.5) constituents and daily cardiovascular disease (CVD) mortality in China. In present study, a time-series analysis was conducted to evaluate the associations of PM2.5 constituents (two carbonaceous fractions, eight water-soluble inorganic ions and fifteen elements) with daily CVD mortality in Pudong New Area of Shanghai, China, from 2014 to 2016. Results showed that the effect estimates for the associations of PM2.5 and its constituents with CVD mortality were generally strongest when using the exposures of the previous two day concentrations. The associations of organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead with daily CVD mortality were robust to the adjustment of PM2.5 total mass, their collinearity with PM2.5 total mass, and criteria gaseous air pollutants. An interquartile range increase in the previous two day concentrations of PM2.5, organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead were associated with significant increments of 2.21% (95% confidence interval [95%CI]: 0.54%, 3.88%), 2.83% (95% CIs: 1.16%, 4.50%), 1.90% (95% CIs: 0.35%, 3.45%), 2.29% (95% CIs: 0.80%, 3.77%), 0.94% (95% CIs: 0.13%, 1.75%), 1.53% (95% CIs: 0.37%, 2.69%), 2.08% (95% CIs: 0.49%, 3.68%) and 1.98% (95% CIs: 0.49%, 3.47%) in daily CVD mortality, respectively, in single-pollutant models. In conclusion, this study suggested that organic carbon, sulfate, ammonia, potassium, copper, arsenic, and lead might be mainly responsible for the associations between short-term PM2.5 exposures and increased CVD mortality in Shanghai, China.

2.
Sci Total Environ ; 707: 135989, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31874395

RESUMO

BACKGROUND: Systemic inflammation is considered one of the key mechanisms in the development of cardiovascular diseases induced by fine particulate matter (PM2.5) air pollution. However, evidence concerning the effects of various PM2.5 constituents on circulating inflammatory biomarkers were limited and inconsistent. OBJECTIVES: To evaluate the associations of short-term exposure to a variety of PM2.5 constituents with circulating inflammatory biomarkers. METHODS: We conducted a panel study from May to October 2016 among 40 healthy adults in Shanghai, China. We monitored the concentrations of 27 constituents of PM2.5. We applied linear mixed-effect models to analyze the associations of PM2.5 and its constituents with 7 inflammatory biomarkers, and further assessed the robustness of the associations by fitting models adjusting for PM2.5 mass and/or their collinearity. Benjamini-Hochberg false discovery rate was used to correct for multiple comparisons. RESULTS: The associations of PM2.5 were strongest at lag 0 d with tumor necrosis factor-α (TNF-α), at lag 1 d with interleukin-6, interleukin-8, and interleukin-17A, at lag 02 d with monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1). After correcting for multiple comparisons in all models, Cl-, K+, Si, K, As, and Pb were significantly associated with interleukin-8; SO42- and Se were marginally significantly associated with interleukin-8; SO42-, As, and Se were marginally significantly associated with TNF-α; and Si, K, Zn, As, Se, and Pb were marginally significantly associated with MCP-1. CONCLUSIONS: Our results suggested that some constituents (SO42-, Cl-, K+, and some elements) might be mainly responsible for systemic inflammation triggered by short-term PM2.5 exposure.

3.
Sci Total Environ ; 695: 133780, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31416039

RESUMO

BACKGROUND: The identification of constituents of fine particulate matter (PM2.5) air pollution that had key impacts of ischemic stroke (the predominant subtype of stroke) is important to understand the underlying biological mechanisms and develop air pollution control policies. OBJECTIVES: To explore the associations between PM2.5 constituents and hospitalization for ischemic stroke in Shanghai, China. METHODS: We conducted a time-series study to explore the associations between 27 constituents of PM2.5 and hospitalization for ischemic stroke in Shanghai, China from 2014 to 2016. The over-dispersed generalized additive models with adjustment for time, day of week, holidays, and weather conditions were used to estimate the associations. We also evaluated the robustness of the effect estimates for each constituent after adjusting for the confounding effects of PM2.5 total mass and gaseous pollutants and the collinearity (the residual) between this constituent and PM2.5 total mass. We also compared the associations between seasons. RESULTS: In total, we identified 4186 ischemic stroke hospitalizations during the study period. The associations of ischemic stroke were consistently significant with elemental carbon and several elemental constituents (Chromium, Iron, Copper, Zinc, Arsenic, Selenium, and Lead) at lag 1 day in single-constituent models, models adjusting for PM2.5 total mass or gaseous pollutants and models adjusting for collinearity. The associations were much stronger in cool season than in warm season. CONCLUSIONS: The current study provides suggestive evidence that elemental carbon and some metallic elements may be mainly responsible for the risks of ischemic stroke hospitalization induced by short-term PM2.5 exposure.


