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1.
Sci Rep ; 7: 39885, 2017 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-28071720

RESUMEN

The intrauterine environment is particularly vulnerable to environmental exposures. We previously established a mouse model that provided evidence for pregnancy complications and placental anti-angiogenesis in response to Aroclor 1254 (A-1254), a mixture of polychlorinated biphenyls (PCBs). Importantly, these effects were observed in IL-10-/-, but not wild type, mice, suggesting that IL-10 deficiency predisposes to pregnancy disruptive effects of environmental toxicants. However, the mechanisms by which PCBs cause anti-angiogenic effects are unclear. Here, we evaluated PCB-mediated anti-angiogenic effects by diverse but complementary approaches, including HUVEC-mediated trophoblast invasion in nude mice, in vitro three-dimensional capillary tube formation involving HUVEC and/or HTR8 trophoblasts, and aortic ring endothelial cell outgrowth/sprouting. Taken together, our data suggest that PCBs act as potent anti-angiogenic agents. Importantly, we show that treatment of pregnant IL-10-/- mice with A-1254 resulted in placental activation of the Notch/Delta-like ligand (Dll) pathway, a master regulator of cell-cell interaction and vascular patterning. Similar results were obtained with HUVEC and HTR8 trophoblasts. Rescue of A-1254-induced disruption of HUVEC-based tube formation by γ-secretase inhibitor L1790 confirmed the critical role of the Notch/Dll pathway. Our data suggest that PCBs impart pregnancy disruptive functions by activating the Notch/Dll pathway and by inducing anti-angiogenic effects at the maternal-fetal interface.


Asunto(s)
Inhibidores de la Angiogénesis/toxicidad , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Bifenilos Policlorados/toxicidad , Complicaciones del Embarazo/metabolismo , Receptor Notch4/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-10/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , Complicaciones del Embarazo/inducido químicamente , Transducción de Señal
2.
Chem Res Toxicol ; 29(5): 851-9, 2016 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-26967026

RESUMEN

Hepatic levels of the essential micronutrient, zinc, are diminished by several hepatotoxicants, and the dietary supplementation of zinc has proven protective in those cases. 3,3',4,4',5-Pentachlorobiphenyl (PCB126), a liver toxicant, alters hepatic nutrient homeostasis and lowers hepatic zinc levels. The current study was designed to determine the mitigative potential of dietary zinc in the toxicity associated with PCB126 and the role of zinc in that toxicity. Male Sprague-Dawley rats were divided into three dietary groups and fed diets deficient in zinc (7 ppm Zn), adequate in zinc (30 ppm Zn), and supplemented in zinc (300 ppm). The animals were maintained for 3 weeks on these diets, then given a single IP injection of vehicle or 1 or 5 µmol/kg PCB126. After 2 weeks, the animals were euthanized. Dietary zinc increased the level of ROS, the activity of CuZnSOD, and the expression of metallothionein but decreased the levels of hepatic manganese. PCB126 exposed rats exhibited classic signs of exposure, including hepatomegaly, increased hepatic lipids, increased ROS and CYP induction. Liver histology suggests some mild ameliorative properties of both zinc deficiency and zinc supplementation. Other metrics of toxicity (relative liver and thymus weights, hepatic lipids, and hepatic ROS) did not support this trend. Interestingly, the zinc supplemented high dose PCB126 group had mildly improved histology and less efficacious induction of investigated genes than did the low dose PCB126 group. Overall, decreases in zinc caused by PCB126 likely contribute little to the ongoing toxicity, and the mitigative/preventive capacity of zinc against PCB126 exposure seems limited.


Asunto(s)
Dieta , Hígado/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Zinc/farmacología , Animales , Conducta Alimentaria , Expresión Génica , Masculino , Metalotioneína/genética , Estrés Oxidativo , Ratas , Receptores de Hidrocarburo de Aril/metabolismo , Superóxido Dismutasa/metabolismo , Zinc/administración & dosificación
3.
Environ Sci Pollut Res Int ; 21(10): 6400-9, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23532536

