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S N Pennington

Publications and source records attributed to S N Pennington.

At least 19 recordsLinked to original sources
PubMed2006

Rat adult offspring serum lipoproteins are altered by maternal consumption of a liquid diet.

Palatable liquid diets for the administration of ethanol (EtOH) to animals have proven to be a major advance for the study of the effects of EtOH consumption under conditions of isocaloric nutrition of the control animals. Using a liquid diet, the original aim of the reported studies was to examine the effect of maternal EtOH consumption during pregnancy on the lipoprotein (Lp) profiles of the adult offspring measured by means of nuclear magnetic resonance spectroscopy. However, initial data suggested that compared to a maternal chow diet, the basal maternal liquid diet (without EtOH) had a significant effect on specific serum Lp of the adult offspring. The adult offspring of mothers who had consumed a basal liquid diet without EtOH exhibited significant increases in their plasma triglycerides (TG) and cholesterol content compared to adult offspring whose mothers consumed a chow diet. Further, there were significant increases in the offspring's VLDL and low density Lp (LDL) subfractions' particle number, regardless of whether the maternal liquid diet was ad libitum-fed, pair-fed, or EtOH-containing. The increase in offspring plasma TG was due to increases in specific VLDL subfraction particle numbers and not to increased TG content per particle. Similarly, the increase in plasma cholesterol was the result of elevated level of the very small LDL particles but not to an increased amount of cholesterol per LDL particle. These findings should be further examined in light of the widespread use of liquid diets in research to administer EtOH, especially for studies of fetal alcohol syndrome.

Animals↗
PubMed2002

Insulin resistance in adult rat offspring associated with maternal dietary fat and alcohol consumption.

Maternal diet during pregnancy has been reported to alter the offspring's ability to respond to a glucose challenge. The current studies report changes in basal and insulin-stimulated, in vitro glucose uptake in red (soleus) and white (extensor digitorum longus) muscle fiber types, as well as whole body insulin responsiveness of adult rat offspring associated with their mother's dietary fat and alcohol content during pregnancy. The offspring of Harlan-derived Sprague-Dawley female rats, dosed during pregnancy with ethanol (ETOH) via a liquid diet (35% of calories as ETOH) with either 12% or 35% of calories as fat, were compared with offspring from litters whose mothers were pair-fed an isocaloric amount of the liquid diet without ETOH. Maternal access to the liquid diets was terminated on day 20 of the pregnancies (sperm plug=day 0). The offspring were surrogate fostered within 48 h of birth to mothers which had consumed commercial chow throughout their pregnancy. Following weaning at 21 days of age, the offspring consumed only commercial rat chow and they were examined over the next 14 months for changes in glucose homeostasis as a consequence of in utero exposure to maternal dietary fat and/or alcohol. The 35% maternal fat diet resulted in both in vivo and in vitro decreases in insulin sensitivity. Thus, compared with adults whose mother's diet contained 12% fat, significant, in vitro muscle and in vivo whole body insulin resistance (measured by hyperinsulinemic-euglycemic clamping) was observed in adult rats whose mothers consumed 35% of dietary calories as fat. The addition of ethanol to the maternal 35% fat diet further reduced the offspring's red muscle tissues in vitro response to insulin, but did not affect whole body insulin sensitivity. Muscle basal and insulin-stimulated receptor tyrosine kinase activity were significantly decreased (approximately -50%) by the 35% fat maternal diet but there was no compensatory increase in serum insulin or glucose levels. Based upon both in vivo and in vitro data, these studies suggested that in utero exposure to 35% fat has a sustained effect on the adult offspring's glucose uptake/insulin sensitivity and that the effect is paralleled, at least in part, by decreased insulin receptor tyrosine kinase activity. In utero ETOH exposure resulted in the loss of basal and insulin-stimulated, in vitro glucose uptake in red muscle fibers but maternal dietary ETOH had no detectable effect on either in vivo insulin sensitivity or muscle tyrosine kinase activity.

Analysis of Variance↗
PubMed2002

Maternal dietary ethanol consumption is associated with hypertriglyceridemia in adult rat offspring.

