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1.
Toxicol Sci ; 191(1): 106-122, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36269214

RESUMO

Recent epidemiological findings link asthma to adverse cardiovascular responses. Yet, the precise cardiovascular impacts of asthma have been challenging to disentangle from the potential cardiovascular effects caused by asthma medication. The purpose of this study was to determine the impacts of allergic airways disease alone on cardiovascular function in an experimental model. Female Wistar rats were intranasally sensitized and then challenged once per week for 5 weeks with saline vehicle or a mixture of environmental allergens (ragweed, house dust mite, and Aspergillus fumigatus). Ventilatory and cardiovascular function, measured using double-chamber plethysmography and implantable blood pressure (BP) telemetry and cardiovascular ultrasound, respectively, were assessed before sensitization and after single and final allergen challenge. Responses to a single 0.5 ppm ozone exposure and to the cardiac arrhythmogenic agent aconitine were also assessed after final challenge. A single allergen challenge in sensitized rats increased tidal volume and specific airways resistance in response to provocation with methacholine and increased bronchoalveolar lavage fluid (BALF) eosinophils, neutrophils, lymphocytes, cytokines interleukin (IL)-4, IL-5, IL-10, IL-1ß, tumor necrosis factor-α, and keratinocyte chemoattract-growth-related oncogene characteristic of allergic airways responses. Lung responses after final allergen challenge in sensitized rats were diminished, although ozone exposure increased BALF IL-6, IL-13, IL-1 ß, and interferon-γ and modified ventilatory responses only in the allergen group. Final allergen challenge also increased systolic and mean arterial BP, stroke volume, cardiac output, end-diastolic volume, sensitivity to aconitine-induced cardiac arrhythmia, and cardiac gene expression with lesser effects after a single challenge. These findings demonstrate that allergic airways responses may increase cardiovascular risk in part by altering BP and myocardial function and by causing cardiac electrical instability.


Assuntos
Asma , Doenças Cardiovasculares , Hipersensibilidade , Ozônio , Ratos , Feminino , Animais , Eosinófilos/patologia , Aconitina , Doenças Cardiovasculares/patologia , Ratos Wistar , Fatores de Risco , Pulmão , Citocinas , Alérgenos/toxicidade , Líquido da Lavagem Broncoalveolar , Fatores de Risco de Doenças Cardíacas
2.
Inhal Toxicol ; 35(3-4): 59-75, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35867597

RESUMO

OBJECTIVE: Inhalation of ozone activates central sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal stress axes. While airway neural networks are known to communicate noxious stimuli to higher brain centers, it is not known to what extent responses generated from pulmonary airways contribute to neuroendocrine activation. MATERIALS AND METHODS: Unlike inhalational exposures that involve the entire respiratory tract, we employed intratracheal (IT) instillations to expose only pulmonary airways to either soluble metal-rich residual oil fly ash (ROFA) or compressor-generated diesel exhaust particles (C-DEP). Male Wistar-Kyoto rats (12-13 weeks) were IT instilled with either saline, C-DEP or ROFA (5 mg/kg) and necropsied at 4 or 24 hr to assess temporal effects. RESULTS: IT-instillation of particulate matter (PM) induced hyperglycemia as early as 30-min and glucose intolerance when measured at 2 hr post-exposure. We observed PM- and time-specific effects on markers of pulmonary injury/inflammation (ROFA>C-DEP; 24 hr>4hr) as corroborated by increases in lavage fluid injury markers, neutrophils (ROFA>C-DEP), and lymphocytes (ROFA). Increases in lavage fluid pro-inflammatory cytokines differed between C-DEP and ROFA in that C-DEP caused larger increases in TNF-α whereas ROFA caused larger increases in IL-6. No increases in circulating cytokines occurred. At 4 hr, PM impacts on neuroendocrine activation were observed through depletion of circulating leukocytes, increases in adrenaline (ROFA), and decreases in thyroid-stimulating-hormone, T3, prolactin, luteinizing-hormone, and testosterone. C-DEP and ROFA both increased lung expression of genes involved in acute stress and inflammatory processes. Moreover, small increases occurred in hypothalamic Fkbp5, a glucocorticoid-sensitive gene. CONCLUSION: Respiratory alterations differed between C-DEP and ROFA, with ROFA inducing greater overall lung injury/inflammation; however, both PM induced a similar degree of neuroendocrine activation. These findings demonstrate neuroendocrine activation after pulmonary-only PM exposure, and suggest the involvement of pituitary- and adrenal-derived hormones.


