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1.
Toxicol Appl Pharmacol ; 469: 116526, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37088303

RESUMO

Air pollution is associated with increased risk of metabolic diseases including type 2 diabetes, of which dysregulation of the insulin-signaling pathway is a feature. While studies suggest pollutant exposure alters insulin signaling in certain tissues, there is a lack of comparison across multiple tissues needed for a holistic assessment of metabolic effects, and underlying mechanisms remain unclear. Air pollution increases plasma levels of glucocorticoids, systemic regulators of metabolic function. The objectives of this study were to 1) determine effects of ozone on insulin-signaling genes in major metabolic tissues, and 2) elucidate the role of glucocorticoids. Male Fischer-344 rats were treated with metyrapone, a glucocorticoid synthesis inhibitor, and exposed to 0.8 ppm ozone or clean air for 4 h, with tissue collected immediately or 24 h post exposure. Ozone inhalation resulted in distinct mRNA profiles in the liver, brown adipose, white adipose and skeletal muscle tissues, including effects on insulin-signaling cascade genes (Pik3r1, Irs1, Irs2) and targets involved in glucose metabolism (Hk2, Pgk1, Slc2a1), cell survival (Bcl2l1), and genes associated with diabetes and obesity (Serpine1, Retn, Lep). Glucocorticoid-dependent regulation was observed in the liver and brown and white adipose tissues, while effects in skeletal muscle were largely unaffected by metyrapone treatment. Gene expression changes were accompanied by altered phosphorylation states of insulin-signaling proteins (BAD, GSK, IR-ß, IRS-1) in the liver. The results show that systemic effects of ozone inhalation include tissue-specific regulation of insulin-signaling pathway genes via both glucocorticoid-dependent and independent mechanisms, providing insight into mechanisms underlying adverse effects of pollutants.


Assuntos
Diabetes Mellitus Tipo 2 , Ozônio , Ratos , Masculino , Animais , Glucocorticoides , Insulina , Ozônio/toxicidade , Metirapona , Ratos Endogâmicos F344 , Transdução de Sinais
3.
Environ Res ; 185: 109483, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32278163

RESUMO

Air pollution is associated with adverse impacts on the brain, including cognitive decline and increased incidence of dementia, depression and anxiety; however, underlying mechanisms remain unclear. We have shown that both ozone and particulate matter activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing plasma glucocorticoids and altering mRNA profiles in multiple tissues including the brain. HPA axis dysregulation has been associated with central nervous system impacts, including key effects in the hippocampus; accordingly, we hypothesized that pollutant-dependent increases in glucocorticoid levels impact biological pathways relevant to brain health. Fischer-344 rats were treated with metyrapone (0 or 50 mg/kg), a glucocorticoid synthesis inhibitor, and exposed to ozone (0 or 0.8 ppm) for 4 h (n = 5/group) to investigate the role of glucocorticoids in ozone-dependent effects on tryptophan metabolism and expression of serotonin receptors and neurotrophic factors. Ozone increased plasma levels of the tryptophan metabolite kynurenine (~2-fold) and decreased tryptophan levels (~1.2 fold). Hippocampal expression of serotonin receptors exhibited differential regulation following exposure, and expression of key neurotrophic factors (brain-derived neurotrophic factor, vascular endothelial growth factor A, insulin-like growth factor-1, tyrosine kinase receptor B, b-cell lymphoma 2) was decreased. Some, but not all effects were abrogated by metyrapone treatment, suggesting both glucocorticoid-dependent and -independent regulation. Exposure to exogenous corticosterone (10 mg/kg) followed by clean air reproduced the ozone effects that were blocked with metyrapone, confirming the specificity of effects to glucocorticoids. These results indicate that ozone can modify pathways relevant to brain health and establish a role for the HPA axis in mediating these effects.