Assuntos
Poluição do Ar/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Material Particulado/análise , Acidente Vascular Cerebral/epidemiologia , Poluentes Atmosféricos , China/epidemiologia , Hospitalização/estatística & dados numéricos
4.
Part Fibre Toxicol ; 16(1): 27, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266526

RESUMO

BACKGROUND: Obesity is an uncontrolled global epidemic and one of the leading global public health challenges. Maternal exposure to ambient fine particulate matter (PM2.5) may adversely program offspring's adiposity, suggesting a specialized role of PM2.5 pollution in the global obesity epidemic. However, the vulnerable window for this adverse programming and how it is cross-generationally transmitted have not been determined. Therefore, in the present study, female C57Bl/6 J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during different periods, and the development and adulthood adiposity of their four-generational offspring were assessed. RESULTS: Our data show that the pre-conceptional but not gestational exposure to CAP was sufficient to cause male but not female offspring's low birth weight, accelerated postnatal weight gain, and increased adulthood adiposity. These adverse developmental traits were transmitted into the F2 offspring born by the female but not male F1 offspring of CAP-exposed dams. In contrast, no adverse development was noted in the F3 offspring. CONCLUSIONS: The present study identified a pre-conceptional window for the adverse programming of adiposity by maternal exposure to PM2.5, and showed that it was maternally transmitted into the third generation. These data not only call special attention to the protection of women from exposure to PM2.5, but also may facilitate the development of intervention to prevent this adverse programming.


Assuntos
Adiposidade/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Exposição Materna/efeitos adversos , Obesidade/induzido quimicamente , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adiposidade/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Predisposição Genética para Doença , Recém-Nascido de Baixo Peso , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Tamanho da Partícula , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Sexuais , Ganho de Peso
5.
Environ Int ; 131: 105019, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31330363

RESUMO

BACKGROUND: Fine particulate matter (PM2.5) has been widely associated with airway inflammation represented by increased fractional concentration of exhaled nitric oxide (FeNO). However, it remains unclear whether various PM2.5 constituents have different impacts on FeNO and its production process from the arginase (ARG)-nitric oxide synthase (NOS) pathway. OBJECTIVES: To investigate the acute effects of PM2.5 constituents on FeNO and DNA methylation of genes involved. METHODS: We conducted a longitudinal panel study among 43 young adults in Shanghai, China from May to October in 2016. We monitored the concentrations of 25 constituents of PM2.5. We applied the linear mixed-effect model to evaluate the associations of PM2.5 constituents with FeNO and DNA methylation of the ARG2 and NOS2A genes. RESULTS: Following PM2.5 exposure, NOS2A methylation decreased and ARG2 methylation increased only on the concurrent day, whereas FeNO increased most prominently on the second day. Nine constituents (OC, EC, K, Fe, Zn, Ba, Cr, Se, and Pb) showed consistent associations with elevated FeNO and decreased NOS2A methylation or increased ARG2 methylation in single-constituent models and models adjusting for PM2.5 total mass and collinearity. An interquartile range increase of these constituents was associated with respective decrements of 0.27-1.20 in NOS2A methylation (%5mC); increments of 0.48-1.56 in ARG2 methylation (%5mC); and increments of 7.12%-17.54% in FeNO. CONCLUSIONS: Our results suggested that OC, EC, and some metallic elements may be mainly responsible for the development and epigenetic regulation of airway inflammatory response induced by short-term PM2.5 exposure.


Assuntos
Arginase/metabolismo , Metilação de DNA/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Material Particulado/farmacologia , Adulto , China , Expiração , Feminino , Humanos , Estudos Longitudinais , Masculino , Material Particulado/análise , Adulto Jovem
6.
J Liver ; 8(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341723