Assuntos
Poluentes Atmosféricos , Lesão Pulmonar , Ratos , Animais , Masculino , Material Particulado/toxicidade , Material Particulado/metabolismo , Poluentes Atmosféricos/toxicidade , Líquido da Lavagem Broncoalveolar , Ratos Sprague-Dawley , Ratos Endogâmicos WKY , Pulmão , Cinza de Carvão , Lesão Pulmonar/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Hormônios/metabolismo , Hormônios/farmacologia
3.
Toxicology ; 463: 152972, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34606950

RESUMO

The effects of Endocrine Disrupting Chemicals (EDCs) on the current obesity epidemic is a growing field of interest. Numerous EDCs have shown the potential to alter energy metabolism, which may increase the risk of obesity, in part, through direct actions on adipose tissue. While white adipose tissue has historically been the primary focus of this work, evidence of the EDC-induced disruption of brown and beige adipose tissues continues to build. Both brown and beige fat are thermogenic adipose depots rich in mitochondria that dispense heat when activated. Due to these properties, brown and beige fat are implicated in metabolic diseases such as obesity, diabetes, and cachexia. This review delves into the current literature of different EDCs, including bisphenols, dioxins, air pollutants, phthalates, and phytochemicals. The possible implications that these EDCs have on thermogenic adipose tissues are covered. This review also introduces the possibility of using brown and beige fat as a therapeutic target organ by taking advantage of some of the properties of EDCs. Collectively, we provide a comprehensive discussion of the evidence of EDC disruption in white, brown, and beige fat and highlight gaps worthy of further exploration.


Assuntos
Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Disruptores Endócrinos/toxicidade , Metabolismo Energético/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Obesidade/metabolismo , Termogênese/efeitos dos fármacos
4.
PLoS One ; 12(9): e0184155, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898253

RESUMO

Epithelial-mesenchymal interactions drive embryonic fusion events during development, and perturbations of these interactions can result in birth defects. Cleft palate and neural tube defects can result from genetic defects or environmental exposures during development, yet very little is known about the effect of chemical exposures on fusion events during human development because of a lack of relevant and robust human in vitro assays of developmental fusion behavior. Given the etiology and prevalence of cleft palate and the relatively simple architecture and composition of the embryonic palate, we sought to develop a three-dimensional culture system that mimics the embryonic palate and could be used to study fusion behavior in vitro using human cells. We engineered size-controlled human Wharton's Jelly stromal cell (HWJSC) spheroids and established that 7 days of culture in osteogenesis differentiation medium was sufficient to promote an osteogenic phenotype consistent with embryonic palatal mesenchyme. HWJSC spheroids supported the attachment of human epidermal keratinocyte progenitor cells (HPEKp) on the outer spheroid surface likely through deposition of collagens I and IV, fibronectin, and laminin by mesenchymal spheroids. HWJSC spheroids coated in HPEKp cells exhibited fusion behavior in culture, as indicated by the removal of epithelial cells from the seams between spheroids, that was dependent on epidermal growth factor signaling and fibroblast growth factor signaling in agreement with palate fusion literature. The method described here may broadly apply to the generation of three-dimensional epithelial-mesenchymal co-cultures to study developmental fusion events in a format that is amenable to predictive toxicology applications.


Assuntos
Bioengenharia , Técnicas de Cultura de Órgãos , Palato/embriologia , Esferoides Celulares , Fosfatase Alcalina/metabolismo , Bioengenharia/métodos , Diferenciação Celular/genética , Análise por Conglomerados , Biologia Computacional/métodos , Proteínas da Matriz Extracelular , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Técnicas In Vitro , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Palato/metabolismo , Fatores de Tempo , Transcriptoma
5.
Chem Biol Interact ; 194(1): 79-89, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21864511