BACKGROUND: The consumption of significant amounts of alcohol (ethanol, EtOH) may markedly increase serum triglyceride levels. This study describes a significant increase in fasting serum triglyceride (TG) levels in adult male rats whose mothers consumed EtOH. The hypertriglyceridemia occurred although the offspring never directly consumed EtOH and had consumed only rat chow for the preceding 14 months. Furthermore, both male and female adult offspring had an additional, significant increase in TG levels if their mothers consumed EtOH and experienced stress (restraint) during the pregnancy. METHODS: Harlan-derived Sprague Dawley female rats were dosed during pregnancy with EtOH via a liquid diet, and their offspring were compared with offspring of mothers who were either fed ad libitum or pair-fed the liquid diet without EtOH. At birth, the offspring of EtOH mothers exhibited no visible abnormalities except reduced weight, and all offspring were surrogate fostered within 48 hr of birth to mothers who had consumed commercial rat chow throughout their pregnancy. After weaning, all offspring consumed only commercial rat chow, and they were examined over the next 14 months for changes in triglyceride homeostasis as a function of maternal alcohol intake. RESULTS: Adult male offspring of mothers that consumed EtOH during their pregnancy had significant increases in fasting serum triglycerides associated with an increase in the very low density lipoprotein serum fraction. Acute administration of insulin to the offspring of all maternal dietary groups resulted in a rapid clearing of the serum triglycerides, and there were no differences in basal or heparin-releasable lipoprotein lipase activity between any of the progeny. Castration of the male offspring of EtOH-treated mothers prevented the development of elevated TG levels. Administration of testosterone to littermate female offspring increased circulating TG levels compared with testosterone-treated offspring of pair-fed mothers. EtOH-consuming mothers who also underwent five periods of restraint-induced stress (approximately 10 min each session) produced offspring whose fasting serum TG levels were higher than those whose mothers consumed EtOH but experienced no restraint or who experienced restraint but no EtOH. Maternal stress significantly reduced lipoprotein lipase activity in some offspring treatment groups, but the changes did not correspond to changes in the serum TG levels of the offspring. That is, maternal restraint-induced stress was associated with a loss of heparin-releasable lipoprotein lipase activity by male progeny from pair-fed and EtOH-fed mothers and the female offspring of ad libitum-fed and EtOH-fed mothers. CONCLUSIONS: Although serum triglycerides increased with age in all offspring, the increase was much more pronounced in the progeny of mothers who consumed EtOH during their pregnancy. The hypertriglyceridemia was significantly more pronounced in the male offspring and in female offspring treated with testosterone. Castration of male offspring inhibited the hypertriglyceridemia development, which suggests that male sex hormones may play a role in the development of this condition. Maternal EtOH consumption coupled with maternal restraint-induced stress significantly increased the level of hypertriglyceridemia in both male and female offspring compared with offspring whose mothers experienced restraint but no EtOH or EtOH with no restraint. If this study models the human condition, the results could represent an unrecognized risk factor in a number of adult disease states hypothesized to be associated with hypertriglyceridemia, such as cardiovascular disease, hypertension, and diabetes.

Alcohol Drinking↗
PubMed2001

Differential expression of glucose transporters during chick embryogenesis.

The patterns of Glut1 and Glut3 glucose transporter protein and mRNA expression were assessed during embryogenesis of chicken brain and skeletal muscle, Glut4 protein levels were also evaluated in skeletal muscle and heart, and Glut1 was examined in the developing heart and liver. Glut1 protein expression was detectable throughout brain ontogeny but was highest during early development. Glut1 mRNA levels in the brain remained very high throughout development. Glut3 protein was highest very early and very late and mRNA was highest during the last half of development. In embryonic skeletal muscle, the levels of Glut1 and Glut3 proteins and mRNA were highest very early, and declined severely by mid-development. Glut1 protein and mRNA in the heart also peaked early and then decreased steadily. Although Glut1 mRNA levels were consistently high in the embryonic liver, Glut1 protein expression was not detected. These results suggest that (1) Glut1 is developmentally regulated in chick brain, skeletal muscle, and heart, (2) Glut1 mRNA is present in liver but does not appear to be translated, (3) Glut3 in brain increases developmentally but is virtually absent in muscle, and (4) Glut4 protein and mRNA appear to be absent from chick heart and skeletal muscle.

Animals↗
PubMed2001

Alcohol-induced modulation of the insulin-like growth factor system in early chick embryo cranial tissue.

