RESUMEN
Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 µg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model.
Asunto(s)
Ocratoxinas/toxicidad , Proteína p53 Supresora de Tumor/genética , Animales , Ingestión de Alimentos/efectos de los fármacos , Inmunohistoquímica , Riñón/efectos de los fármacos , Leucocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Tamaño de los Órganos/efectos de los fármacos , Pruebas de Toxicidad CrónicaRESUMEN
Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a "complete carcinogen", but acts as a "co-carcinogen" by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters.
Asunto(s)
Acrilamida/efectos adversos , Neoplasias del Colon/etiología , Neoplasias del Colon/patología , Dieta , Acrilamida/administración & dosificación , Animales , Peso Corporal , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Ratas , Carga TumoralRESUMEN
Epidemiological studies demonstrated that human exposure to methylmercury (MeHg) may contribute to the development and progression of metabolic and cardiovascular disorders. However, the mechanisms involved and the role of selenium (Se) and vitamin E (V(E)) supplementation in modulating MeHg cardiovascular toxicities remain unclear. This study examined the effects of Se and V(E) supplementation on MeHg-mediated systemic oxidative stress, antioxidant defense, inflammation, and endothelial dysfunction in an animal model. Male Sprague-Dawley rats were fed a starch-based casein diet or the same diet supplemented with 1 or 3 mg Se/kg diet and with or without 250 or 750 mg V(E)/kg diet. After 28 days of dietary treatment, rats were gavaged with 0 or 3 mg MeHg/kg BW for 14 consecutive days. Results suggested that exposure to MeHg may increase the risk of cardiovascular disease by decreasing circulating paraoxonase-1 activities, increasing serum oxidized low density lipoprotein levels, and associated systemic inflammation and endothelial dysfunction as reflected by increased leukocyte counts and serum levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1. Se and V(E) supplementation may either alleviate or augment the effects of MeHg, depending on their doses and combinations.
Asunto(s)
Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/orina , Suplementos Dietéticos , Compuestos de Metilmercurio/toxicidad , Selenio/fisiología , Vitamina E/fisiología , Animales , Antioxidantes/administración & dosificación , Biomarcadores/sangre , Biomarcadores/orina , Enfermedades Cardiovasculares/prevención & control , Masculino , Compuestos de Metilmercurio/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Selenio/administración & dosificación , Vitamina E/administración & dosificaciónRESUMEN
We studied the effects of lifetime exposure to dietary soy isoflavones in an azoxymethane (AOM)-induced rat colon cancer model. Male pups born to Sprague-Dawley rats exposed (including during pregnancy and lactation) to soy isoflavones at either no (0 mg = control), low (40 mg), or high (1000 mg) doses/kg diet were weaned and continued receiving their respective parental diets until the end of the study. Weaned rats received 2 subcutaneous injections (15 mg/kg body weight) of AOM 1 wk apart. After 26 wk, rats were killed and the coordinates of colon aberrant crypt foci (ACF) and tumors were determined. Expression of estrogen receptor (ER)-beta was assessed in rat colon tumors and in DLD-1 human colon adenocarcinoma cells exposed to soy isoflavones. Compared with the control, soy isoflavones did not affect incidences or multiplicities of colon ACF or tumors. Low-dose soy isoflavones decreased tumor burden and size compared with the control (P < 0.05). Expression of ERbeta increased in colon tumors of soy isoflavone-treated groups compared with the control. Soy isoflavones dose-dependently arrested the growth of DLD-1 cells and at subcytotoxic levels increased the expression of ERbeta. Our results suggest that pre- and postnatal exposure to dietary soy isoflavones suppresses the growth of colon tumors in male rats. The overexpression of ERbeta in both rat colon tumors and DLD-1 cells caused by soy isoflavones suggests that ERbeta is a critical mediator in mitigating its cancer-preventive effects.
