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1.
Carcinogenesis ; 31(6): 1142-8, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20400480

RESUMEN

Childhood cancer is the leading cause of disease-related death in children aged 1-14 years in Canada and the USA and it has been hypothesized that transplacental exposure to environmental carcinogens such as benzene may contribute to the etiology of these cancers. Our objectives were to determine if transplacental benzene exposure increased tumor incidence in mouse offspring and assess fetal benzene metabolism capability. Pregnant CD-1 and C57Bl/6N mice were given intraperitoneal injections of corn oil, 200 mg/kg, or 400 mg/kg benzene on gestational days 8, 10, 12 and 14. A significant increase in tumor incidence was observed in CD-1, but not C57BL/6N, 1-year-old offspring exposed transplacentally to 200 mg/kg benzene. Hepatic and hematopoietic tumors were predominantly observed in male and female CD-1 offspring, respectively. Female CD-1 offspring exposed transplacentally to 200 mg/kg benzene had significantly suppressed bone marrow CD11b(+) cells 1 year after birth, correlating with reduced colony-forming unit granulocyte/macrophage numbers in 2-day-old pups. CD-1 and C57Bl/6N maternal blood benzene levels and fetal liver benzene, t, t-muconic acid, hydroquinone and catechol levels were analyzed by gas chromatography/mass spectrometry. Significant strain-, gender- and dose-related differences were observed. Male CD-1 fetuses had high hydroquinone levels, whereas females had high catechol levels after maternal exposure to 200 mg/kg benzene. This is the first demonstration that transplacental benzene exposure can induce hepatic and hematopoietic tumors in mice, which may be dependent on fetal benzene metabolism capability.


Asunto(s)
Benceno/toxicidad , Intercambio Materno-Fetal , Neoplasias Experimentales/inducido químicamente , Animales , Secuencia de Bases , Benceno/farmacocinética , Cartilla de ADN , Femenino , Citometría de Flujo , Cromatografía de Gases y Espectrometría de Masas , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo
2.
Toxicol Appl Pharmacol ; 244(3): 273-9, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-20083130

RESUMEN

Benzene is a ubiquitous occupational and environmental toxicant. Exposures to benzene both prenatally and during adulthood are associated with the development of disorders such as aplastic anemia and leukemia. Mechanisms of benzene toxicity are unknown; however, generation of reactive oxygen species (ROS) by benzene metabolites may play a role. Little is known regarding the effects of benzene metabolites on erythropoiesis. Therefore, to determine the effects of in utero exposure to benzene on the growth and differentiation of fetal erythroid progenitor cells (CFU-E), pregnant CD-1 mice were exposed to benzene and CFU-E numbers were assessed in fetal liver (hematopoietic) tissue. In addition, to determine the effect of benzene metabolite-induced ROS generation on erythropoiesis, HD3 chicken erythroblast cells were exposed to benzene, phenol, or hydroquinone followed by stimulation of erythrocyte differentiation. Our results show that in utero exposure to benzene caused significant alterations in female offspring CFU-E numbers. In addition, exposure to hydroquinone, but not benzene or phenol, significantly reduced the percentage of differentiated HD3 cells, which was associated with an increase in ROS. Pretreatment of HD3 cells with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) prevented hydroquinone-induced inhibition of erythropoiesis, supporting the hypothesis that ROS generation is involved in the development of benzene erythrotoxicity. In conclusion, this study provided evidence that ROS generated as a result of benzene metabolism may significantly alter erythroid differentiation, potentially leading to the development of Blood Disorders.