RESUMO

Liver fibrosis is a serious, life-threatening disease with high morbidity and mortality that result from diverse causes. Liver biopsy, considered the "gold standard" to diagnose, grade, and stage liver fibrosis, has limitations in terms of invasiveness, cost, sampling variability, inter-observer variability, and the dynamic process of fibrosis. Compelling evidence has demonstrated that all stages of fibrosis are reversible if the injury is removed. There is a clear need for safe, effective, and reliable non-invasive assessment modalities to determine liver fibrosis in order to manage it precisely in personalized medicine. However, conventional imaging methods used to assess morphological and structural changes related to liver fibrosis, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), are only useful in assessing advanced liver disease, including cirrhosis. Functional imaging techniques, including MR elastography (MRE), US elastography, and CT perfusion are useful for assessing moderate to advanced liver fibrosis. MRE is considered the most accurate noninvasive imaging technique, and US elastography is currently the most widely used noninvasive means. However, these modalities are less accurate in early-stage liver fibrosis and some factors affect the accuracy of these techniques. Molecular imaging is a target-specific imaging mechanism that has the potential to accurately diagnose early-stage liver fibrosis. We provide an overview of recent advances in molecular imaging for the diagnosis and staging of liver fibrosis which will enable clinicians to monitor the progression of disease and potentially reverse liver fibrosis. We compare the promising technologies with conventional and functional imaging and assess the utility of molecular imaging in precision and personalized clinical medicine in the early stages of liver fibrosis.

7.
Environ Health Perspect ; 127(5): 57009, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095431

RESUMO

BACKGROUND: Pulmonary inflammation is believed to be central to the pathogenesis due to exposure to fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]). This central role, however, has not yet been systemically examined. OBJECTIVE: In the present study, we exploited a lung epithelial cell-specific inhibitor [Formula: see text] kinase 2 (IKK2) knockout mouse model to determine the role of pulmonary inflammation in the pathophysiology due to exposure to diesel exhaust particulate matter (DEP). METHODS: [Formula: see text] (lung epithelial cell-specific IKK2 knockout, KO) and [Formula: see text] (wild-type, tgWT) mice were intratracheally instilled with either vehicle or DEP for 4 months, and their inflammatory response and glucose homeostasis were then assessed. RESULTS: In comparison with tgWT mice, lung epithelial cell-specific IKK2-deficient mice had fewer DEP exposure-induced bronchoalveolar lavage fluid immune cells and proinflammatory cytokines as well as fewer DEP exposure-induced circulating proinflammatory cytokines. Glucose and insulin tolerance tests revealed that lung epithelial cell-specific IKK2 deficiency resulted in markedly less DEP exposure-induced insulin resistance and greater glucose tolerance. Akt phosphorylation analyses of insulin-responsive tissues showed that DEP exposure primarily targeted hepatic insulin sensitivity. Lung epithelial cell-specific IKK2-deficient mice had significantly lower hepatic insulin resistance than tgWT mice had. Furthermore, this difference in insulin resistance was accompanied by consistent differences in hepatic insulin receptor substrate 1 serine phosphorylation and inflammatory marker expression. DISCUSSION: Our findings suggest that in a tissue-specific knockout mouse model, an IKK2-dependent pulmonary inflammatory response was essential for the development of abnormal glucose homeostasis due to exposure to DEP. https://doi.org/10.1289/EHP4591.

8.
Environ Pollut ; 247: 953-963, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30823350

RESUMO

Chronic ambient fine particulate matter (PM2.5) exposure correlates with various adverse health outcomes. Its impact on the circulating metabolome-a comprehensive functional readout of the interaction between an organism's genome and environment-has not however been fully understood. This study thus performed metabolomics analyses using a chronic PM2.5 exposure mouse model. C57Bl/6J mice (female) were subjected to inhalational concentrated ambient PM2.5 (CAP) or filtered air (FA) exposure for 10 months. Their sera were then analyzed by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). These analyses identified 2570 metabolites in total, and 148 of them were significantly different between FA- and CAP-exposed mice. The orthogonal partial least-squares discriminant analysis (OPLS-DA) and heatmap analyses displayed evident clustering of FA- and CAP-exposed samples. Pathway analyses identified 6 perturbed metabolic pathways related to amino acid metabolism. In contrast, biological characterization revealed that 71 differential metabolites were related to lipid metabolism. Furthermore, our results showed that CAP exposure increased stress hormone metabolites, 18-oxocortisol and 5a-tetrahydrocortisol, and altered the levels of circadian rhythm biomarkers including melatonin, retinal and 5-methoxytryptophol.