Asunto(s)
Adenocarcinoma/prevención & control , Neoplasias del Colon/prevención & control , Receptor beta de Estrógeno/metabolismo , Glycine max/química , Isoflavonas/farmacología , Adenocarcinoma/tratamiento farmacológico , Animales , Animales Recién Nacidos , Azoximetano/toxicidad , Carcinógenos/toxicidad , Línea Celular Tumoral , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/tratamiento farmacológico , Dieta , Receptor beta de Estrógeno/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Isoflavonas/química , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
Weanling male Sprague-Dawley rats were administered semi-purified isocaloric diet containing soy oil (SO), seal oil (SE), docosahexaenoic acid (DHA), fish oil (FO) or lard (LA) for 28 days, and then gavaged with 0, 1 or 3 mg MeHg kg(-1) body weight per day and fed the same diet for 14 days. Serum and 24 h urine samples were collected on the day of necropsy, and analyzed for markers of kidney function and diseases. Kidney slices were analyzed for para-amino-hippurate (PAH) and tetraethylammonium (TEA) uptake, total mercury and MeHg content, and examined for pathological lesions. Total mercury and MeHg contents increased significantly and dose-dependently in all dietary groups. MeHg significantly increased relative kidney weight in all groups, serum creatinine in all except SO group, serum uric acid in the DHA and LA groups, serum Mg in all except the LA group, and urinary protein in the SO group. MeHg significantly decreased serum urea nitrogen in SE, FO and LA groups, urinary creatinine in the DHA group, PAH uptake in all except the SE group, and TEA uptake in all groups. MeHg caused nephrosis in all dietary groups. MeHg also significantly increased neutrophil counts in all except the SE group, decreased serum albumin and triglyceride in all except the DHA group, and increased serum total cholesterol in all groups, suggesting a nephrotic syndrome-like outcome. These results confirmed that kidney tubules are major targets of MeHg nephrotoxicity. Treatment with dietary fats did not prevent, but rather altered the profile of, nephrotoxicity of MeHg in rats.
Asunto(s)
Grasas de la Dieta/farmacología , Riñón/efectos de los fármacos , Compuestos de Metilmercurio/toxicidad , Animales , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Calcio/sangre , Colesterol/sangre , Creatinina/sangre , Creatinina/orina , Dieta , Grasas de la Dieta/clasificación , Ácidos Docosahexaenoicos/farmacología , Relación Dosis-Respuesta a Droga , Riñón/metabolismo , Riñón/patología , Magnesio/sangre , Masculino , Tasa de Depuración Metabólica , Compuestos de Metilmercurio/sangre , Compuestos de Metilmercurio/farmacocinética , Nefrosis/inducido químicamente , Nefrosis/patología , Tamaño de los Órganos/efectos de los fármacos , Concentración Osmolar , Compuestos de Amonio Cuaternario/metabolismo , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/metabolismo , Triglicéridos/sangre , Ácido Úrico/sangre , gamma-Glutamiltransferasa/orina , Ácido p-Aminohipúrico/metabolismoRESUMEN
We examined the effects of dietary fats on methylmercury (MeHg)-induced systemic oxidative stress and oxidative DNA damage in liver and kidney of male Sprague-Dawley rats. Rats were treated with a casein-based purified isocaloric diet containing 15% by weight soy oil, docosahexaenoic acid (DHA), seal oil, fish oil, or lard for 28 days, and then gavaged with 0, 1, or 3 mg MeHg/kg BW/day for 14 days. Urine was analyzed for 8-hydroxydeoxyguanosine (8-OHdG) and isoprostane, and serum for total antioxidant capacity (TAC). Liver and kidney were analyzed immunohistochemically for 8-OHdG. Both diet and MeHg showed significant main effects on some of these markers. As compared with the vehicle control, 3 mg MeHg/kg BW significantly increased urinary 8-OHdG in the lard group, urinary isoprostane in the DHA, seal oil, and fish oil groups, while significantly decreasing serum TAC in the lard and fish oil groups. In all dietary groups, 8-OHdG positive staining was located mainly in the nuclei of various cell types in liver and kidney. MeHg expressed a significant main increasing effect on 8-OHdG-positive cells in kidney. These results suggest that both dietary fats and MeHg are important mediators of systemic oxidative stress and oxidative DNA damage.
