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1.
Toxicol Appl Pharmacol ; 491: 117046, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39084266

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease, affecting 38% of adults globally. If left untreated, NAFLD may progress to more advanced forms of the disease, including non-alcoholic steatohepatitis (NASH), liver cirrhosis, and fibrosis. Early NAFLD detection is critical to prevent disease progression. Using an obesogenic high-fat and high-sucrose (HF/HS) diet, we characterized the progression of NAFLD in male and female Collaborative Cross CC042 mice after 20-, 40-, and 60-week intervals of chronic HF/HS diet feeding. The incidence and severity of liver steatosis, inflammation, and fibrosis increased in both sexes over time, with male mice progressing to a NASH-like disease state faster than female mice, as indicated by earlier and more pronounced changes in liver steatosis. Histopathological indication of macrovesicular steatosis and gene expression changes of key lipid metabolism genes were found to be elevated in both sexes after 20 weeks of HF/HS diet. Measurement of circulating markers of inflammation (CXCL10 and TNF-α), histopathological analysis of immune cell infiltrates, and gene expression changes in inflammation-related genes indicated significant liver inflammation after 40 and 60 weeks of HF/HS diet exposure in both sexes. Liver fibrosis, as assessed by Picosirius red and Masson's trichrome staining and changes in expression of key fibrosis related genes indicated significant changes after 40 and 60 weeks of HF/HS diet exposure. In conclusion, we present a preclinical animal model of dietary NAFLD progression, which recapitulates human pathophysiological and pathomorphological changes, that could be used to better understand the progression of NAFLD and support development of new therapeutics.


Asunto(s)
Dieta Alta en Grasa , Modelos Animales de Enfermedad , Hígado , Enfermedad del Hígado Graso no Alcohólico , Animales , Enfermedad del Hígado Graso no Alcohólico/patología , Dieta Alta en Grasa/efectos adversos , Masculino , Femenino , Ratones , Hígado/patología , Hígado/metabolismo , Hígado/efectos de los fármacos , Progresión de la Enfermedad , Sacarosa en la Dieta/efectos adversos , Metabolismo de los Lípidos/efectos de los fármacos , Cirrosis Hepática/patología , Cirrosis Hepática/inducido químicamente
2.
Atmos Environ (1994) ; 128(March 2016): 235-245, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27313488

RESUMEN

The functional and 13C isotopic compositions of water-soluble organic carbon (WSOC) in atmospheric aerosol were determined by nuclear magnetic resonance (1H-NMR) and isotope ratio mass spectrometry (IRMS) in an urban location in the Southern Mississippi Valley. The origin of WSOC was resolved using the functional distribution of organic hydrogen, δ13C ratio, and positive matrix factorization (PMF). Three factors were retained based on NMR spectral bins loadings. Two factors (factors 1 and 3) demonstrated strong associations with the aliphatic region in the NMR spectra and levoglucosan resonances. Differences between the two factors included the abundance of the aromatic functional group for factor 1, indicating fresh emissions and, for factor 3, the presence of resonances attributed to secondary ammonium nitrate and low δ13C ratio values that are indicative of secondary organic aerosol. Factors 1 and 3 added 0.89 and 1.08 µgC m-3, respectively, with the highest contribution in the summer and fall. Factor 2 retained resonances consistent with saccharides and was attributed to pollen particles. Its contribution to WSOC varied from 0.22 µgC m-3 in winter to 1.04 µgC m-3 in spring.

3.
Environ Toxicol ; 31(5): 609-23, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-25410937

RESUMEN

Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.