Assuntos
Poluentes Atmosféricos/toxicidade , Redes e Vias Metabólicas/efeitos dos fármacos , Material Particulado/toxicidade , Filtros de Ar , Animais , Biomarcadores/metabolismo , Cromatografia Líquida , Feminino , Filtração , Cromatografia Gasosa-Espectrometria de Massas , Hidrocortisona/análogos & derivados , Hidrocortisona/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Espectrometria de Massas , Metabolômica , Camundongos Endogâmicos C57BL
9.
Arterioscler Thromb Vasc Biol ; 38(11): 2651-2664, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354243

RESUMO

Objective- Mutations affecting contractile-related proteins in the ECM (extracellular matrix), microfibrils, or vascular smooth muscle cells can predispose the aorta to aneurysms. We reported previously that the LRP1 (low-density lipoprotein receptor-related protein 1) maintains vessel wall integrity, and smLRP1-/- mice exhibited aortic dilatation. The current study focused on defining the mechanisms by which LRP1 regulates vessel wall function and integrity. Approach and Results- Isometric contraction assays demonstrated that vasoreactivity of LRP1-deficient aortic rings was significantly attenuated when stimulated with vasoconstrictors, including phenylephrine, thromboxane receptor agonist U-46619, increased potassium, and L-type Ca2+ channel ligand FPL-64176. Quantitative proteomics revealed proteins involved in actin polymerization and contraction were significantly downregulated in aortas of smLRP1-/- mice. However, studies with calyculin A indicated that although aortic muscle from smLRP1-/- mice can contract in response to calyculin A, a role for LRP1 in regulating the contractile machinery is not revealed. Furthermore, intracellular calcium imaging experiments identified defects in calcium release in response to a RyR (ryanodine receptor) agonist in smLRP1-/- aortic rings and cultured vascular smooth muscle cells. Conclusions- These results identify a critical role for LRP1 in modulating vascular smooth muscle cell contraction by regulating calcium signaling events that potentially protect against aneurysm development.


Assuntos
Citoesqueleto de Actina/metabolismo , Sinalização do Cálcio , Proteínas do Citoesqueleto/metabolismo , Músculo Liso Vascular/metabolismo , Receptores de LDL/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Vasoconstrição , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/ultraestrutura , Animais , Aorta/metabolismo , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/ultraestrutura , Receptores de LDL/deficiência , Receptores de LDL/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Técnicas de Cultura de Tecidos , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
10.
J Mol Endocrinol ; 61(4): 153-161, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30021757

RESUMO

Numerous studies have implicated tumor necrosis factor α (TNFα) in the pathogenesis of type 2 diabetes. However, the role of its primary receptor, TNF receptor 1 (TNFR1), in homeostatic regulation of glucose metabolism is still controversial. In addition to TNFα, lymphotoxin α (LTα) binds to and activates TNFR1. Thus, TNFα and LTα together are known as TNF. To delineate the role of TNF signaling in glucose homeostasis, the present study ascertained how TNF signaling deficiency affects major regulatory components of glucose homeostasis. To this end, normal diet-fed male TNFR1 deficient mice (TNFR1-/-), TNFα/LTα/LTß triple deficient mice (TNF/LT∆3), and their littermate controls were subjected to intraperitoneal glucose tolerance test, insulin tolerance test, and oral glucose tolerance test. The present results showed that TNFR1-/- and TNF/LT∆3 mice versus their controls had comparable body weight, tolerance to intraperitoneal glucose, and sensitivity to insulin. However, their tolerance to oral glucose was significantly increased. Additionally, glucose-induced insulin secretion assessments revealed that TNFR1 or TNF/LT deficiency significantly increased oral but not intraperitoneal glucose-induced insulin secretion. Consistently, qPCR and immunohistochemistry analyses showed that TNFR1-/- and TNF/LT∆3 mice versus their controls had significantly increased ileal expression of glucagon-like peptide-1 (GLP-1), one of the primary incretins. Their oral glucose-induced secretion of GLP-1 was also significantly increased. These data collectively suggest that physiological TNF signaling regulates glucose metabolism primarily through effects on GLP-1 expression and secretion and subsequently insulin secretion.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Peptídeo 1 Semelhante ao Glucagon/genética , Insulina/genética , Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/genética
11.
Environ Int ; 119: 186-192, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29960262

