RESUMEN
The effects of environmental enrichment on synaptic spine density in hippocampal area CAI were examined in rats exposed prenatally to alcohol. Pregnant dams were given ethanol via intragastric intubation (6 g/kg/day) from gestational days 8 through 19, or given isocaloric sucrose. An untreated control group was also used. After weaning, offspring from the three groups were then reared for 10 weeks in either isolated (caged alone, not handled) or enriched (group housed with "toys," handled) conditions. Animals were then sacrificed, the brains Golgi impregnated, and CAI pyramidal cell apical and basilar spine densities quantified. Among isolated animals there were no significant differences between control and alcohol-exposed groups. In general, environmental enrichment increased apical or basilar spine densities in untreated and sucrose controls. However, in prenatal alcohol-exposed animals, environmental enrichment did not increase spine densities. Because the environmental enrichment acted postnatally, these findings suggest that the effects of prenatal alcohol exposure included decreased neural plasticity enduring into early adulthood. Such a reduction in neuroanatomical plasticity in hippocampus may be associated with cognitive impairments found following prenatal alcohol exposure.
Asunto(s)
Depresores del Sistema Nervioso Central/toxicidad , Dendritas/ultraestructura , Ambiente , Etanol/toxicidad , Hipocampo/citología , Efectos Tardíos de la Exposición Prenatal , Animales , Colorantes , Dendritas/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Masculino , Embarazo , Células Piramidales/efectos de los fármacos , Células Piramidales/ultraestructura , Ratas , Caracteres Sexuales , Sinapsis/efectos de los fármacos , Sinapsis/ultraestructura , Aumento de Peso/efectos de los fármacosRESUMEN
Alcohol teratogenesis may be due, in part, to inhibition of neuronal differentiation by alcohol. Because decreases in the N-myc and c-myc proteins are believed to be linked causally to neuronal differentiation, we hypothesized that alcohol would increase N-myc and c-myc proteins in undifferentiated neuronal cells and would oppose the decreases in these two proteins that normally precede differentiation. In undifferentiated LA-N-5 cultured human neuroblastoma cells, alcohol increased N-myc protein levels (178% vs. control cells) and c-myc levels (222% of control). Retinoic acid decreased N-myc and c-myc and induced neurite outgrowth (a differentiation marker). Alcohol prevented retinoic acid-elicited decreases in both myc isoforms and prevented neurite outgrowth. A significant 100% increase in c-myc and an upward trend (48%) in N-myc were observed in CA1 pyramidal neurons of the dorsal hippocampus in mouse fetuses exposed prenatally to alcohol. These data suggest that increases in N-myc and c-myc protein levels are associated with inhibition of neurite extension by alcohol.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Neuritas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/biosíntesis , Animales , Neoplasias Encefálicas/metabolismo , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Depresión Química , Expresión Génica/efectos de los fármacos , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/crecimiento & desarrollo , Humanos , Inmunohistoquímica , Ratones , Neuritas/ultraestructura , Neuroblastoma/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/ultraestructura , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
Alcohol teratogenesis may be due in part to inhibition of neuronal differentiation by ethanol. We showed previously that alcohol decreased neuronal differentiation (neurite extension) and increased N-myc and c-myc neuronal protein levels. Since Growth-Associated Protein 43 (GAP43/B50) levels must increase for neurons to differentiate, alcohol may decrease GAP43/B50. Alcohol dose-dependently (0-0.5%) decreased GAP43/B50 protein levels by up to 92% in immature LA-N-5 cells. Five nM retinoic acid alone induced differentiation and increased GAP43/B50 levels to 230% of control. These retinoic acid-induced increases in GAP43/B50 and neurite outgrowth, and decreases in N-myc and c-myc, were reversed dose-dependently by alcohol (0-0.5%). Conversely, the adverse effects of 0.25% alcohol on neurite extension, GAP43/B50, N-myc, and c-myc were prevented by 15 and 45 nM retinoic acid. These results suggest that inhibition of neuronal differentiation by alcohol and prevention of such effects by retinoic acid are related to changes in GAP43/B50, N-myc and c-myc.
