PubMed Health⌕ Search

Biomedical subjects

S N Pennington

Publications and source records attributed to S N Pennington.

67 records · Page 4Linked to original sources
PubMedDate not supplied

Alcohol metabolism and fetal hypoplasia in chick brain.

Chick embryos given a single dose of ethanol (1.0 g/kg) at the start of incubation (day 0) had widely differing levels of blood alcohol when sacrificed on day 7 and the blood alcohol levels were inversely correlated with whole body and brain weight. Clearance of the alcohol by the embryos was inhibited by simultaneous treatment with 4-methyl pyrazole and this treatment potentiated the brain growth inhibition due to ethanol. Treatment with indomethacin lowered blood alcohol levels on day 7 and protected against the growth inhibition. These data suggest that early chick embryos have varying amounts of alcohol dehydrogenase-like metabolic activity and that higher levels of this activity protect against alcohol-induced brain growth inhibition in this model. If similar variations in the ability to metabolize alcohol exist in human fetuses, it may represent a mechanism by which comparable maternal doses of alcohol produce widely varying fetal effects.

Alcohol Dehydrogenase↗
PubMedDate not supplied

The effect of embryonic ethanol exposure on detour learning in the chick.

To examine the effects of embryonic ethanol exposure on survivability, posthatch growth and detour learning, 4 groups of 30 fertile black sex-linked eggs were given 200 microliter injections of a solution of water and 0.0, 12.5, 37.5 or 50.0% (groups IC, L, M and H, respectively) ethanol (v/v) immediately preceding incubation. A fifth group of 33 eggs served as noninjected controls (NC). The results demonstrated that compared to group NC, a smaller percentage of groups M and H hatched and survived for behavioral testing, and that group H required more trials to reach criterion on the detour learning problem than did group IC. It was concluded that the teratogenic effects of ethanol are robust with respect to species and that the chick is an excellent model for studying some developmental and behavioral effects resulting from embryonic ethanol exposure.

Animals↗
PubMedDate not supplied

Embryonic ethanol exposure impairs detour learning in chicks.

Six groups of 30 fertile eggs each were injected with 200 microliters of either sterile water or a 37.5% (v/v) ethanol solution immediately before incubation or on days 7 or 14 of incubation. Regardless of day of injection, the ethanol groups had a lower proportion of chicks who completed pipping and hatching. Of the chicks surviving to pip and hatch, the group injected with ethanol immediately before incubation was delayed significantly in pipping compared to the other ethanol-injected groups and to the group injected with water immediately before incubation (p less than 0.05 in all cases). Also, compared to the chicks injected with water, the chicks in all ethanol groups required more trials to attain criterion on a detour learning task when tested 7-10 days after hatching (p less than 0.05).

Animals↗
PubMedDate not supplied

Drinking of high concentrations of ethanol versus palatable fluids in alcohol-preferring (P) rats: valid animal model of alcoholism.

A genetically based animal model of alcoholism has been characterized in Wistar-derived rats in terms of their preference (P rats) or lack of preference (NP rats) for 10% ethanol over water. The present experiments were designed to determine: 1) whether a 10% solution of ethanol is the optimal concentration for differentiation of these lines; 2) what concentrations of ethanol are maximally preferred by P and NP rats; and 3) whether highly palatable fluids presented simultaneously with each rat's preferred solution of ethanol would alter the patterns of drinking by either the P or NP or both lines of rats. A three-bottle procedure was used to establish preference for ethanol in the presence of water as well as highly palatable solutions. The results showed that, when concentrations ranging from 3-30% were presented over a 12-day test interval, the mean absolute intake of ethanol of the P rats was 6.7 g/kg per day, with a maximum intake of 10.9 g/kg per day at the 25% concentration. These levels of intake were significantly higher than the 4.3 g/kg per day consumed during the presentation of the commonly used constant concentration of 10%. Similarly, the mean absolute intake of ethanol by the NP rats was also elevated significantly at concentrations of 15-30% (2.0 g/kg per day) above that consumed at the 10% concentration (0.4 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMedDate not supplied

Cyclic AMP-dependent protein kinase activity in the brains of alcohol-preferring (P) and nonpreferring (NP) rats.

In contrast to the reported response of inbred male mice [Beeker et al. (2)], young male rats with differing preferences for ethanol (P and NP lines) exhibited no significant change in brain cyclic AMP-binding activity following free-choice consumption of ethanol for 28 days. However, for the NP line, phosphorylation of the kinase regulatory subunit (RII) by basal kinase activity in the cytoplasmic fraction was significantly suppressed by free-choice ethanol consumption but the preferring (P) line showed no such changes. Thus the changes in phosphorylating activity appeared to be associated with differences in the animals' responses to ethanol exposure. The lower preference line (NP) consumed a smaller amount of ethanol (mean = 1.7 +/- 0.1 g/kg/24 hours) and showed a significant decrease in phosphorylating activity relative to vehicle-treated animals whereas the high preference line (P) showed no such change in kinase catalytic activity relative to controls, even though these animals consumed a significantly larger dose of ethanol (mean = 5.9 +/- 0.7 g/kg/24 hours). The data suggest that the P and NP lines differ as to their sensitivity to ethanol-induced changes in the phosphorylation of brain protein kinase regulatory subunit, an important parameter in the overall regulation of kinase activity.