RESUMO

Fine particulate matter (PM2.5) has recently been associated with the activation of the hypothalamus-pituitary-adrenal (HPA) axis, increasing cardiometabolic risks. However, it is unknown which constituents of PM2.5 were mainly responsible for these associations. In a longitudinal panel study with 4 repeated measurements among 43 college students in Shanghai, China, we measured serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol, as indicators of HPA axis activation. Then, we evaluated the associations of 22 constituents of PM2.5 with these stress hormones using linear mixed-effect models. During the study period, the average daily concentration of PM2.5 was 41.1 µg/m3. We found that short-term exposure to PM2.5 was associated with elevated levels of the 3 stress hormones. We observed that water-soluble inorganic ions, especially nitrate (NO3-) and ammonium, had stronger influences on 3 hormones. Six metallic elements, including Zn, Mn, Cu, Fe, Br, and Cr, had positive but generally instable associations with 3 hormones. The effects of organic carbon and elemental carbon on hormones were generally weak. When correcting for multiple comparisons using false discovery rate, NO3- was still significantly associated with CRH, but other important associations turned to be insignificant. An interquartile range increase in NO3- on the previous day were associated with 12.13% increase (95% confidence interval: 4.45%, 20.37%) in CRH. Our findings suggested that water-soluble inorganic constituents of PM2.5 (especially, NO3-) might have stronger influences on the activation of HPA axis than carbonaceous and elemental components.


Assuntos
Poluentes Atmosféricos/análise , Hormônio Liberador da Corticotropina/sangue , Sistema Hipotálamo-Hipofisário/fisiologia , Material Particulado/análise , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/sangue , China , Humanos , Hidrocortisona/sangue , Estudos Longitudinais , Estudantes/estatística & dados numéricos , Universidades
12.
Part Fibre Toxicol ; 15(1): 17, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665823

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) correlates with abnormal glucose homeostasis, but the underlying biological mechanism has not been fully understood. The gut microbiota is an emerging crucial player in the homeostatic regulation of glucose metabolism. Few studies have investigated its role in the PM2.5 exposure-induced abnormalities in glucose homeostasis. METHODS: C57Bl/6J mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) for 12 months using a versatile aerosol concentration enrichment system (VACES) that was modified for long-term whole-body exposures. Their glucose homeostasis and gut microbiota were examined and analysed by correlation and mediation analysis. RESULTS: Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) showed that CAP exposure markedly impaired their glucose and insulin tolerance. Faecal microbiota analysis demonstrated that the impairment in glucose homeostasis was coincided with decreased faecal bacterial ACE and Chao-1 estimators (the indexes of community richness), while there was no significant change in all faecal fungal alpha diversity estimators. The Pearson's correlation analyses showed that the bacterial richness estimators were correlated with glucose and insulin tolerance, and the mediation analyses displayed a significant mediation of CAP exposure-induced glucose intolerance by the alteration in the bacterial Chao-1 estimator. LEfSe analyses revealed 24 bacterial and 21 fungal taxa differential between CAP- and FA-exposed animals. Of these, 14 and 20 bacterial taxa were correlated with IPGTT AUC and ITT AUC, respectively, and 5 fungal taxa were correlated with abnormalities in glucose metabolism. CONCLUSIONS: Chronic exposure to PM2.5 causes gut dysbiosis and may subsequently contribute to the development of abnormalities in glucose metabolism.


Assuntos
Poluentes Atmosféricos/toxicidade , Disbiose/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Material Particulado/toxicidade , Aerossóis , Animais , Disbiose/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Tamanho da Partícula
13.
Environ Health Perspect ; 126(2): 027003, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29410383

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2/NF-κB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM2.5 (CAP). OBJECTIVES: In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM2.5. METHODS: We assessed inflammatory and vascular responses in Nestin-creIKK2flox/flox (IKK2Neu-KO) and littermate Nestin-creIKK2flox/+ (control) mice after 4 mo of exposure to filtered air (FA) or CAP. RESULTS: CAP exposure was associated with significantly higher tumor necrosis factor-α (TNFα) and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2Neu-KO mice. In addition, CAP exposure-induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFα and IL-1ß levels, adipose macrophage infiltration and IL-1ß expression, and endothelial dysfunction were reduced or absent in IKK2Neu-KO mice compared with controls. CONCLUSIONS: Our findings support a role of neural IKK2 in CAP exposure-induced local and systemic pro-inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM2.5 exposure. https://doi.org/10.1289/EHP2311.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Quinase I-kappa B/genética , Inflamação/induzido quimicamente , Material Particulado/toxicidade , Tecido Adiposo/patologia , Poluentes Atmosféricos/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/fisiopatologia , Exposição Ambiental/efeitos adversos , Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Inflamação/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tamanho da Partícula
14.
Mol Imaging ; 17: 1536012117749051, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29318932

RESUMO

Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease-induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.