RESUMEN

Copper (Cu) metabolism is altered in rats fed diets high in molybdenum (Mo) and low in Cu. This 10-week study was carried out to examine the effects of supplemental Mo (7.5-240 µg/g diet) on male Sprague-Dawley rats fed diets adequate in Cu (5 µg/g diet) and to determine the susceptibility of Mo-treated animals to the environmental pollutant 3,3',4,4'-tetrabromobiphenyl (TBB). After 7 weeks of dietary treatment, half of the rats in each group received a single IP injection of TBB (150 µM/kg bw), while the other half received the corn oil vehicle. Rats sacrificed at 10 weeks showed no effects of Mo on growth, feed efficiency, or selected organ or tissue weights. Dose-dependent effects on plasma Mo (0-5.1 µg/mL), plasma Cu (0.95-0.20 µg/mL), and bone Cu (3.4-10 µg/g) in control through the high dose were found. Cu sequestration in the bone of Mo-treated rats is a new finding. TBB treatment resulted in dramatic weight loss and loss of absolute organ mass. Relative organ weights were increased, except for the thymus. TBB altered the concentrations of certain amino acids. Compared to control rats, this polybrominated biphenyl congener significantly decreased plasma Cu and ceruloplasmin at higher concentrations of dietary Mo and promoted the process of plasma Cu decrease by Mo, suggesting a combined effect.


Asunto(s)
Cobre/toxicidad , Sustancias Peligrosas/toxicidad , Molibdeno/toxicidad , Bifenilos Polibrominados/toxicidad , Animales , Ceruloplasmina/metabolismo , Cobre/metabolismo , Dieta , Suplementos Dietéticos , Sustancias Peligrosas/administración & dosificación , Sustancias Peligrosas/metabolismo , Inyecciones Intraperitoneales , Masculino , Molibdeno/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Bifenilos Polibrominados/administración & dosificación , Bifenilos Polibrominados/metabolismo , Ratas , Ratas Sprague-Dawley
4.
Environ Sci Pollut Res Int ; 21(10): 6384-99, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23644946

RESUMEN

Environmental pollutants polychlorinated biphenyls (PCBs), especially dioxin-like PCBs, cause oxidative stress and associated toxic effects, including cancer and possibly atherosclerosis. We previously reported that PCB 126, the most potent dioxin-like PCB congener, not only decreases antioxidants such as hepatic selenium (Se), Se-dependent glutathione peroxidase, and glutathione (GSH) but also increases levels of the antiatherosclerosis enzyme paraoxonase 1 (PON1) in liver and serum. To probe the interconnection of these three antioxidant systems, Se, GSH, and PON1, we examined the influence of varying levels of dietary Se and N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS) and precursor for GSH synthesis, on PON1 in the absence and presence of PCB 126 exposure. Male Sprague-Dawley rats, fed diets with differing Se levels (0.02, 0.2, or 2 ppm) or NAC (1%), were treated with a single intraperitoneal injection of corn oil or various doses of PCB 126 and euthanized 2 weeks later. PCB 126 significantly increased liver PON1 mRNA, protein level and activity, and serum PON1 activity in all dietary groups but did not consistently increase thiobarbituric acid levels (thiobarbituric acid reactive substances, TBARS), an indicator of lipid oxidation and oxidative stress, in liver or serum. Inadequate (high or low) dietary Se decreased baseline and PCB 126-induced aryl hydrocarbon receptor (AhR) expression but further increased PCB 126-induced cytochrome P450 1A1 (CYP1A1) expression, the enzyme believed to be the cause for PCB 126-induced oxidative stress. In addition, a significant inverse relationship was observed not only between dietary Se levels and PON1 mRNA and PON1 activity but also with TBARS levels in the liver, suggesting significant antioxidant protection from dietary Se. NAC lowered serum baseline TBARS levels in controls and increased serum PON1 activity but lowered liver PON1 activities in animals treated with 1 µmol/kg PCB 126, suggesting antioxidant activity by NAC primarily in serum. These results also show an unexpected predominantly inverse relationship between Se or NAC and PON1 during control and PCB 126 exposure conditions. These interactions should be further explored in the development of dietary protection regimens.


Asunto(s)
Acetilcisteína/metabolismo , Arildialquilfosfatasa/metabolismo , Contaminantes Ambientales/toxicidad , Bifenilos Policlorados/toxicidad , Selenio/metabolismo , Animales , Antioxidantes/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Dieta/estadística & datos numéricos , Glutatión/metabolismo , Hígado/metabolismo , Masculino , Oxidación-Reducción , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Receptores de Hidrocarburo de Aril/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
5.
Chem Res Toxicol ; 26(5): 634-44, 2013 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-23527585

RESUMEN

Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague-Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 µmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats, the hallmark signs of AhR activation were present, including increased cytochrome P450 and lipid levels and decreased glutathione. In addition, a doubling of hepatic copper levels was seen, and overall metal homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc, and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD), or increased (tyrosinase and metallothioneins 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e., oxidative stress and steatosis, is clearly associated with disturbed metal homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other AhR agonists.