Asunto(s)
Benceno/toxicidad , Diferenciación Celular/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Células Eritroides/efectos de los fármacos , Exposición Materna , Especies Reactivas de Oxígeno/metabolismo , Animales , Benceno/metabolismo , Contaminantes Ambientales/metabolismo , Células Eritroides/citología , Células Eritroides/metabolismo , Células Precursoras Eritroides/citología , Células Precursoras Eritroides/efectos de los fármacos , Eritropoyesis/efectos de los fármacos , Femenino , Inhibidores de Crecimiento/toxicidad , Hidroquinonas/toxicidad , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Redes y Vías Metabólicas , Ratones , Modelos Animales , Fenol/toxicidad , Embarazo , Superóxido Dismutasa/metabolismo
3.
Toxicology ; 229(3): 177-85, 2007 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-17161514

RESUMEN

Chronic occupational exposure to benzene has been correlated with aplastic aneamia and acute myelogenous leukemia, however mechanisms behind benzene toxicity remain unknown. Interestingly, benzene-initiated hematotoxicity is absent in mice lacking the aryl hydrocarbon receptor (AhR) suggesting an imperative role for this receptor in benzene toxicities. This study investigated two potential roles for the AhR in benzene toxicity using hepa 1c1c7 wild type and AhR deficient cells. Considering that many toxic effects of AhR ligands are dependent on AhR activation, our first objective was to determine if benzene, hydroquinone (HQ) or benzoquinone (BQ) could activate the AhR. Secondly, because the AhR regulates a number of enzymes involved in oxidative stress pathways, we sought to determine if the AhR had a role in HQ and BQ induced production of reactive oxygen species (ROS). Dual luciferase assays measuring dioxin response element (DRE) activation showed no significant change in DRE activity after exposure to benzene, HQ or BQ for 24h. Immunofluorescence staining showed cytosolic localization of the AhR after 2h incubations with benzene, HQ or BQ. Western blot analysis of cells exposed to benzene, HQ or BQ for 1, 12 and 24h did not demonstrate induction of CYP1A1 protein expression. Dichlorodihydrofluorescein staining of cells exposed to benzene, HQ or BQ revealed that the presence of the AhR did not affect BQ and HQ induced ROS production. These results indicate that the involvement of the AhR in benzene toxicity does not seem to be through classical activation of this receptor or through interference of oxidative stress pathways.


Asunto(s)
Benceno/toxicidad , Carcinógenos/toxicidad , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Benzoquinonas/toxicidad , Línea Celular Tumoral , Citocromo P-450 CYP1A1/metabolismo , Expresión Génica/efectos de los fármacos , Hidroquinonas/toxicidad , Ratones , Especies Reactivas de Oxígeno/metabolismo , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Elementos de Respuesta/genética
4.
Chem Biol Interact ; 153-154: 171-8, 2005 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-15935814

RESUMEN

Chronic exposure to benzene has been correlated with increased oxidative stress and leukemia. Oncogene activation, including c-Myb activation, is one of the earliest steps leading to the formation of leukemic cells, however the molecular mechanisms involved in these events are poorly understood. Given that oxidative stress can alter the activity and fate of cell signaling pathways we hypothesize that the bioactivation of benzene leads to the formation of reactive oxygen species (ROS), which if not detoxified can alter the c-Myb signaling pathway. Using chicken erythroblast HD3 cells we have shown that exposure to the benzene metabolites catechol, benzoquinone, and hydroquinone leads to increased c-Myb activity, increased phosphorylation of c-Myb and increased production of ROS supporting our hypothesis. Activation of the aryl hydrocarbon receptor (AhR) by environmental contaminants has also been associated with carcinogenesis and mice lacking this receptor are resistant to benzene-initiated hematotoxicity. Using wild type and AhR deficient cells we are investigating the role of this receptor in benzene-initiated alterations in the c-Myb signaling pathway. We have found that both wild type and AhR deficient cells are sensitive to catechol and hydroquinone-initiated increases in c-Myb activity while both cell types are resistant to benzene-initiated alterations leaving the role of the AhR still undetermined. Interestingly, protein expression of c-Myb is increased after catechol exposure in AhR deficient cells while decreased in wild-type cells. Further studies on the role of the AhR in benzene-initiated alterations on the c-Myb signaling pathway are on going.