Assuntos
Comportamento Animal , Creatina/metabolismo , Comportamento Alimentar , Espectroscopia de Prótons por Ressonância Magnética , Taurina/metabolismo , Tálamo/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Etanol , Feminino , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Atividade Motora , Degeneração Neural/complicações , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/metabolismo , Neurônios/patologia , Projetos Piloto , Reprodutibilidade dos Testes , Tálamo/fisiopatologia
15.
Am J Physiol Endocrinol Metab ; 315(1): E72-E80, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29351483

RESUMO

Environmental stressors that encounter in early-life and cause abnormal fetal and/or neonatal development may increase susceptibility to non-communicable diseases such as diabetes. Maternal exposure to ambient fine particulate matter (PM2.5) is associated with various fetal abnormalities, suggesting that it may program offspring's susceptibility to diabetes. In the present study, we therefore examined whether maternal exposure to diesel exhaust PM2.5 (DEP), one of the major sources of ambient PM2.5 in urban areas, programs adult offspring's glucose metabolism. Female C57Bl/6J mice were intratracheally instilled with DEP or vehicle throughout a 7-wk preconceptional period, gestation, and lactation, and the glucose homeostasis of their adult male offspring was assessed. Intraperitoneal glucose tolerance test (IPGTT) revealed that the maternal exposure to DEP significantly impaired adult male offspring's glucose tolerance. Unexpectedly, it did not influence their insulin sensitivity, whereas it significantly decreased their glucose-induced insulin secretion (GIIS). This deficit in insulin secretion was corroborated by their significant decrease in arginine-induced insulin secretion. Histological analysis demonstrated that the deficit in insulin secretion was accompanied by the decrease in pancreatic islet and ß cell sizes. To differentiate the effects of maternal exposure to DEP before birth and during lactation, some offspring were cross-fostered once born. We did not observe any significant effect of cross-fostering on the glucose homeostasis of adult male offspring and the function and morphology of their ß cells. Prenatal exposure to DEP programs the morphology and function of ß cells and thus homeostatic regulation of glucose metabolism in adult male offspring.


Assuntos
Poluentes Atmosféricos/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Material Particulado/toxicidade , Emissões de Veículos/toxicidade , Animais , Tamanho Celular/efeitos dos fármacos , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo
16.
Toxicol Sci ; 162(1): 318-326, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165613

RESUMO

Epidemiological studies link ambient fine particulate matter (PM2.5) pollution to abnormalities in the male reproductive system. However, few toxicological studies have investigated this potentially important adverse effect of PM2.5 pollution. Therefore, in the present study, we analyzed the effects of PM2.5 exposure on spermatogenesis and hypothalamic-pituitary-gonadal (HPG) axis in a murine model. Fourteen male C57BL/6J mice were subjected to a 4-month exposure to filtered air or concentrated ambient PM2.5 (CAP). Their sperm count, testicular histology, spermatogenic parameters, and the major components of HPG axis were assessed. Exposure to CAP significantly reduced sperm count in the epididymis. This was accompanied by Sertoli cell vacuolization, immature germ cell dislocation, and decreases in pachytene spermatocytes and round spermatids of stage VII seminiferous tubules, suggesting a marked impairment of spermatogenesis in these mice. This impairment of spermatogenesis appeared to be attributable to a suppression of HPG axis subsequent to CAP exposure-induced hypothalamic inflammation, as exposure to CAP significantly increased TNFα and IL1b mRNA levels and meanwhile decreased gonadotropin-releasing hormone mRNA expression in the hypothalamus. Moreover, CAP exposure significantly reduced circulating testosterone and follicle-stimulating hormone, testicular testosterone and mRNA expression of follicle-stimulating hormone target gene SHBG and luteinizing hormone target genes P450scc, 17ßHSD, and StAR. The present data demonstrate that exposure to ambient PM2.5 impairs spermatogenesis in murine model, raising the concern over effects of ambient PM2.5 pollution on the male reproductive function.