Asunto(s)
Piel/química , Triclosán/metabolismo , Adsorción , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Heces/química , Femenino , Masculino , Espectrometría de Masas , Ratones , Curva ROC , Piel/efectos de los fármacos , Piel/metabolismo , Distribución Tisular , Triclosán/análisis , Triclosán/farmacología
5.
J Nutr Biochem ; 109: 109108, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35858665

RESUMEN

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Colina , Ratones de Colaboración Cruzada , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ácidos Grasos , Ácidos Grasos Monoinsaturados , Ácidos Grasos no Esterificados , Ácidos Grasos Insaturados , Femenino , Ácido Fólico , Lipidómica , Hígado , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/etiología , Sacarosa
6.
Neurotoxicol Teratol ; 72: 49-57, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30738146

RESUMEN

High levels of inorganic arsenic (iAs) exposure are associated with severe health effects. Less clear are effects of lower exposure levels on neurodevelopment. Relative to maternal intake, there is limited lactational transfer of arsenic in humans or rodents, yet there are few rodent studies which directly exposed preweaning animals. To more clearly determine iAs developmental neurotoxicity, 28 pregnant Sprague-Dawley rats were exposed to arsenate (AsV) via drinking water (0, 23.6, 47.7, 71.0 ppm) (n = 5-7/group) from gestational day (GD) 6 through GD 22 with targeted doses of 0, 2.33, 4.67, 7.00 mg/kg/day, respectively. Offspring were dosed by gavage daily with the same mg/kg AsV dose as intended for their dam from postnatal day (PND) 1 to 21. Gestational water intake was reduced at all AsV doses, but returned to control levels on lactational day (LD) 1 when control water was returned. Gestational body weight was reduced only at the highest dose on GD 22 and lactational body weight was unaffected. Food intake was unaffected. iAs exposure did not alter offspring body weight (PNDs 1-21) or age at fur development and bilateral ear opening. Incisor eruption, however, was significantly delayed in offspring of the 4.67 and 7.00 mg/kg groups. Further, all iAs groups were significantly delayed in bilateral eye opening. Righting reflex (PNDs 3-6) was unaffected, while slant board performance (PNDs 8-11) was significantly poorer at the highest dose. Brains of culled pups (PND 1) showed dose-dependent increases of iAs. There were no significant AsV-related effects on PND 21 brain regional concentrations of dopamine, DOPAC, HVA, 5-HT or 5-HIAA. These hazard identification results will guide the study designs of developmental iAs exposure at human-relevant levels essential for risk-assessment.


Asunto(s)
Arseniatos/toxicidad , Conducta Animal/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Síndromes de Neurotoxicidad/etiología , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Animales Recién Nacidos , Arseniatos/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/farmacocinética , Femenino , Masculino , Exposición Materna , Síndromes de Neurotoxicidad/psicología , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos
7.
Artículo en Inglés | MEDLINE | ID: mdl-29179064

RESUMEN

According to the World Health Organization, the consumption of tobacco products is the single largest cause of preventable deaths in the world, exceeding the total aggregated number of deaths caused by diseases such as AIDS, tuberculosis, and malaria. An important element in the evaluation of the health risks associated with the consumption of tobacco products is the assessment of the internal exposure to the tobacco constituents responsible for their addictive (e.g. nicotine) and carcinogenic (e.g. N-nitrosamines such as NNN and NNK) properties. However, the assessment of the serum levels of these compounds is often challenging from an analytical standpoint, in particular when limited sample volumes are available and low detection limits are required. Currently available analytical methods often rely on complex multi-step sample preparation procedures, which are prone to low analyte recoveries and ex-vivo contamination due to the ubiquitous nature of these compounds as background contaminants. In order to circumvent these problems, we report a facile and highly sensitive method for the simultaneous quantification of nicotine, cotinine, NNN, and NNK in serum samples. The method relies on a simple "one pot" liquid-liquid extraction procedure and isotope dilution ultra-high pressure (UPLC) hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass spectrometry. The method requires only 10µL of serum and presents a limit of quantification of 0.02nmol (3000pg/mL) nicotine, 0.6pmol (100pg/mL) cotinine, 0.05pmol NNK (10pg/mL), and 0.06pmol NNN (10pg/mL), making it appropriate for pharmacokinetic evaluations.


Asunto(s)
Carcinógenos/análisis , Cotinina/sangre , Nicotina/sangre , Nitrosaminas/sangre , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Humanos , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/métodos
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