Asunto(s)
Etanol/farmacología , Glicoproteínas de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuritas/efectos de los fármacos , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Proteína GAP-43 , Sustancias de Crecimiento/metabolismo , Humanos , Neuritas/fisiología , Neuronas/citología , Células Tumorales CultivadasRESUMEN
Animals exposed prenatally to alcohol (4 g/kg/day) via maternal peroral intubation or control offspring were reared after weaning either alone in standard steel/wire cages or in groups of eight, for 6 weeks. Rats exposed prenatally to alcohol and reared in isolation had a dysmetric stride length indicative of an ataxic gait. However, following postweaning environmental enrichment, prenatal alcohol-exposed rats showed no evidence of ataxia. In addition, the prenatal alcohol-exposed rats showed the same magnitude of improved Morris maze performance after enrichment as did the control offspring. These preliminary results suggest that postnatal environment can influence the expression of alcohol-related birth defects in rats, that rats exposed prenatally to alcohol can benefit from the effects of enriched postweaning environment and that postnatal factors can attenuate some of the deficits due to prenatal alcohol exposure.
Asunto(s)
Conducta Animal/efectos de los fármacos , Ambiente , Etanol/toxicidad , Efectos Tardíos de la Exposición Prenatal , Animales , Ataxia/inducido químicamente , Conducta Animal/fisiología , Conducta Exploratoria/efectos de los fármacos , Femenino , Marcha/efectos de los fármacos , Miembro Posterior/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Embarazo , Ratas , Aumento de Peso/efectos de los fármacosRESUMEN
Previous studies have implicated renal ultrastructural abnormalities in the pathogenesis of tubular dysfunction in fetal alcohol syndrome. Scanning electron microscopic studies were performed to examine the role of glomerular and tubular structural changes in this syndrome. Pregnant Sprague-Dawley rats were fed a liquid diet in which ethanol constituted 35% of the total caloric content or pair-fed an isocaloric control diet from gestational day 8 to the day of birth. After delivery, offspring were housed with the dam and left undisturbed until 18 days of age when they were weaned and given free access to standard chow diet and water. At random, kidneys from 11 offspring of ethanol-fed (E) rats and 7 pair-fed control (C) rats were fixed by in vivo retrograde perfusion at 90 days of age for ultrastructural studies. The E rats showed cytoplasmic mitochondrial atrophy and vacuolar structures of the epithelial cells of the distal tubules and collecting ducts not seen in C rats. No obvious difference was found in the glomerular, proximal tubule, or loop of Henle architecture between the two groups. These findings suggest that rats prenatally exposed to ethanol have renal ultrastructural abnormalities that may be important in the genesis of functional disturbances.
Asunto(s)
Etanol/toxicidad , Feto/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/ultraestructura , Animales , Femenino , Trastornos del Espectro Alcohólico Fetal/patología , Microscopía Electrónica de Rastreo , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Since the first reports of fetal alcohol syndrome (FAS), thousands of studies have examined the effects of antenatal alcohol exposure in humans and in animal models. Research with animal models has led to discoveries which would be difficult if not impossible in human subjects. Most importantly, these models have resulted in valuable insights into the actions of alcohol on various parts of the developing embryo and have helped researchers come closer to identifying the mechanisms of its teratogenic action. Both the direct and indirect biological effects of alcohol exposure in utero appear to work in conjunction with other concurrent and predisposing factors such as genotype, nutritional status, pattern of exposure and use of other drugs such as nicotine and cocaine. At present animal research indicates a multifactorial mechanism of the teratogenicity of alcohol resulting from nutrient deficiencies, fetal hypoxia and alterations in enzyme activities and cell function important in cell division and membrane integrity. This review examines how animal models are used to clarify issues associated with alcohol-related birth defects and to shed light on the underlying mechanisms.