BACKGROUND: Fetal alcohol exposure has been shown to reduce fetal/embryonic growth. The insulin-like growth factor (IGF) system plays a major role in normal growth and development of the embryo. The purpose of this study was to gain a better understanding of the effects of alcohol (ethanol, EtOH) exposure on the insulin-like growth factors, their binding proteins, and receptors during embryonic development. METHODS: After the administration of either alcohol or chick Ringer's solution to individual eggs at the start of incubation, type-1 IGF receptors, IGF-binding proteins (IGFBPs) as well as IGF-1 and IGF-2 levels were measured in chick embryo craniums on days 5, 6, 7, and 8 of incubation. RESULTS: Levels of the IGF-1 receptor protein were not significantly different between treatment groups on any day studied. In EtOH-treated embryos, the 30 kDa IGFBP levels were significantly higher than vehicle levels on days 5 and 6. On day 6, IGF-1 levels were significantly lower in the alcohol-treated embryos compared with levels in vehicle-treated embryos of the same age. By day 8 of incubation, IGF-1 levels were significantly higher and the 30 kDa IGFBP levels were significantly lower in the alcohol-treated group compared with vehicles. These results indicate an initial EtOH-associated reduction in the amount of IGF-1 available to bind to its receptor (bioavailability), followed by increased IGF-1 bioavailability by day 8. CONCLUSIONS: The elevated IGFBP levels and reduced IGF-1 levels on days 5 and 6 of incubation are congruent with an overall reduction in the bioavailability of IGF-1 during this period and correlate with the decreased embryo weight observed in the alcohol-treated embryos. An increased bioavailability of IGF-1 observed by day 8 may represent a rebound effect and is associated with increases in ornithine decarboxylase activity, a marker of increased growth.

Age Factors↗
PubMed1999

Increased intracellular localization of brain GLUT-1 transporter in response to ethanol during chick embryogenesis.

Fetal exposure to ethanol is associated with growth retardation of the developing central nervous system. We have previously described a chick model to study the molecular mechanism of ethanol effects on glucose metabolism in ovo. Total membrane fractions were prepared from day 4, day 5, and day 7 chick embryos exposed in ovo to ethanol or to vehicle. By Western blotting analysis, ethanol exposure caused a mean 7- to 10-fold increase in total GLUT-1 and a 2-fold increase in total GLUT-3. However, glucose uptake by ethanol-treated cells increased by only 10%. Analysis of isolated plasma (PM) and intracellular (IM) membranes from day 5 cranial tissue revealed a mean 25% decrease in GLUT-1 in the PM and a 66% increase in the IM in the ethanol group vs. control. The amount of PM GLUT-3 was unchanged but that of IM GLUT-3 was significantly decreased. The data suggest that GLUT-3 cell surface expression may be resistant to the suppressive effects of ethanol in the developing brain of ethanol-treated embryos. The overall increase in GLUT-1 may reflect a deregulation of the transporter induced by ethanol exposure. The increased IM localization and decreased amount of PM GLUT-1 may be a mechanism used by the ethanol-treated cell to maintain normal glucose uptake despite the overall increased level of the transporter.

Animals↗
PubMed1998

Rat striatal adenosinergic modulation of ethanol-induced motor impairment: possible role of striatal cyclic AMP.

We have previously reported the involvement of the striatum in acute ethanol-induced motor incoordination and the striatal adenosinergic modulation of ethanol-induced motor incoordination through A1 receptor-mediated mechanism(s). The present study, a continuation of our previous work, was carried out to investigate the possible functional correlation between striatal cyclic AMP and ethanol-induced motor incoordination, and its modulation by striatal adenosine in Sprague-Dawley rats. Forskolin (0.1, 0.5 and 1.0 pmol), a known activator of adenylate cyclase, significantly attenuated ethanol-induced motor incoordination in a dose-dependent manner following its direct intrastriatal microinfusion. Forskolin also antagonized the accentuating effect of intrastriatal N6-cyclohexyladenosine on ethanol-induced motor incoordination. These results suggested that ethanol-induced motor incoordination might be functionally correlated to a decrease in the striatal cyclic AMP levels and that the striatal adenosine A1 receptors might modulate ethanol-induced motor incoordination through cyclic AMP signaling mechanism(s). Further support to this hypothesis was obtained by the actual measurement of the striatal cyclic AMP levels in the same experimental conditions as in motor coordination studies using high-performance liquid chromatography with fluoroscence detection. Regardless of the method (focused microwave irradiation, cervical dislocation or decapitation into a dry ice-ethanol mixture) used to kill the animals, a significant decrease in the striatal cyclic AMP levels was observed due to ethanol. Intrastriatal adenosine A1-selective agonist, N6-cyclohexyladenosine (24 ng), caused a further significant decrease in the striatal cyclic AMP levels in the ethanol- but not in the vehicle-treated animals. The further enhancement in the ethanol-induced decrease in the striatal cyclic AMP levels by intrastriatal N6-cyclohexyladenosine, therefore, functionally correlated with the observed potentiating effect of intrastriatal N6-cyclohexyladenosine on ethanol-induced motor incoordination. The effects of intrastriatal N6-cyclohexyladenosine+ethanol and of ethanol alone on the striatal cyclic AMP levels were blocked by intrastriatal pertussis toxin (500 ng) pretreatment, indicating the involvement of pertussis toxin-sensitive G-proteins (Gi, Go) and possibly of the adenosine A1 receptor coupled to the G-proteins in the striatum. Furthermore, ethanol alone significantly decreased the basal as well as the cyclic AMP-stimulated catalytic activities of the striatal cyclic AMP protein kinase, which were further reduced by intrastriatal N6-cyclohexyladenosine. The results of the present study therefore support an involvement of a cyclic AMP signaling pathway in the striatal adenosinergic modulation of ethanol-induced motor incoordination at the post-adenosine A1 receptor level.