Alcohol Drinking↗
PubMedDate not supplied

Ethanol-induced insulin resistance suppresses the expression of embryonic ornithine decarboxylase activity.

In utero exposure to ethanol is associated with significant increases in fetal morbidity and mortality as well as with behavioral and learning problems that appear later in life. Growth suppression of the developing child is the most frequent physical effect of ethanol exposure and is correlated with specific molecular changes within the developing organism. The present report suggests that embryonic ethanol exposure suppresses the normal developmental increase in ornithine decarboxylase (ODC) activity. The loss of ODC activity during the early stages of development is dose-dependent and is correlated with the degree of growth suppression. Because ODC is the rate-limiting step for the synthesis of the polyamines and thus appears to be a focal enzyme for the regulation of growth, we have investigated the biochemical consequences of an ethanol-induced inhibition of ODC activity. Using intact chick embryos as well as cultured embryonic tissue, these studies indicate that ethanol-induced changes in tissue putrescine content result in growth suppression because a single dose of exogenous putrescine blocked the growth suppression. In cultured tissue, ethanol exposure inhibited the ability of a known trophic factor (insulin) to induce ODC activity. The loss of insulin-inducible decarboxylase activity as a result of ethanol exposure was specific to ODC, but ethanol per se had no effect on ODC activity in vitro. The data suggest that exposure to ethanol results in a resistance of the embryonic tissue to the action of insulin and thereby disrupts the molecular path by which this mitogenic compound induces the expression of ODC enzymatic activity.

Animals↗
PubMedDate not supplied

Sodium ion-dependent (N-methylamino)-alpha-isobutyric [correction of isobutryic] acid uptake by embryonic chick cells exposed to ethanol in ovo:response to the stimulation/downregulation of protein kinases.

Amino acid uptake, critical for embryonic development, was studied in cultured chick cells isolated from 5-day-old chick embryos that had received treatment in ovo with either vehicle (sterile chick Ringer's solution) or vehicle plus ethanol (1.5 g/kg). Upon being placed in culture, the cells were grown in the absence of ethanol per se. The uptake of (N-methylamino)-alpha-isobutyric [correction of isobutryic] acid (AIB) was used to estimate amino acid uptake via system A, a Na+-dependent system that transports short-chain amino acids. The uptake of AIB in cultured chick embryo cells in response to the stimulation/downregulation of three protein kinases [tyrosine kinase, cyclic AMP-dependent kinase A (PKA) and protein kinase C (PKC)] was determined. Acute activation of PKC by treatment of the cells with a phorbol ester (TPA) inhibited Na+-dependent AIB uptake. Conversely, treatment of the cells with TPA for 24 h, to downregulate PKC activity, significantly increased AIB uptake. The data suggest that in these cells, PKC plays an important role in the regulation of amino acid uptake via system A. Activation of PKA via treatment of the cells with forskolin, an adenylyl cyclase activator, had little effect on AIB uptake in cells from vehicle-treated embryos and only a slight depressing effect on uptake by cells from ethanol-treated embryos. Insulin and insulin-like growth factor-1 (IGF-1) both stimulated AIB uptake, but the higher concentrations of insulin necessary to increase uptake to a level comparable to that of IGF-1 stimulation suggested that insulin could be acting through the IGF-1 receptor. Thus, while AIB uptake by cells of in ovo ethanol-treated embryos was significantly increased by treatment with either insulin or IGF-1, IGF-1 appeared to be the more physiologically important compound in the chick embryo. Overall, there was a consistent trend for cells isolated from in ovo ethanol-treated embryos to have higher levels of AIB uptake relative to cells isolated from vehicle-treated embryos, regardless of the in vitro treatment.

Animals↗
PubMedDate not supplied

Experimental models used to measure direct and indirect ethanol teratogenicity.

The teratogenic effects of ethanol have been widely studied in a variety of experimental models. In humans, ethanol teratogenicity results from both direct and indirect effects. This paper reviews the differences between direct and indirect effects of ethanol on the developing fetus. Experimental paradigms are discussed that attempt to differentiate between direct and indirect effects. For the purpose of this review, direct effects of ethanol are caused by ethanol interacting with the fetal cell. Indirect effects of ethanol teratogenicity are defined as any perturbation of the developing fetus resulting from ethanol exposure but not caused by ethanol's interacting with the fetal cell. Indirect effects of ethanol teratogenicity include: ethanol-induced maternal undernutrition; ethanol-induced placental dysfunction and acetaldehyde teratogenicity.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Metabolic and mitotic changes associated with the fetal alcohol syndrome.