Asunto(s)
Daño del ADN/efectos de los fármacos , Grasas de la Dieta/farmacología , Compuestos de Metilmercurio/antagonistas & inhibidores , Compuestos de Metilmercurio/toxicidad , Estrés Oxidativo/efectos de los fármacos , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antioxidantes/metabolismo , Biomarcadores , Desoxiguanosina/análogos & derivados , Desoxiguanosina/orina , Dieta , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Indicadores y Reactivos , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Fish consumption is the most important source of human exposure to methylmercury (MeHg). Since fish is also a rich source of n-3 polyunsaturated fatty acids, this study was conducted to examine the effects of dietary fats on MeHg-induced acute toxicity in rats. Weanling male Sprague Dawley rats were administered semi-purified casein-based isocaloric diet containing soy oil, seal oil, docosahexaenoic acid (DHA), fish oil, or lard for 28 days. Rats were then gavaged with 0, 1, or 3 mg MeHg/kg body weight (BW) per day and fed the same diet for 14 consecutive days. On 43rd day of the experiment, rats were sacrificed and blood samples were collected and analyzed for hematology. Liver and spleen were removed, fixed, and examined for pathological changes. Blood, feces, liver, and brain were analyzed for total mercury and/or MeHg contents. Serum samples were analyzed for clinical markers of hepatic injury and immunoglobulin. Total mercury contents in all tissues measured increased with dose. Mercury excretion in feces increased with dose and duration of MeHg treatment. Both diets and MeHg showed significant effects and interacted significantly on many of the toxicological endpoints measured. Many of the effects of MeHg were diet-dependent. For example, in the rats fed the lard diet, 3mg MeHg/kg BW significantly increased relative liver and spleen weight as compared with vehicle control; whereas in rats fed the fish oil, soy oil, seal oil, or DHA, this effect of MeHg was less obvious or absent, suggesting a protective effect of these diets. MeHg at 3mg/kg BW significantly decreased serum albumin level in all except DHA dietary groups, implying a protection by the DHA diet on this parameter. Only in the lard dietary group, did 3mg MeHg/kg BW significantly increase serum bilirubin level, indicating an enhancing effect of this diet on MeHg toxicity. MeHg suppressed the adaptive immune system and stimulated the innate immune system in rats in a diet-dependent fashion. The seal oil diet provided more resistance, while the fish oil diet rendered greater sensitivity to these effects of MeHg on the immune system. These results imply significant modulating effects of dietary fats on MeHg toxicity which may translate into more severe or protective clinical outcomes. Therefore, dietary fats are important factors to be considered in the risk assessment of MeHg exposure.
Asunto(s)
Grasas de la Dieta/farmacología , Compuestos de Metilmercurio/farmacocinética , Compuestos de Metilmercurio/toxicidad , Animales , Encéfalo/metabolismo , Bovinos , Dieta , Ingestión de Alimentos , Recuento de Eritrocitos , Ácidos Grasos/química , Ácidos Grasos/farmacología , Heces/química , Aceites de Pescado/farmacología , Crecimiento/efectos de los fármacos , Inmunoglobulinas/metabolismo , Recuento de Leucocitos , Peróxidos Lipídicos/química , Hígado/química , Hígado/patología , Pruebas de Función Hepática , Masculino , Intoxicación por Mercurio/patología , Compuestos de Metilmercurio/sangre , Aceites/química , Aceites/farmacología , Tamaño de los Órganos/efectos de los fármacos , Recuento de Plaquetas , Ratas , Ratas Sprague-Dawley , Phocidae , Aceite de Soja/farmacología , Bazo/patología , Distribución Tisular , Vitamina E/metabolismoRESUMEN
The effect of dietary isoflavones in the form of NOVASOY (NS) was investigated on methylnitrosourea-initiated mammary gland cancer in F1 generation female Sprague Dawley rats from parents who had undergone lifetime exposure to variable levels of dietary NS. In comparison to NS-free dietary groups, lifetime exposure of F1 rats to 40 and 1000 mg/kg diets of NS reduced tumor latency, but did not significantly affect tumor incidence, tumor size, or tumor multiplicity. A significantly lower tumor multiplicity was, however, observed in rats fed the soy-based, NS-free diet compared to the casein-based, NS-free diet. An evaluation of a dose-response relationship pointed towards a biphasic effect, with a trend showing lower tumor incidence, lower tumor multiplicity, and lower tumor size in rats fed 1000 mg/kg diet NS compared to 40 mg/kg diet NS; however, the data failed to achieve statistical significance. Histologically, tumor type significantly differed according to the administered basal diet variety and NS dose. Our data and that of others provide conflicting evidence for chemopreventive effects of soy isoflavones on mammary gland tumor induction. We suggest standardization of interlaboratory experimental approaches for establishing low dose-response relationships for soy and its isoflavones to aid in risk assessment.