Asunto(s)
Modelos Animales de Enfermedad , Trastornos del Espectro Alcohólico Fetal , Anomalías Inducidas por Medicamentos/etiología , Animales , Femenino , Trastornos del Espectro Alcohólico Fetal/etiología , Humanos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Factores de Riesgo , Especificidad de la EspecieRESUMEN
Effects of prenatal ethanol exposure on postnatal renal function and structure in the rat. Renal function and morphology were studied in 90-day-old offspring of ethanol-fed (E) rats and were compared to pair-fed control (C) animals. Compared to C rats, E rats were smaller at birth, had higher fractional sodium excretion (p less than 0.01) and lower fractional potassium excretion (p less than 0.01). In E rats, sodium (Na) restriction resulted in a significant increase in urine flow and Na wastage, whereas C rats remained in Na balance. E rats developed hyperkalemia, when potassium (K) intake was increased from 2.8 to 14 mEq/day. Baseline creatinine clearance, urine and blood osmolalities and pH, plasma electrolytes and aldosterone concentrations were similar in both groups. There was no significant difference in wet or dry kidney weight, renal water content, or renal tissue concentrations of Na or K between the two groups. No difference was found in gross morphology or light microscopic appearances of the kidneys between E and C rats. Thus rats exposed to ethanol during fetal life have a defect in urine concentration and Na conservation when fed a low Na diet and a defect in K excretion when given a K load without evidence of any gross or light microscopic renal structural abnormalities at 90 days of age.
Asunto(s)
Etanol/toxicidad , Feto/efectos de los fármacos , Riñón/efectos de los fármacos , Animales , Dieta Hiposódica , Femenino , Riñón/patología , Riñón/fisiología , Potasio/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Polydrug abuse has increased substantially in recent years amongst obstetric patients. One of the most common drug combinations is alcohol and cocaine. To better understand the adverse consequences of this drug combination on pregnancy and the offspring, alcohol (2 g/kg, b.i.d.) and cocaine HCl (30 mg/kg, b.i.d.) were administered individually and in combination to separate groups of pregnant Long-Evans rats from gestation days 7-20. The pregnant dams were evaluated for maternal weight gain, food and water consumption, mortality, and gestational length. The offspring were evaluated for physical maturation, mortality, and behavior. The drug combination was found to have greater effects regarding decreased birth weight, increased postnatal mortality, and delayed physical maturation than either drug alone. Drug treatments also influenced activity monitor behavior in that prenatal cocaine exposure was associated with hypoactivity while the alcohol and the alcohol-plus-cocaine treatments were associated with hyperactivity in periweanling pups. Drug treatments had no significant effects on passive or active avoidance behaviors. These results suggest that combining alcohol and cocaine increases the risk to the offspring.
Asunto(s)
Conducta Animal/efectos de los fármacos , Cocaína/toxicidad , Etanol/toxicidad , Animales , Reacción de Prevención/efectos de los fármacos , Peso al Nacer/efectos de los fármacos , Cocaína/administración & dosificación , Sinergismo Farmacológico , Etanol/administración & dosificación , Femenino , Muerte Fetal/inducido químicamente , Crecimiento/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Aumento de Peso/efectos de los fármacosRESUMEN
Pregnant Sprague-Dawley rats consumed an ethanol-containing liquid diet containing 0%, 17.5% or 35% ethanol-derived calories (EDC) from gestation day 8 until parturition. A fourth group was fed standard rat chow as an ad lib diet control. Animals prenatally exposed to ethanol had lower birth weights and impaired passive avoidance learning at 17 days of age. At 90 days of age synaptic potentials in area CA1 were characterized electrophysiologically in hippocampal slices. Slices from ethanol-exposed rats had significantly greater paired-pulse facilitation compared to 0% EDC and ad lib controls. Histological examination of brains from litter mates did not indicate altered number, density or nuclear volumes for neurons in area CA1. These data indicate that prenatal ethanol exposure can result in abnormal hippocampal synaptic physiology and suggest that these changes may contribute to the learning impairments observed in rats following such exposure.