Assuntos
Ozônio , Animais , Hipocampo , Sistema Hipotálamo-Hipofisário , Cinurenina , Ozônio/toxicidade , Sistema Hipófise-Suprarrenal , Ratos , Receptores de Serotonina , Triptofano , Fator A de Crescimento do Endotélio Vascular
4.
Environ Res ; 178: 108717, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31520820

RESUMO

Air pollution is associated with adverse effects on brain health including cognitive decline, dementia, anxiety, depression, and suicide. While toxicological studies have demonstrated the potential for repeated or chronic pollutant exposure to lead to disease states, characterisation of initial biological responses to exposure is needed to better understand underlying mechanisms. The brain is highly sensitive to glucocorticoids (primarily cortisol in humans, corticosterone in rodents), stress hormones that play important roles in cognition and mental health. We tested whether glucocorticoids could be implicated in central nervous system (CNS) effects of pollutant exposure by examining glucocorticoid-dependent signaling across brain regions after exposure to the common pollutant ozone. Male Fischer-344 rats were exposed for 4 h to air or 0.8 ppm ozone ±â€¯metyrapone (50 mg/kg), a drug that blocks corticosterone synthesis (n = 5/group). Key glucocorticoid-responsive genes (serum- and glucocorticoid-inducible kinase, SGK; glucocorticoid-inducible leucine zipper, GILZ), and a gene responsive to both glucocorticoids and oxidative stress (metallothionein (MT)-1), were increased by ozone in all brain regions (olfactory bulb, frontal lobe, cortex, midbrain, hippocampus, cerebellum, brainstem), correlating with plasma corticosterone levels. Metyrapone prevented the increase in SGK and GILZ, and reduced but did not eliminate the effect on MT-1, suggesting glucocorticoid-dependent and -independent regulation. Administering exogenous corticosterone (10 mg/kg) to air-exposed rats reproduced the ozone effects, confirming specificity. The results demonstrate that early pollutant effects include stress hormone-dependent signaling. As both ozone and particulate matter activate the hypothalamic-pituitary-adrenal axis, and elevated glucocorticoids are implicated in brain pathologies, stress hormones could contribute to CNS impacts of air pollutants.


Assuntos
Poluentes Atmosféricos , Encéfalo/fisiologia , Exposição Ambiental/estatística & dados numéricos , Glucocorticoides/genética , Estresse Fisiológico/fisiologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário , Masculino , Sistema Hipófise-Suprarrenal , Ratos
5.
Part Fibre Toxicol ; 15(1): 34, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-30097052

RESUMO

BACKGROUND: There is a paucity of mechanistic information that is central to the understanding of the adverse health effects of source emission exposures. To identify source emission-related effects, blood and saliva samples from healthy volunteers who spent five days near a steel plant (Bayview site, with and without a mask that filtered many criteria pollutants) and at a well-removed College site were tested for oxidative stress, inflammation and endothelial dysfunction markers. METHODS: Biomarker analyses were done using multiplexed protein-array, HPLC-Fluorescence, EIA and ELISA methods. Mixed effects models were used to test for associations between exposure, biological markers and physiological outcomes. Heat map with hierarchical clustering and Ingenuity Pathway Analysis (IPA) were used for mechanistic analyses. RESULTS: Mean CO, SO2 and ultrafine particles (UFP) levels on the day of biological sampling were higher at the Bayview site compared to College site. Bayview site exposures "without" mask were associated with increased (p < 0.05) pro-inflammatory cytokines (e.g IL-4, IL-6) and endothelins (ETs) compared to College site. Plasma IL-1ß, IL-2 were increased (p < 0.05) after Bayview site "without" compared to "with" mask exposures. Interquartile range (IQR) increases in CO, UFP and SO2 were associated with increased (p < 0.05) plasma pro-inflammatory cytokines (e.g. IL-6, IL-8) and ET-1(1-21) levels. Plasma/saliva BET-1 levels were positively associated (p < 0.05) with increased systolic BP. C-reactive protein (CRP) was positively associated (p < 0.05) with increased heart rate. Protein network analyses exhibited activation of distinct inflammatory mechanisms after "with" and "without" mask exposures at the Bayview site relative to College site exposures. CONCLUSIONS: These findings suggest that air pollutants in the proximity of steel mill site can influence inflammatory and vascular mechanisms. Use of mask and multiple biomarker data can be valuable in gaining insight into source emission-related health impacts.


Assuntos
Poluentes Atmosféricos/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Citocinas/sangue , Endotelinas/análise , Exposição por Inalação/efeitos adversos , Metalurgia , Material Particulado/toxicidade , Adolescente , Adulto , Poluentes Atmosféricos/análise , Biomarcadores/análise , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/imunologia , Estudos Cross-Over , Endotelinas/sangue , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Inflamação , Exposição por Inalação/análise , Masculino , Material Particulado/análise , Proteômica , Saliva/química , Aço , Adulto Jovem
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