Asunto(s)
Cobre/toxicidad , Suplementos Dietéticos , Hígado/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Animales , Cobre/administración & dosificación , Cobre/metabolismo , Relación Dosis-Respuesta a Droga , Hígado/metabolismo , Hígado/patología , Masculino , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Bifenilos Policlorados/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
6.
Toxicology ; 302(1): 25-33, 2012 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-22824115

RESUMEN

Potent aryl hydrocarbon receptor agonists like PCB 126 (3,3',4,4',5-pentachlorobiphenyl) cause oxidative stress and liver pathology, including fatty liver. Our question was whether dietary supplementation with N-acetylcysteine (NAC), an antioxidant, can prevent these adverse changes. Male Sprague-Dawley rats were fed a standard AIN-93G diet (sufficient in cysteine) or a modified diet supplemented with 1.0% NAC. After one week, rats on each diet were exposed to 0, 1, or 5µmol/kg body weight PCB 126 by i.p. injection (6 rats per group) and euthanized two weeks later. PCB-treatment caused a dose-dependent reduction in growth, feed consumption, relative thymus weight, total glutathione and glutathione disulfide (GSSG), while relative liver weight, glutathione transferase activity and hepatic lipid content were dose-dependently increased with PCB dose. Histologic examination of liver tissue showed PCB 126-induced hepatocellular steatosis with dose dependent increase in lipid deposition and distribution. Dietary NAC resulted in a reduction in hepatocellular lipid in both PCB groups. This effect was confirmed by gravimetric analysis of extracted lipids. Expression of CD36, a scavenger receptor involved in regulating hepatic fatty acid uptake, was reduced with high dose PCB treatment but unaltered in PCB-treated rats on NAC-supplemented diet. These results demonstrate that NAC has a protective effect against hepatic lipid accumulation in rats exposed to PCB 126. The mechanism of this protective effect appears to be independent of NAC as a source of cysteine/precursor of glutathione.


Asunto(s)
Acetilcisteína/farmacología , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hígado Graso/prevención & control , Bifenilos Policlorados/toxicidad , Animales , Antígenos CD36/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado Graso/inducido químicamente , Hígado Graso/patología , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Inyecciones Intraperitoneales , Masculino , Tamaño de los Órganos/efectos de los fármacos , Bifenilos Policlorados/administración & dosificación , Ratas , Ratas Sprague-Dawley , Receptores de Hidrocarburo de Aril/agonistas , Índice de Severidad de la Enfermedad
7.
J Environ Pathol Toxicol Oncol ; 30(4): 273-82, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22181977

RESUMEN

We report the role of dietary glycine and the type of oil used as a vehicle in the hepatotoxicity of control rats and rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153). In our first experiment, glycine or valine (as control) was fed in an unrefined diet at 5% for the entire study duration (5 days) to inhibit Kupffer cell activity. PCB-153 (100 or 300 µmol/kg) dissolved in medium chain triglyceride (MCT) oil, was injected intraperitoneally 2 days before euthanasia; the peroxisome proliferator Wy-14,643 was included as a positive control. MCT oil decreased cell proliferation by approximately 50%. PCB-153 slightly increased hepatic cell proliferation, but dietary glycine did not reduce cell proliferation. Because of the inhibition of cell proliferation in rats receiving MCT oil compared with rats receiving no injection, we hypothesized that MCT oil may have been inhibiting the hepatocyte proliferation in PCB-153-treated rats. We therefore performed another experiment using 3 types of oil as a vehicle for PCB-153: MCT oil, corn oil, and olive oil. Rats were injected with PCB-153 (300 µmol/kg) or one of the vehicles, again 2 days before euthanasia. MCT oil again decreased the hepatocyte proliferation by approximately 50%. In rats receiving PCB-153, hepatocyte proliferation was slightly higher than their respective vehicle controls for corn oil and olive oil but not for MCT oil. These studies show that the oil vehicle is important in cell proliferation after PCB exposure, with MCT oil appearing to be protective.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Glicina/farmacología , Hígado/efectos de los fármacos , Aceites/farmacología , Vehículos Farmacéuticos/farmacología , Bifenilos Policlorados/toxicidad , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Aceite de Maíz/farmacología , Citocromo P-450 CYP2B1/metabolismo , Hígado/patología , Masculino , Aceite de Oliva , Aceites de Plantas/farmacología , Bifenilos Policlorados/química , Ratas , Ratas Sprague-Dawley , Esteroide Hidroxilasas/metabolismo , Triglicéridos/química , Triglicéridos/farmacología
8.
Toxicol Sci ; 124(1): 202-14, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21865291