Asunto(s)
Benceno/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myb/biosíntesis , Proteínas Proto-Oncogénicas c-myb/metabolismo , Animales , Benceno/metabolismo , Proteínas Proto-Oncogénicas c-myb/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos
5.
Toxicol Sci ; 113(1): 207-15, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19812361

RESUMEN

It is hypothesized that the increasing incidence of childhood leukemia may be due to in utero exposure to environmental pollutants, such as benzene, but the mechanisms involved remain unknown. We hypothesize that reactive oxygen species (ROS) contribute to the deregulation of fetal hematopoiesis caused by in utero benzene exposure. To evaluate this hypothesis, pregnant C57Bl/6N mice were exposed to benzene or polyethylene glycol-conjugated catalase (PEG-catalase) (antioxidative enzyme) and benzene. Colony formation assays on fetal liver cells were performed to measure erythroid and myeloid progenitor cell growth potential. The presence of ROS in CD117(+) fetal liver cells was measured by flow cytometric analysis. Oxidative cellular damage was assessed by Western blot analysis of 4-hydroxynonenol (4-HNE) and nitrotyrosine products, as well as reduced to oxidized glutathione ratios. Alterations in the redox-sensitive signaling pathway nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-kappaB) were measured by Western blot analysis of Inhibitor of NF-kB-alpha (IkappaB-alpha) protein levels in fetal liver tissue. In utero exposure to benzene caused a significant increase in ROS production and significantly altered fetal liver erythroid and myeloid colony numbers but did not increase the levels of 4-HNE or nitrotyrosine products or alter reduced to oxidized glutathione ratios. However, in utero exposure to benzene did cause a significant decrease in fetal liver IkappaB-alpha protein levels, suggesting activation of the NF-kappaB pathway. Benzene-induced ROS formation, abnormal colony growth, and decreased IkappaB-alpha levels were all abrogated by pretreatment with PEG-catalase. These results suggest that ROS play a key role in the development of in utero-initiated benzene toxicity potentially through disruption of hematopoietic cell signaling pathways.


Asunto(s)
Benceno/toxicidad , Proliferación Celular/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Células Madre Fetales/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Aldehídos/metabolismo , Animales , Antioxidantes/farmacología , Western Blotting , Catalasa/farmacología , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Femenino , Células Madre Fetales/metabolismo , Células Madre Fetales/patología , Citometría de Flujo , Edad Gestacional , Disulfuro de Glutatión/metabolismo , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Proteínas I-kappa B/metabolismo , Hígado/embriología , Hígado/metabolismo , Hígado/patología , Exposición Materna , Ratones , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa , FN-kappa B/metabolismo , Polietilenglicoles/farmacología , Embarazo , Proteínas Proto-Oncogénicas c-kit/análisis , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/metabolismo
6.
Chem Biol Interact ; 184(1-2): 218-21, 2010 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-19913523

RESUMEN

Approximately 90% of childhood cancers are of unknown etiology; however, it is hypothesized that in utero carcinogen exposure may contribute. Epidemiological studies have correlated parental exposure to benzene with an increased incidence of childhood leukemias. However, mechanisms of benzene-induced carcinogenesis following in utero exposure remain unknown. We hypothesize that in utero exposure to benzene causes alterations in the redox-sensitive signaling pathways involving c-Myb, Pim-1, AKT, ERK-MAPK, p38-MAPK, and NF-kappaB via the production of reactive oxygen species (ROS) as a possible mechanism of in utero-initiated carcinogenesis. Using a CD-1 mouse model we have shown increased oxidative stress in fetal tissue from embryos exposed in utero to benzene by measuring reduced to oxidized glutathione ratios, and increased levels of ROS in male fetuses using flow cytometry and the ROS sensitive fluorescent probe dichlorofluoroscein diacetate (DCFDA). In addition, using Western blotting techniques we observed increased expression of fetal Pim-1, Pim-1 phosphorylation, c-Myb, and phosphorylated p38-MAPK (activated form) and lower protein levels of IkappaBalpha, while phosphorylated ERK-MAPK and AKT protein levels did not change. Interestingly, we found male fetuses more susceptible to benzene-induced oxidative stress, which is in agreement with the literature suggesting that males are more susceptible to benzene toxicity. Further studies evaluating the reason for this gender difference are ongoing.


Asunto(s)
Benceno/efectos adversos , Carcinógenos/farmacología , Embrión de Mamíferos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Embrión de Mamíferos/metabolismo , Femenino , Feto/efectos de los fármacos , Feto/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Embarazo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myb/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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