Asunto(s)
Etanol/toxicidad , Feto/efectos de los fármacos , Hipocampo/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Peso al Nacer/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Femenino , Hipocampo/patología , Hipocampo/fisiología , Técnicas In Vitro , Embarazo , Ratas , Ratas EndogámicasRESUMEN
The potential contribution of maternal age to tetrahydrocannabinol's (THC) in utero effects in rats was studied. Pregnant animals were intubated with 25, 10 or 0 mg/kg of THC from gestation day six to parturition. Animals in the 10 and 0 mg/kg groups were pair fed to those given the 25 mg/kg dose. Each series of doses was administered to females three, four or six months of age. THC lowered maternal weight gain and weights of offspring at birth and at 21 days of age, but did not affect litter size, spontaneous alternation or passive avoidance learning in offspring. Increased maternal age was associated with smaller litter size and lower birth weight and weight at 21 days, but did not interact significantly with THC.
Asunto(s)
Dronabinol/toxicidad , Desarrollo Embrionario y Fetal/efectos de los fármacos , Edad Materna , Preñez/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Peso al Nacer/efectos de los fármacos , Femenino , Tamaño de la Camada/efectos de los fármacos , Masculino , Embarazo , Distribución Aleatoria , Ratas , Caracteres Sexuales , Aumento de Peso/efectos de los fármacosRESUMEN
Two studies were conducted to evaluate the interactive effects of alcohol and lead during pregnancy in rats. Our purpose was to see if lead, as lead acetate, would influence the alcohol effect already known to exist. In the first study, pregnant Long-Evans rats received lead (as lead acetate), alcohol (20% w/v), or lead plus alcohol once a day on gestation days (GD) 10-20. On GD 20, when animals were sacrificed, mean blood alcohol levels were consistently higher for the lead-plus-alcohol-dosed groups compared to alcohol alone, but these two groups did not differ in maternal weight gain, percent resorptions, litter size, or fetal weight. Mean blood lead levels were not consistently higher in the lead-plus-alcohol groups compared to lead only, but the lead-plus-alcohol groups differed significantly from the lead-only groups at higher doses in the previously mentioned parameters. The lead-only groups did not differ from vehicle controls in any parameter in spite of blood lead levels as high as 300 micrograms/dl. In the second experiment, animals given a combination of alcohol and lead did not differ in activity, passive avoidance, or active avoidance learning compared to animals given alcohol or lead alone. Animals given lead only or the combination of lead plus alcohol had longer first trial latencies in the passive avoidance test. The data indicate that neither lead nor alcohol attenuates or potentiates each other's effects on reproduction or learning behavior in the Long-Evans rat even at high blood lead levels.
Asunto(s)
Desarrollo Embrionario y Fetal/efectos de los fármacos , Etanol/efectos adversos , Plomo/toxicidad , Aprendizaje/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Reabsorción del Feto , Tamaño de la Camada/efectos de los fármacos , Embarazo , Ratas , Ratas Endogámicas , Análisis de Regresión , Aumento de Peso/efectos de los fármacosRESUMEN
The red nucleus of Swiss Webster mouse fetuses was examined for morphological changes following maternal ethanol exposure. Pregnant females were given a liquid diet containing 30% or 0% ethanol-derived calories. Changes in numerical density of neurons and in neuronal nuclear volume were found in the rostral red (RR) nucleus of ethanol-exposed pups but not in the caudal red (CR) nucleus. Because of the integrative nature of the RR, changes in neuronal morphology that might relate to synaptic connections could affect the behavioral response mechanisms of these offspring.
Asunto(s)
Etanol/toxicidad , Núcleo Rojo/embriología , Animales , Femenino , Masculino , Intercambio Materno-Fetal , Ratones , Neuronas Aferentes/efectos de los fármacos , EmbarazoRESUMEN
Pregnant Swiss Webster mice were given a liquid diet with ethanol (EtOH) or isocaloric amounts of maltose dextrin on gestation day (GD) 0 through 18. On GD 18, maternal blood samples were obtained. Fetuses were then removed and fetal brains were prepared for light microscopy. Fetal weight was reduced in the EtOH-exposed group. The ratio of midbrain cross sectional area to cerebral aqueduct was reduced in the ethanol group, while the density of neuronal nuclear population in both the dense outer layer (DS) and sparse inner layer (SS) of the developing superior colliculus was increased. Mean nuclear volume was decreased in the SS.