Adenosine↗
PubMed1997

Changes in brain glucose levels and glucose transporter protein isoforms in alcohol- or nicotine-treated chick embryos.

Suppression of fetal brain growth during pregnancy as the result of maternal smoking or alcohol consumption leads to significant problems for the offspring as well as for the society who must care for these individuals. Chronic maternal intake of cigarette smoke is frequently observed in humans and studies using animal models suggest that in utero nicotine exposure is an important component of the growth suppression that results. Similarly, maternal consumption of alcohol (ethanol) has a profound, negative effect on fetal growth. The developing fetal central nervous system (CNS) is sensitive to the growth inhibitory effect of nicotine or alcohol and morphological as well as functional CNS deficits may result from fetal exposure. Using an embryonic chick model which minimizes drug-induced changes in maternal nutrition and behavior, the studies presented here indicate that nicotine or alcohol exposure during early embryonic development inhibits brain growth to a degree comparable to that seen in the rest of the organism, i.e., there was no 'brain sparing' in this model. Glucose content per milligram tissue was markedly decreased in brains of the nicotine-treated embryos but was not significantly different in the alcohol-exposed embryos. Western blots of fetal brain glucose transporter protein isoforms showed no change in the Glut 3 transporter content in the growth suppressed brains compared to vehicle-treated brains. The Glut 1 55 kilodalton (kd) isoform protein content was significantly decreased in the nicotine-treated brains but unchanged in the ethanol-treated brains, while the reverse was true for the Glut 1 45 kd isoform. Thus, the changes in the 55 kd isoform protein content were correlated with tissue glucose levels in the ethanol- and nicotine-treated embryos.

Analysis of Variance↗
PubMed1997

Ethanol differentially affects metabolic and mitotic processes in chick embryonic cells.

Our laboratory has been investigating the mechanisms by which ethanol-induced growth inhibition occurs in a developing embryo, and our studies have focused on disruption of cellular signaling pathways. Previous work on ethanol-induced changes in signaling systems that regulate ornithine decarboxylase activity indicated that the pathways containing protein kinase A, protein kinase C (PKC), and insulin-dependent tyrosine kinase were important for the control of ornithine decarboxylase in chick embryonic cells. Herein, we report ethanol's effect on the regulation of glucose uptake and thymidine uptake by these same kinase pathways. A pronounced increase in glucose uptake was associated with PKC downregulation in both vehicle- and ethanol-exposed cells, with the larger increase occurring in ethanol-exposed cells. An increase in thymidine uptake was associated with an activation of all three kinases, as well as with downregulation of PKC. Because previous work on signaling pathways has looked for changes in the insulin signaling pathway, the work herein focuses on the signaling pathways involving protein kinase A and PKC. cAMP levels were increased by ethanol treatment, but the increase was relatively small. Analysis of changes in PKC activity induced by ethanol exposure showed a significant suppression of PKC activity in the ethanol-treated cells and suggested that, overall, ethanol treatment affects the regulation of glucose uptake in embryonic cells predominantly by PKC downregulation.

Animals↗
PubMed1995

Ethanol's effect on tissue polyamines and ornithine decarboxylase activity: a concise review.