RESUMEN

Homeostasis of selenium (Se), a critical antioxidant incorporated into amino acids and enzymes, is disrupted by exposure to aryl hydrocarbon receptor (AhR) agonists. Here we examined the importance of dietary Se in preventing the toxicity of the most toxic polychlorinated biphenyl congener, 3,3',4,4',5-pentachlorobiphenyl (PCB 126), a potent AhR agonist. Male Sprague-Dawley rats were fed a modified AIN-93 diet with differing dietary Se levels (0.02, 0.2, and 2 ppm). Following 3 weeks of acclimatization, rats from each dietary group were given a single ip injection of corn oil (vehicle), 0.2, 1, or 5 µmol/kg body weight PCB 126, followed 2 weeks later by euthanasia. PCB exposure caused dose-dependent increases in liver weight and at the highest PCB 126 dose decreases in whole body weight gains. Hepatic cytochrome P-450 (CYP1A1) activity was significantly increased even at the lowest dose of PCB 126, indicating potent AhR activation. PCB exposure diminished hepatic Se levels in a dose-dependent manner, and this was accompanied by diminished Se-dependent glutathione peroxidase activity. Both these effects were partially mitigated by Se supplementation. Conversely, thioredoxin (Trx) reductase activity and Trx oxidation state, although significantly diminished in the lowest dietary Se groups, were not affected by PCB exposure. In addition, PCB 126-induced changes in hepatic copper, iron, manganese, and zinc were observed. These results demonstrate that supplemental dietary Se was not able to completely prevent the toxicity caused by PCB 126 but was able to increase moderately the levels of several key antioxidants, thereby maintaining them roughly at normal levels.


Asunto(s)
Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hígado/efectos de los fármacos , Bifenilos Policlorados/toxicidad , Compuestos de Selenio/uso terapéutico , Administración Oral , Animales , Antioxidantes/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocromo P-450 CYP1A1/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hígado/enzimología , Hígado/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Oxidación-Reducción , Ratas , Ratas Sprague-Dawley , Receptores de Hidrocarburo de Aril/agonistas , Ácido Selénico , Compuestos de Selenio/administración & dosificación , Compuestos de Selenio/farmacocinética
9.
Environ Int ; 36(8): 918-23, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19969354

RESUMEN

Although polychlorinated biphenyl (PCBs) production, and new uses for PCBs, was halted in the 1970s in the United States, PCBs continue to be used in closed systems and persist in the environment, accumulating in fatty tissues. PCBs are efficacious inducers of drug metabolism and may increase oxidative events and alter many other biochemical and morphologic parameters within cells and tissues. The goal of the present study was to evaluate the effects of a single, very low dose of PCB 126 (3,3',4,4',5-pentachlorobiphenyl), a coplanar, dioxin-like PCB congener and aryl hydrocarbon receptor (AhR) agonist, on redox status, metals homeostasis, antioxidant enzymes, and cellular morphology. To examine these parameters, male Sprague-Dawley rats were fed a purified AIN-93 basal diet containing 0.2 ppm selenium for two weeks, then administered a single i.p. injection of corn oil (5 ml/kg body weight) or 1µmol PCB 126/kg body weight (326µg/kg body weight) in corn oil. Rats were maintained on the diet for an additional two weeks before being euthanized. This dose of PCB 126 did not alter feed intake or growth, but significantly increased liver weight (42%) and hepatic microsomal cytochrome P-450 (CYP1A) enzyme activities (10-40-fold increase). Hepatic zinc, selenium, and glutathione levels were significantly decreased 15%, 30%, and 20%, respectively, by PCB 126. These changes were accompanied by a 60% decrease in selenium-dependent glutathione peroxidase activity. In contrast, hepatic copper levels were increased 40% by PCB 126. PCB 126-induced pathology was characterized by hepatocellular hypertrophy and mild steatosis in the liver and a mild decrease in cortical T-cells in the thymus. This controlled study in rats fed a purified diet shows that even a single, very low dose of PCB 126 that did not alter feed intake or growth, significantly perturbed redox and metals homeostasis and antioxidant and enzyme levels in rodent liver.