RESUMO

Propiconazole induces hepatocellular carcinomas and hepatocellular adenomas in mice and promotes liver tumors in rats. Transcriptional, proteomic, metabolomic and biochemical studies of hepatic tissues from mice treated with propiconazole under the conditions of the chronic bioassay indicated that propiconazole induced oxidative stress. Here we sought to identify the source of the reactive oxygen species (ROS) induced by propiconazole using both AML12 immortalized mouse hepatocytes in culture and liver tissues from mice. We also sought to further characterize the nature and effects of ROS formation induced by propiconazole treatment in mouse liver. ROS was induced in AML12 cells by propiconazole as measured by fluorescence detection and its formation was ameliorated by N-acetylcysteine. Propiconazole induced glutathione-S-transferase (GSTα) protein levels and increased the levels of thiobarbituric acid reactive substances (TBARS) in AML12 cells. The TBARS levels were decreased by diphenylene iodonium chloride (DPIC), a cytochrome P450 (CYP) reductase inhibitor revealing the role of CYPs in ROS generation. It has been previously reported that Cyp2b and Cyp3a proteins were induced in mouse liver by propiconazole and that Cyp2b and Cyp3a proteins undergo uncoupling of their CYP catalytic cycle releasing ROS. Therefore, salicylic acid hydroxylation was used as probe for ROS formation using microsomes from mice treated with propiconazole. These studies showed that levels of 2,3-dihydroxybenzoic acid (an ROS derived metabolite) were decreased by ketoconazole, melatonin and DPIC. In vivo, propiconazole increased hepatic malondialdehyde levels and GSTα protein levels and had no effect on hepatic catalase or superoxide dismutase activities. Based on these observations we conclude that propiconazole induces ROS in mouse liver by increasing CYP protein levels leading to increased ROS levels. Our data also suggest that propiconazole induces the hydroxyl radical as a major ROS form.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Hepatócitos/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Triazóis/toxicidade , Adenoma de Células Hepáticas/metabolismo , Adenoma de Células Hepáticas/patologia , Animais , Células Cultivadas , Hepatócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos
6.
Cell Biol Toxicol ; 27(3): 207-16, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21243523

RESUMO

Gap junction communication (GJC) is involved in controlling cell proliferation and differentiation. Alterations in GJC are associated with carcinogenesis, but the mechanisms involved are unknown. Chloral hydrate (CH), a by-product of chlorine disinfection of water, is carcinogenic in mice, and we demonstrated that CH reduced GJC in a rat liver epithelial cell line (Clone 9). To examine the mechanism(s) by which CH inhibits GJC, Clone 9 cells treated with CH were examined using Western blot, real-time polymerase chain reaction, immunocytochemical, and dye-communication techniques. Treatment with CH (0.1­5 mM for 24 h) resulted in a dose-dependent inhibition of GJC as measured by Lucifer yellow dye transfer. Western blot analysis demonstrated expression of connexin (Cx) 43 and 26 in control cells and reduced expression of Cx 43 but not Cx 26 protein from 0.1 to 1 mM CH. CH treatment from 2.5 to 5 mM caused an apparent increase in expression of both connexins that was concomitant with a reduction in mRNA expression for both connexins. Similarly, with immunocytochemistry, a dose-dependent decrease in Cx 43 staining at sites of cell­cell contact was apparent in CH (0.5­5 mM)-treated cultures, whereas no Cx 26 staining was observed. Thus, Clone 9 cells contain two types of connexins but only one type of plasma membrane channel. Understanding of the regulation of connexin may shed light on mechanisms responsible for inhibition of GJC by chemical carcinogens.


Assuntos
Comunicação Celular/efeitos dos fármacos , Hidrato de Cloral/toxicidade , Células Epiteliais/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Fígado/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Linhagem Celular , Conexina 26 , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Células Epiteliais/metabolismo , Junções Comunicantes/fisiologia , Humanos , Fígado/citologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
7.
Toxicology ; 262(2): 106-13, 2009 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-19450653