An extraordinarily diverse literature describes the cellular/tissue systems in which the molecular effects of both acute and chronic alcohol exposure seem to be mediated by changes in polyamine levels and/or ornithine decarboxylase (ODC) activity. The single unifying factor that links most of these studies is that they all, in some way, involve tissues that are undergoing relatively rapid cell division. Non-dividing cells expressing the NMDA receptor are a notable exception in that ethanol and the polyamines seem to act via discrete regions of that receptor. Under most cellular conditions, ODC activity is a reflection of the relative tissue polyamine content, and an increase in ODC activity and polyamine content seems to be one of the early events in the progression of quiescent cells toward cell division. Thus, it is not surprising that ethanol, which has been widely reported to delay cell division, should be found to interact with the ODC/polyamine pathway. Perhaps the most unique aspect of these studies is the fact that, with rare exception, both acute and chronic ethanol exposure have been found to slow growth and to lower tissue polyamine (putrescine) content. Furthermore, in most studies, the ethanol-induced suppression of cell division could be overcome by the administration of exogenous putrescine. These data suggest that the ethanol-induced suppression of cell division resulted from the loss of putrescine. In addition, because the cells were able to respond to the exogenous putrescine, the studies suggest that the signaling pathway remained intact beyond the polyamine synthesis step.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1995

Insulin signaling in chick embryos exposed to alcohol.

Although insulin is known to be an important generator of regulatory signals during fetal growth and development, neither the immediate nor long-term effects of alcohol (ethanol) on insulin action are well understood. In the rat, fetal exposure to alcohol has been shown to be correlated with a subsequent abnormal response to a glucose load in the neonate and adult. Further, fetal hypoplasia secondary to maternal alcohol consumption is correlated with decreased placental glucose transport and with a lowering of the glucose levels in fetal tissues. However, the fetal effects of alcohol cannot be completely overcome by glucose/caloric supplementation, suggesting that factors other than glucose transport are involved. Using an embryonic chick model that negates the factors of maternal/placental metabolism and transport, the current study found that fetal alcohol exposure markedly increased insulin binding in developing tissue, but had little effect on the binding of the insulin-like growth factors. Competitive binding experiments revealed a marked increase in insulin receptor numbers, but no change in binding affinity as a result of the alcohol exposure. Basal uptake of 2-deoxyglucose by fetal tissue was lowered by alcohol exposure, but incubation with exogenous porcine insulin (1 x 10(-7) M) resulted in a significant increase in glucose uptake by the alcohol-exposed embryos. The increases in insulin binding and in insulin-dependent glucose uptake notwithstanding, exogenous insulin could not induce normal levels of ornithine decarboxylase activity in embryonic cells previously exposed to alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Signaling pathways regulating ornithine decarboxylase activity in the embryonic chicken.

The pathways regulating ornithine decarboxylase (ODC) activity in the chick embryo were studied to determine which kinase-signaling pathways regulate ODC activity levels during development. Insulin-dependent tyrosine kinase, protein kinase C and cAMP-dependent protein kinase were activated by the addition of insulin, tetradecanoylphorbol-12,13-acetate, and forskolin, respectively. All three drugs increased ODC activity and forskolin combined with insulin increased ODC activity above the increase caused by either drug alone. These results suggest that all three signaling pathways regulate ODC activity during development and that common intermediates exist among the pathways downstream of the kinases.

Animals↗
PubMed1994

Biochemical changes, early brain growth suppression and impaired detour learning in nicotine-treated chicks.

Fetal growth suppression associated with chronic maternal intake of cigarette smoke is frequently observed in humans and studies using animal models suggest that in utero nicotine exposure is an important component of this growth suppression. The developing fetal central nervous system (CNS) is sensitive to the growth inhibitory effect of nicotine and morphological as well as functional CNS deficits may result from fetal nicotine exposure. The studies presented here show that nicotine exposure during early embryonic development ultimately inhibits the ability of 7-11 day old chicks to learn a detour task. The brain growth suppression caused by nicotine is paralleled by a failure of the early embryo brain to express the normal developmental increase in ornithine decarboxylase (ODC) activity. This biochemical change may be germane to the mechanism of nicotine-induced growth inhibition and/or nicotine-induced behavioral changes because the appropriate expression of ODC activity is essential to normal growth and differentiation in the fetal CNS. In the chick embryo, nicotine exposure alters several important signaling pathways that regulate ODC expression. For example, nicotine exposure lowers embryonic brain glucose levels and causes significant decreases in whole brain cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels and in cyclic AMP binding proteins (protein kinase-A regulatory activity). Also, in cultured chick cells, nicotine inhibits the ability of a potent mitogen (insulin) to induce ODC activity, but, paradoxically, in ovo nicotine exposure increased insulin binding and stimulated insulin receptor autophosphorylation in brain membranes.