Asunto(s)
Glutatión/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Metales/metabolismo , Mutágenos/toxicidad , Estrés Oxidativo , Bifenilos Policlorados/toxicidad , Animales , Aceite de Maíz/administración & dosificación , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/toxicidad , Inyecciones Intravenosas , Hígado/química , Masculino , Mutágenos/administración & dosificación , Bifenilos Policlorados/administración & dosificación , Ratas , Ratas Sprague-Dawley
10.
Environ Int ; 36(8): 980-6, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19735942

RESUMEN

Dietary habits that expose populations to potential toxicants as well as protective agents simultaneously are a realistic scenario where a meaningful assessment of the interactions and net benefit or damage can be made. A group of Inuit from Salluit, Northern Canada are exposed to high levels of PCBs and selenium, both present in the Inuit traditional foods such as blubber from sea mammals and fatty fish. Blood samples were collected from 83 Inuit, 22-70 years old. Blood selenium and PCB levels were determined previously and ranged from 227 to 2069µg/L and 1.7 to 143µg/L, respectively. DNA isolated from white blood cells were analyzed by modified (32)P-postlabeling adductomics technology that detects a multitude of highly polar to lipophilic adducts. The levels of 8-oxodG adducts ranged from 470 to 7400 adducts/10(9) nucleotides. Other as yet unidentified polar adducts showed a 30 to 800-fold inter-individual variability. Adduct levels were negatively associated with PCB and selenium levels. The subjects were classified into high and low ratio groups, with respect to selenium/PCB. In the high ratio group, the coefficient of selenium is significantly negatively correlated with 8-oxodG (r = -0.38, p = 0.014) and total adducts (r = -0.41, p = 0.009) while there was no correlation within the low selenium/PCB group. This study suggests that increasing selenium has mitigating effect in reducing DNA adducts and therefore, possible negative effects of PCB were not seen. A protective effect of selenium is highlighted.


Asunto(s)
ADN/metabolismo , Mutágenos/metabolismo , Bifenilos Policlorados/metabolismo , Selenio/metabolismo , Adolescente , Adulto , Anciano , Análisis Químico de la Sangre , Canadá , Femenino , Humanos , Inuk , Masculino , Persona de Mediana Edad , Radioisótopos de Fósforo/metabolismo , Coloración y Etiquetado/métodos , Adulto Joven
11.
J Magn Reson ; 195(2): 219-25, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18829354

RESUMEN

In this communication, a scheme is described whereby in vivo (13)C MRS can safely be performed in the frontal lobe, a human brain region hitherto precluded on grounds of SAR, but important in being the seat of impaired cognitive function in many neuropsychiatric and developmental disorders. By combining two well known features of (13)C NMR-the use of low power NOE and the focus on (13)C carbon atoms which are only minimally coupled to protons, we are able to overcome the obstacle of SAR and develop means of monitoring the (13)C fluxes of critically important metabolic pathways in frontal brain structures of normal volunteers and patients. Using a combination of low-power WALTZ decoupling, variants of random noise for nuclear overhauser effect enhancement it was possible to reduce power deposition to 20% of the advised maximum specific absorption rate (SAR). In model solutions (13)C signal enhancement achieved with this scheme were comparable to that obtained with WALTZ-4. In human brain, the low power procedure effectively determined glutamine, glutamate and bicarbonate in the posterior parietal brain after [1-(13)C] glucose infusion. The same (13)C enriched metabolites were defined in frontal brain of human volunteers after administration of [1-(13)C] acetate, a recognized probe of glial metabolism. Time courses of incorporation of (13)C into cerebral glutamate, glutamine and bicarbonate were constructed. The results suggest efficacy for measurement of in vivo cerebral metabolic rates of the glutamate-glutamine and tricarboxylic acid cycles in 20 min MR scans in previously inaccessible brain regions in humans at 1.5 T. We predict these will be clinically useful biomarkers in many human neuropsychiatric and genetic conditions.