Assuntos
Poluentes Atmosféricos/toxicidade , Genitália Masculina/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Material Particulado/toxicidade , Espermatogênese/efeitos dos fármacos , Animais , Citocinas/genética , Relação Dose-Resposta a Droga , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/genética , Genitália Masculina/metabolismo , Genitália Masculina/patologia , Hormônio Liberador de Gonadotropina/genética , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Exposição por Inalação/efeitos adversos , Exposição por Inalação/análise , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Contagem de Espermatozoides , Testosterona/sangue , Testosterona/genética , Fatores de Tempo
17.
J Liver ; 7(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30906674

RESUMO

Background: In vivo proton magnetic resonance spectroscopy (1H MRS) has been used to semi-quantify hepatic lipids in preclinical and clinical studies of fatty liver disease. Quantifying absolute amount of liver lipids utilizing 1H MRS and computerized tomography (CT) is essential to accurately interpret hepatic steatosis. Purpose: To establish reliable parameters to convert relative hepatic lipid levels obtained by 1H-MRS and liver volumes by CT to the absolute amount of liver lipids in a mild hepatic steatosis, and to determinate the correlation between these absolute liver lipids with liver triglyceride (TG) and cholesterol (Chol) measured by biochemistry assays. Methods: Mild steatosis was induced in mice by a 3 week ethanol diet containing standard lipids. Evaporated liver water was measured after baking liver tissues and volume of liver was measured using water displacement. 1H MRS semiquantitation of hepatic lipids and CT measurement of liver volume were performed and then used to calculate amount of liver lipids. These data were compared with liver TG and Chol. Results: Percentage of liver water and liver density were persistent in two groups and were used to convert the percentage of liver lipids to liver water by 1H-MRS to the absolute amount of liver lipids per gram of liver or per milliliter of CT volume. Using 1H-MRS and biochemical assays, an increase of liver lipids was confirmed in mild steatosis mice compared to controls (P<0.01). The amounts of imaging detected liver lipids were strongly correlated to liver TG and Chol measured by biochemical assays in mild steatosis mice. Conclusion: 1H MRS and CT liver imaging techniques are able to quantify absolute hepatic lipid levels utilizing relative persistent parameters percentage of liver water and liver density in a preclinical mild steatosis setting.

18.
Toxicol Sci ; 160(1): 4-14, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29036520

RESUMO

The lung is constantly exposed to ambient pollutants such as ambient fine particulate matter (PM2.5), making it one of the most frequent locations of inflammation in the body. Given the establishment of crucial role of inflammation in the pathogenesis of cardiometabolic diseases, pulmonary inflammation is thus widely believed to be an important risk factor for cardiometabolic diseases. However, the causality between them has not yet been well established. To determine if pulmonary inflammation is sufficient to cause adverse cardiometabolic effects, SFTPC-rtTA+/-tetO-cre+/-pROSA-inhibitor κB kinase 2(IKK2)ca+/- (LungIKK2ca) and littermate SFTPC-rtTA+/-tetO-cre-/-pROSA-IKK2ca+/- wildtype (WT) mice were fed with doxycycline diet to induce constitutively active Ikk2 (Ikk2ca) overexpression in the lung and their pulmonary, systemic, adipose, and hypothalamic inflammations, vascular function, and glucose homeostasis were assessed. Feeding with doxycycline diet resulted in IKK2ca overexpression in the lungs of LungIKK2ca but not WT mice. This induction of IKK2ca was accompanied by marked pulmonary inflammation as evidenced by significant increases in bronchoalveolar lavage fluid leukocytes, pulmonary macrophage infiltration, and pulmonary mRNA expression of tumor necrosis factor α (Tnfα) and interleukin-6 (Il-6). This pulmonary inflammation due to lung-specific overexpression of IKK2ca was sufficient to increase circulating TNFα and IL-6 levels, adipose expression of Tnfα and Il-6 mRNA, aortic endothelial dysfunction, and systemic insulin resistance. Unexpectedly, no significant alteration in hypothalamic expression of Tnfα and Il-6 mRNA and glucose intolerance were observed in these mice. Pulmonary inflammation is sufficient to induce systemic inflammation, endothelial dysfunction, and insulin resistance, but not hypothalamic inflammation and glucose intolerance.


Assuntos
Tecido Adiposo/enzimologia , Encefalite/enzimologia , Intolerância à Glucose/enzimologia , Hipotálamo/enzimologia , Quinase I-kappa B/metabolismo , Pulmão/enzimologia , Paniculite/enzimologia , Pneumonia/enzimologia , Animais , Aorta/enzimologia , Aorta/fisiopatologia , Glicemia/metabolismo , Encefalite/genética , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Predisposição Genética para Doença , Intolerância à Glucose/sangue , Intolerância à Glucose/genética , Quinase I-kappa B/genética , Resistência à Insulina , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/patologia , Camundongos Transgênicos , Paniculite/genética , Fenótipo , Pneumonia/genética , Pneumonia/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Toxicology ; 390: 100-108, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28917655