RESUMO

Epidemiological studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Previous experimental studies have demonstrated increased incidence of liver, lung, ovary, and uterine tumors in mice exposed to 85 ppm (approximately 8 mg/kg) inorganic arsenic during gestation. To further characterize age susceptibility to arsenic carcinogenesis we administered 85 ppm inorganic arsenic in drinking water to C3H mice during gestation, prior to pubescence and post-pubescence to compare proliferative lesion and tumor outcomes over a one-year exposure period. Inorganic arsenic significantly increased the incidence of hyperplasia in urinary bladder (48%) and oviduct (36%) in female mice exposed prior to pubescence (beginning on postnatal day 21 and extending through one year) compared to control mice (19 and 5%, respectively). Arsenic also increased the incidence of hyperplasia in urinary bladder (28%) of female mice continuously exposed to arsenic (beginning on gestation day 8 and extending though one year) compared to gestation only exposed mice (0%). In contrast, inorganic arsenic significantly decreased the incidence of tumors in liver (0%) and adrenal glands (0%) of male mice continuously exposed from gestation through one year, as compared to levels in control (30 and 65%, respectively) and gestation only (33 and 55%, respectively) exposed mice. Together, these results suggest that continuous inorganic arsenic exposure at 85 ppm from gestation through one year increases the incidence and severity of urogenital proliferative lesions in female mice and decreases the incidence of liver and adrenal tumors in male mice. The paradoxical nature of these effects may be related to altered lipid metabolism, the effective dose in each target organ, and/or the shorter one-year observational period.


Assuntos
Neoplasias das Glândulas Suprarrenais/induzido quimicamente , Arsenitos/toxicidade , Carcinógenos/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Oviductos/efeitos dos fármacos , Compostos de Sódio/toxicidade , Bexiga Urinária/efeitos dos fármacos , Administração Oral , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Esquema de Medicação , Feminino , Hiperplasia/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Exposição Materna , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos C3H , Oviductos/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fatores de Tempo , Bexiga Urinária/patologia , Abastecimento de Água
8.
Mutat Res ; 572(1-2): 98-112, 2005 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-15790493

RESUMO

1,1-Dichloropropene (1,1-DCPe) is a contaminant of some source waters used to make drinking water. Because of this and the fact that no toxicological data were available for this compound, which is structurally similar to the rodent carcinogen 1,3-dichloropropene (1,3-DCPe), 1,1-DCPe was placed on the Contaminant Candidate List of the US Environmental Protection Agency. Consequently, we have performed a hazard characterization of 1,1-DCPe by evaluating its mutagenicity in the Salmonella assay and its DNA damaging (comet assay) and apoptotic (caspase assay) activities in human lymphoblastoid cells. In Salmonella, 1,1-DCPe was not mutagenic in strains TA98, TA100, TA1535, or TA104 +/-S9 mix. However, it was clearly mutagenic in strain RSJ100, which expresses the rat GSTT1-1 gene. 1,1-DCPe did not induce DNA damage in GSTT1-1-deficient human lymphoblastoid cells, and it induced apoptosis in these cells only at 5 mM. Consistent with its mutagenesis in RSJ100, 1,1-DCPe reacted with glutathione (GSH) in vitro, suggesting an addition-elimination mechanism to account for the detected GSH conjugate. 1,1-DCPe was approximately 5000 times more mutagenic than its ethene congener 1,1-dichloroethylene (1,1-DCE or vinylidene chloride). Neither 1,1-DCE nor 1,3-DCPe showed enhanced mutagenicity in strain RSJ100, indicating a lack of activation of these congeners by GSTT1-1. Thus, 1,1-DCPe is a base-substitution mutagen requiring activation by GSTT1-1, possibly involving the production of a reactive episulfonium ion. This bioactivation mechanism of 1,1-DCPe is different from that of its congeners 1,1-DCE and 1,3-DCPe. The presence of 1,1-DCPe in source waters could pose an ecological or human health risk. Occurrence data for 1,1-DCPe in finished drinking water are needed to estimate human exposure to, and possible health risks from, this mutagenic compound.


Assuntos
Compostos Alílicos/toxicidade , Glutationa Transferase/metabolismo , Mutagênicos/toxicidade , Poluentes Químicos da Água/toxicidade , Compostos Alílicos/metabolismo , Animais , Apoptose , Biotransformação , Linhagem Celular , Ensaio Cometa , Humanos , Hidrocarbonetos Clorados , Microssomos Hepáticos/metabolismo , Mutagênicos/metabolismo , Ratos , Salmonella typhimurium/genética , Relação Estrutura-Atividade , Poluentes Químicos da Água/metabolismo
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