Asunto(s)
Encéfalo/metabolismo , Isótopos de Carbono/análisis , Lóbulo Frontal/metabolismo , Ácido Glutámico/análisis , Espectroscopía de Resonancia Magnética/métodos , Trastornos Mentales/diagnóstico , Trastornos Mentales/metabolismo , Biomarcadores/análisis , Humanos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
12.
Food Chem Toxicol ; 46(11): 3467-74, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18796325

RESUMEN

Polychlorinated biphenyls (PCBs) have promoting activity in the liver, which may be brought about in part by the induction of oxidative stress. In this study we examined the effects of several antioxidant phytochemicals on the tumor promoting activity of 3,3',4'4-tetrachlorobiphenyl (PCB-77). Female Sprague Dawley rats were first injected with diethylnitrosamine (DEN, 150 mg/kg) and one week later the rats were fed an AIN-93 based purified diet or the same diet containing ellagic acid (0.4%), beta-carotene (0.5%), curcumin (0.5%), N-acetyl cysteine (NAC, 1.0%), coenzyme CoQ10 (CoQ10, 0.4%), resveratrol (0.005%), lycopene (10% as Lycovit, which contains 10% lycopene), or a tea extract (1%, containing 16.5% epigallocatechin-3-gallate [EGCG] and 33.4% total catechins). Rats were fed the diets for the remainder of the study. After three weeks, 2/3 of the control rats and all of the antioxidant diet-fed rats were injected i.p. with PCB-77 (300 micromol/kg) every other week for four injections. All rats were euthanized ten days after the last PCB injection. The rats that received PCB-77 alone showed an increase in the number and size of placental glutathione S-transferase (PGST)-positive foci in the liver. Lycopene significantly decreased the number of foci, while curcumin and CoQ10 decreased the size of the foci. In contrast, ellagic acid increased the number but decreased the size of the foci. All of the other phytochemicals showed only slight or no effects. Compared with the PCB-77 group, CoQ10 increased cell proliferation in normal hepatocytes, whereas the other antioxidants had no effect in either normal or PGST-positive hepatocytes. These findings show that none of the antioxidant phytochemicals produced a clear decrease in the promoting activity of PCB-77.


Asunto(s)
Antioxidantes/uso terapéutico , Proliferación Celular/efectos de los fármacos , Dieta , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Administración Oral , Animales , Antioxidantes/farmacología , Carcinógenos Ambientales/toxicidad , Carotenoides/administración & dosificación , Carotenoides/farmacología , Curcumina/administración & dosificación , Curcumina/farmacología , Ácido Elágico/administración & dosificación , Ácido Elágico/farmacología , Femenino , Glutatión Transferasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Inmunohistoquímica , Inyecciones Intraperitoneales , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Licopeno , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/fisiología , Bifenilos Policlorados/toxicidad , Ratas , Ratas Sprague-Dawley , Ubiquinona/administración & dosificación , Ubiquinona/análogos & derivados , Ubiquinona/farmacología
13.
Exp Biol Med (Maywood) ; 233(3): 366-76, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18296742

RESUMEN

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that have promoting activity in the liver. PCBs induce oxidative stress, which may influence carcinogenesis. Epidemiological studies strongly suggest an inverse relationship between dietary selenium (Se) and cancer. Despite evidence linking Se deficiency to hepatocellular carcinoma and liver necrosis, the underlying mechanisms for Se cancer protection in the liver remain to be determined. We examined the effect of dietary Se on the tumor promoting activities of two PCBs congeners, 3,3', 4,4'-tetrachlorobiphenyl (PCB-77) and 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB-153) using a 2-stage carcinogenesis model. An AIN-93 torula yeast-based purified diet containing 0.02 (deficient), 0.2 (adequate), or 2.0 mg (supplemental) selenium/kg diet was fed to Sprague-Dawley female rats starting ten days after administering a single dose of diethylnitrosamine (150 mg/kg). After being fed the selenium diets for 3 weeks, rats received four i.p. injections of either PCB-77 or PCB-153 (150 micromol/kg) administered every 14 days. The number of placental glutathione S-transferase (PGST)-positive foci per cm(3) and per liver among the PCB-77-treated rats was increased as the Se dietary level increased. Unlike PCB-77, rats receiving PCB-153 did not show the same Se dose-response effect; nevertheless, Se supplementation did not confer protection against foci development. However, the 2.0 ppm Se diet reduced the mean focal volume, indicating a possible protective effect by inhibiting progression of preneoplastic lesions into larger foci. Cell proliferation was not inhibited by Se in the liver of the PCB-treated groups. Se did not prevent the PCB-77-induced decrease of hepatic Se and associated reduction in glutathione peroxidase (GPx) activity. In contrast, thioredoxin reductase (TrxR) activity was not affected by the PCBs treatment or by Se supplementation. These findings indicate that Se does not inhibit the number of PGST-positive foci induced during promotion by PCBs, but that the size of the lesions may be inhibited. The effects of Se on altered hepatic foci do not correlate with its effects on GPx and TrxR.