RESUMO

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with increased cardiometabolic morbidity and mortality. This is widely believed to be attributable to PM2.5 exposure-induced pulmonary and subsequent systemic inflammation. Tumor necrosis factor alpha (TNFα), lymphotoxin α (LTα), and lymphotoxin ß (LTß) are three homologous pro-inflammatory cytokines, each with both unique and redundant activities in inflammation. Their role in PM2.5 exposure-induced inflammation and adverse cardiometabolic effects has to be determined. METHODS AND RESULTS: LTα/TNFα/LTß triple-knockout (TNF/LT KO) and wildtype (WT) mice were exposed to concentrated ambient PM2.5 (CAP) for 5 months. Lung pathological analysis revealed that TNF/LT deficiency reduced CAP exposure-induced pulmonary inflammation. However, glucose homeostasis assessments showed that TNF/LT deficiency significantly aggravated CAP exposure-induced glucose intolerance and insulin resistance. Consistent with glucose homeostasis assessments, CAP exposure significantly increased the body weight and adiposity of TNF/LT KO but not WT mice. In contrast to its body weight effects, CAP exposure reduced food intake of WT but not TNF/LT KO mice. On the other hand, CAP exposure induced marked fat droplet accumulation in brown adipose tissues of WT mice and significantly decreased their uncoupling protein 1 (UCP1) expression, and these effects were markedly exacerbated in TNF/LT KO mice. CONCLUSION: The present study suggests that TNF/LT deficiency influences PM2.5 exposure-induced response of energy metabolism through alterations in both food intake and energy expenditure.


Assuntos
Inativação Gênica , Transtornos do Metabolismo de Glucose/induzido quimicamente , Linfotoxina-alfa/deficiência , Linfotoxina-beta/deficiência , Obesidade/induzido quimicamente , Material Particulado/toxicidade , Pneumonia/prevenção & controle , Fator de Necrose Tumoral alfa/deficiência , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Genótipo , Transtornos do Metabolismo de Glucose/genética , Transtornos do Metabolismo de Glucose/metabolismo , Insulina/sangue , Resistência à Insulina , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Linfotoxina-alfa/genética , Linfotoxina-beta/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Tamanho da Partícula , Fenótipo , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/genética , Proteína Desacopladora 1/metabolismo
20.
Circulation ; 136(7): 618-627, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28808144

RESUMO

BACKGROUND: Exposure to ambient particulate matter (PM) is associated with a number of adverse health outcomes, but potential mechanisms are largely unknown. Metabolomics represents a powerful approach to study global metabolic changes in response to environmental exposures. We therefore conducted this study to investigate changes in serum metabolites in response to the reduction of PM exposure among healthy college students. METHODS: We conducted a randomized, double-blind crossover trial in 55 healthy college students in Shanghai, China. Real and sham air purifiers were placed in participants' dormitories in random order for 9 days with a 12-day washout period. Serum metabolites were quantified by using gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-mass spectrometry. Between-treatment differences in metabolites were examined using orthogonal partial least square-discriminant analysis and mixed-effect models. Secondary outcomes include blood pressure, corticotropin-releasing hormone, adrenocorticotropic hormone, insulin resistance, and biomarkers of oxidative stress and inflammation. RESULTS: The average personal exposure to PMs with aerodynamic diameters ≤2.5 µm was 24.3 µg/m3 during the real purification and 53.1 µg/m3 during the sham purification. Metabolomics analysis showed that higher exposure to PMs with aerodynamic diameters ≤2.5 µm led to significant increases in cortisol, cortisone, epinephrine, and norepinephrine. Between-treatment differences were also observed for glucose, amino acids, fatty acids, and lipids. We found significantly higher blood pressure, hormones, insulin resistance, and biomarkers of oxidative stress and inflammation among individuals exposed to higher PMs with aerodynamic diameters ≤2.5 µm. CONCLUSIONS: This study suggests that higher PM may induce metabolic alterations that are consistent with activations of the hypothalamus-pituitary-adrenal and sympathetic-adrenal-medullary axes, adding potential mechanistic insights into the adverse health outcomes associated with PM. Furthermore, our study demonstrated short-term reductions in stress hormone following indoor air purification. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02712333.


Assuntos
Filtros de Ar , Hormônios/sangue , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Biomarcadores/sangue , China , Cromatografia Líquida de Alta Pressão , Cortisona/sangue , Estudos Cross-Over , Método Duplo-Cego , Exposição Ambiental , Epinefrina/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Hidrocortisona/sangue , Hipertensão/etiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metabolômica , Material Particulado/análise , Adulto Jovem
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