In the USA, fetal alcohol syndrome (FAS) is the leading known cause of mental retardation. FAS is estimated to affect 4000 infants yearly in the USA with an additional 7000 children suffering various forms of fetal alcohol effects in the absence of the full syndrome. A comparable incidence would be expected in other industrialized countries, but essentially no data are available from either developing or third world countries. An understanding of the biochemical causes of FAS has been slow to develop, but progress has been made toward a molecular causation theory of FAS. This paper summarizes much of the current work as to the effects of fetal ethanol exposure on mitotic and metabolic parameters as well as ethanol's effect on the cellular signalling pathways thought to regulate these processes. Based upon these studies, it is apparent that exposure of embryonic tissue to ethanol results in decreased growth and that alcohol adversely affects a multitude of cellular functions critical for the growth of the developing organism, including inhibition of protein and DNA synthesis. In addition, ethanol alters the uptake of critical nutrients such as glucose and amino acids and causes changes in several kinase-mediated signal transduction pathways that regulate these biochemical processes.

Central Nervous System Depressants↗
PubMedDate not supplied

A single dose of ethanol suppresses rat embryo development in vivo.

In humans and animal models, maternal ethanol consumption during pregnancy results in a variety of fetal defects collectively termed the fetal alcohol syndrome (FAS). Limited follow-up studies suggest that FAS children fail to achieve normal physical or mental development despite significant postnatal intervention. Although the complete FAS appears to result only when chronic, excessive alcohol consumption occurs throughout pregnancy, several investigators have suggested that ethanol consumption at intermediate levels may induce components of FAS. The defect most consistently observed in neonates exposed to ethanol is growth retardation. Even those children whose mothers consume limited amounts of ethanol during pregnancy have a significant incidence of fetal growth deficiency. We now report that a single dose of ethanol administered to female Holtzman rats within 8 hr after mating results in a dose-dependent retardation of cell division in the fertilized ova. The growth retardation is sustained up to 42 hr after the dose and the embryos of young mothers are especially sensitive to ethanol. Animals with high blood alcohol levels (greater than 150 mg/100 ml) show a significant increase in abnormal embryo morphology. These data suggest that maternal consumption of a single dose of ethanol near the time sustained up to 42 hr after the dose and the embryos of young mothers are especially sensitive to ethanol. Animals with high blood alcohol levels (greater than 150 mg/100 ml) show a significant increase in abnormal embryo morphology. These data suggest that maternal consumption of a single dose of ethanol near the time of conception retards embryonic growth and may be detrimental to the developing organism. Further, young female rats receiving a high dose of ethanol had significantly lower uterine weights and a lower number of corpora lutea per ovary, suggesting that a single dose of ethanol has a detrimental effect on maternal reproductive ability.

Alcohol Drinking↗
PubMedDate not supplied

Ethanol-induced inhibition of chick brain growth.

Retarded fetal brain growth is associated with a high incidence of mental retardation among the offspring of chronic alcoholic mothers. Research using an embryonic chick model suggests that ethanol exposure suppresses fetal development including suppression of brain growth. Total brain cyclic AMP content and endogenous brain protein kinase specific activity are not altered by ethanol; however, ethanol exposure does significantly stimulate kinase catalytic activity measured in the presence of saturating amounts of exogenous cyclic AMP.

Animals↗
PubMedDate not supplied

The molecular mechanism of fetal alcohol syndrome (FAS). I. Ethanol-induced growth suppression.

Of the birth defects associated with alcohol consumption during pregnancy, in situ growth retardation resulting in neonates that are small for gestational age is the most common observation in both humans and animal models. A variety of alcohol-induced alterations in maternal, placental and/or fetal physiology have been proposed as the basis for this retarded fetal growth. The molecular mechanism(s) of this retardation, however, is obscure; and it remains to be determined whether the growth suppression is the result of the action of ethanol or its metabolites on embryonic, maternal or placental tissue. Using the embryonic chick as a model which circumvents changes in maternal and placental function, we have measured ethanol-induced growth suppression as a function of embryonic age and ethanol dosage. The data suggest that ethanol per se suppresses the rate of cell division in embryonic tissue resulting in fewer cells/embryo for a given time of gestation. The suppression of cell division is proportional to the ethanol dose and appears to be related to ethanol-induced changes in the metabolism of the prostaglandin hormones and resulting changes in the cyclic-AMP levels of the developing embryos.

Alcohol Dehydrogenase↗