Asunto(s)
Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/prevención & control , Bifenilos Policlorados/farmacología , Selenio/uso terapéutico , Alimentación Animal , Animales , Peso Corporal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Femenino , Glutatión Peroxidasa/metabolismo , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/enzimología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reductasa de Tiorredoxina-Disulfuro/metabolismo
14.
J Nutr ; 135(2): 283-6, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15671227

RESUMEN

In this study, the effect of dietary vitamin E on the hepatic tumor-promoting activity of PCB-77 and PCB-153 in female Sprague-Dawley rats (175-200 g) was investigated. One week after diethylnitrosamine injection, rats were fed purified diets containing 10, 50, or 250 mg/kg vitamin E in the form of alpha-tocopheryl acetate. Starting 1 wk later, we injected rats i.p. with vehicle (corn oil) or PCB-77 or PCB-153 (300 mumol/kg) every 14 d for 4 injections. All rats were killed 10 d after the last PCB injection. The number and volume of placental glutathione S-transferase (PGST)-positive foci were increased by PCB-77 but not by PCB-153. Vitamin E did not affect the induction of PGST-positive foci. PCB-77, but not PCB-153, increased hepatic NF-kappaB activity. In conclusion, dietary vitamin E supplementation does not protect against the induction of altered hepatic focal lesions by PCBs.


Asunto(s)
Dieta , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/prevención & control , Bifenilos Policlorados/toxicidad , Vitamina E/farmacología , Animales , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , FN-kappa B/metabolismo , Ratas , Ratas Sprague-Dawley , Vitamina E/administración & dosificación
15.
Toxicol Sci ; 79(1): 41-6, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-14976334

RESUMEN

We recently reported that several mono- to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 micromol/kg), dihydroxy (200 micromol/kg), and quinone (100 micromol/kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of gamma-glutamyl transpeptidase-positive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.


Asunto(s)
Compuestos de Bifenilo/efectos adversos , Compuestos de Bifenilo/metabolismo , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/prevención & control , 2-Acetilaminofluoreno/administración & dosificación , Adenoma de Células Hepáticas/inducido químicamente , Administración Oral , Animales , Compuestos de Bifenilo/química , Peso Corporal/efectos de los fármacos , Tetracloruro de Carbono/administración & dosificación , Carcinógenos/efectos adversos , Carcinógenos/química , Carcinógenos/metabolismo , Dietilnitrosamina/administración & dosificación , Dietilnitrosamina/efectos adversos , Esquema de Medicación , Evaluación Preclínica de Medicamentos/métodos , Hidroxilación , Inyecciones Intraperitoneales , Intubación Intratraqueal , Hígado/química , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Modelos Biológicos , Tamaño de los Órganos/efectos de los fármacos , Quinonas/efectos adversos , Quinonas/química , Quinonas/metabolismo , Ratas , Ratas Endogámicas F344 , Factores de Tiempo , gamma-Glutamiltransferasa/biosíntesis , gamma-Glutamiltransferasa/química
16.
Int J Hyg Environ Health ; 205(1-2): 95-102, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12018021

RESUMEN

There is an increasing body of evidence suggesting that exposure to Superfund chemicals may have adverse consequences on many organ systems, as well as carcinogenic and atherogenic effects. This is particularly true for polyhalogenated aromatic hydrocarbons such as the polychlorinated biphenyls (PCBs). The vascular endothelium, which is constantly exposed to blood components including environmental contaminants, is extremely vulnerable to chemical insult as well as necrotic and apoptotic injury. Our recent studies suggest that certain PCBs, especially coplanar PCBs, can compromise normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. Our findings suggest that an increase in the level of cellular oxidative stress is a significant event in PCB-mediated endothelial cell dysfunction and that nutrients can modulate PCB-induced oxidative stress and endothelial toxicity. We have demonstrated that the dietary fat linoleic acid, the parent unsaturated fatty acid of the omega-6 family, can increase endothelial dysfunction induced by selected PCBs, probably by contributing to oxidative stress and as the result of the production of toxic metabolites called leukotoxins. The subsequent imbalance in the overall cellular oxidant/antioxidant status can activate oxidative stress- or redoxsensitive transcription factors, which in turn promote gene expression for inflammatory cytokines and adhesion molecules, intensifying the inflammatory response and endothelial cell dysfunction. Our data also suggest that antioxidant nutrients such as vitamin E can protect against endothelial cell damage mediated by PCBs or polyunsaturated dietary fats by interfering with oxidative stress-sensitive and proinflammatory signaling pathways. The concept that nutrition can modify or ameliorate the toxicity of Superfund chemicals is provocative and warrants further study as the implications for human health are significant. The information from such studies could be used to develop dietary recommendations and nutritional interventions for populations at high risk for exposure to PCBs, including communities living near Superfund sites and those exposed via occupation or diet.


Asunto(s)
Endotelio/citología , Contaminantes Ambientales/efectos adversos , Ácidos Grasos Insaturados/farmacología , Estrés Oxidativo , Bifenilos Policlorados/efectos adversos , Vitamina E/farmacología , Dieta , Grasas de la Dieta , Interacciones Farmacológicas , Endotelio/efectos de los fármacos , Endotelio/patología , Ácidos Grasos Omega-6 , Guías como Asunto , Humanos , Ácido Linoleico/farmacología , Salud Pública , Medición de Riesgo
17.
Toxicol Appl Pharmacol ; 179(3): 172-84, 2002 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11906247

RESUMEN

Polychlorinated biphenyls (PCBs) are environmental pollutants that are complete carcinogens and tumor promoters in the liver. The mechanisms of their promoting activities are not clear, but one possible mechanism is the induction of oxidative stress. In the present study we evaluated the ability of two PCB congeners to activate the oxidative stress-responsive transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), as well as hepatocyte cell proliferation and apoptosis, which are influenced by activation of these transcription factors, in rat liver. Two transcription factors not activated by oxidative stress, signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5), were also examined. All the animals in this study received a single dose of diethylnitrosamine (150 mg/kg) followed by four biweekly injections of 3,3',4,4'-tetrachlorobiphenyl (PCB-77) or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) (100 or 300 micromol/kg), or both PCBs (100 micromol/kg each). Ten days after the last PCB injection, all animals were euthanized; 3 days before euthanasia all animals were implanted with Alzet osmotic pumps containing 5-bromo-2'-deoxyuridine (BrdU). The number of placental glutathione S-transferase (PGST)-positive foci were increased in rats administered PCBs, with the highest increase seen in rats administered PCB-77. The number of foci in rats administered both PCBs was intermediate between the numbers seen with either PCB-77 or PCB-153, indicating that a synergistic effect did not occur. There was a significant increase in NF-kappaB and AP-1 binding activities in hepatic nuclear extracts from rats receiving the high dose of PCB-77 or PCB-153 and in rats receiving both PCBs. In contrast, the DNA binding activities of STAT3 and STAT5 were decreased in rats administered PCBs. Cell proliferation in both focal and nonfocal hepatocytes was increased by PCB-77 but was not affected by PCB-153. Apoptotic indexes, as quantified by the TUNEL method, were increased in both focal and nonfocal hepatocytes by PCB-77 but were decreased in focal hepatocytes by PCB-153. This study shows that both PCBs alone or in combination can increase the DNA binding activities of NF-kappaB and AP-1, whereas the DNA binding activities of STAT3 and STAT5 are decreased. The induction of altered hepatic foci appears to be related to compensatory cell proliferation in PCB-77-treated rats, whereas the inhibition of apoptosis appears to be important in PCB-153-treated rats.


Asunto(s)
Neoplasias Hepáticas Experimentales/inducido químicamente , Proteínas de la Leche , Bifenilos Policlorados/toxicidad , Factores de Transcripción/fisiología , Animales , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/biosíntesis , Dietilnitrosamina/administración & dosificación , Ensayo de Cambio de Movilidad Electroforética , Femenino , Immunoblotting , Etiquetado Corte-Fin in Situ , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT3 , Factor de Transcripción STAT5 , Transactivadores/análisis , Transactivadores/biosíntesis , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/metabolismo
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