Animals↗
PubMed1993

Embryonic growth inhibition induced by cocaine is associated with the suppression of ornithine decarboxylase activity.

Cocaine use during pregnancy results in significant increases in fetal morbidity and mortality. Multiple maternal and environmental variables influence the fetal response to cocaine, and growth suppression of the developing child is frequently associated with in utero cocaine exposure. Using intact chick embryos as well as cultured embryonic tissue as a model, we report that the growth suppression induced by cocaine exposure is correlated with molecular changes occurring directly in the embryonic cells and that these molecular changes appear to be distinct from other maternal, placental, or environmental effects of the drug, including anoxia. Specifically, embryonic cocaine exposure suppresses the normal developmental increase in ornithine decarboxylase (ODC) enzymatic activity. The loss of ODC activity during the early stages of development is dose dependent and is correlated with the degree of growth suppression. The cocaine-induced loss of decarboxylase activity is specific to ODC, but cocaine, per se, has no effect on ODC activity in vitro. Moreover, a single dose of exogenous putrescine given at 120 hr of incubation blocks the cocaine-induced growth suppression. In cultured embryonic tissue, cocaine exposure inhibits the ability of a known trophic factor (insulin) to induce growth and also blocks the associated increase in ODC activity. Preliminary data suggest that cocaine hinders the binding of insulin to embryonic cells. Because ODC is a focal enzyme for the regulation of growth, the data suggest that cocaine-induced changes in the mitogenic induction of embryonic/fetal ODC activity may be a part of the biochemical mechanism by which cocaine-induced growth inhibition occurs.

Animals↗
PubMed1990

Genetically determined alcohol preference and cyclic AMP binding proteins in mouse brain.

Free-choice consumption of alcohol by mice with differing phenotypic alcohol preferences caused uniformly large decreases in brain cyclic AMP-dependent protein kinase activity toward an exogenous substrate (histone 2b) but the effect of alcohol on brain cyclic AMP binding activity was strain-specific. Furthermore, particulate kinase phosphorylating activity toward an endogenous protein (kinase regulatory subunit, RII) was altered by alcohol consumption in a strain-specific manner. The changes in cyclic AMP binding and phosphorylating activity appeared to result from phenotypic differences in the brain's response to alcohol. Thus, low preference animals were sensitive to alcohol and showed a large decrease in cyclic AMP binding and an increase in phosphorylation of regulatory subunit in response to alcohol. In contrast, high preference strain had only a small decrease in cyclic AMP binding and a decrease in phosphorylation, even though these animals consumed a significantly larger dose of alcohol. These data suggest that changes in cyclic AMP binding and/or phosphorylation of kinase regulatory subunit may be phenotypic markers of alcohol preference in inbred mice.

Alcoholism↗
PubMed1990

Molecular changes associated with ethanol-induced growth suppression in the chick embryo.

In humans and in animal models the most frequently observed alcohol-related birth defect (ARBD) is intrauterine growth retardation (IUGR). The central nervous system (CNS) is sensitive to the growth inhibitory effects of in utero ethanol exposure and neonatal CNS alterations with associated behavioral deficits are a likely result of maternal ethanol consumption. Presently, little information exists as to the biochemical mechanism by which ethanol inhibits fetal CNS growth. Further, it is unknown if there are genetic differences in maternal or fetal responses to ethanol. Ongoing research using a chick model indicates that pharmacologically appropriate doses of ethanol (less than 30 mM) inhibit brain growth and reduce CNS 3',5'-cyclic adenosine monophosphate (cyclic AMP) with an associated 50% decrease in the binding of cyclic AMP by the regulatory subunit (RII) of protein kinase A. Furthermore, there is a specific loss of phosphorylation of RII by kinase catalytic subunit as a result of ethanol exposure. Because tissue cyclic AMP content and the degree of RII phosphorylation are important parameters for the regulation of protein kinase A catalytic activity, it is hypothesized that these alterations may be biochemical transformations that underlie ethanol-induced growth suppression.

Animals↗
PubMed1987

Eicosanoid production by peritoneal and splenic macrophages in mice depleted of bone marrow by 89Sr.

Previous studies showed that the prostaglandin-forming macrophages (M phi) induced in the spleens of CBA/J mice by intraperitoneal administration of Corynebacterium parvum (CP) could not be demonstrated following the depletion of bone marrow and blood monocytes with 89Sr. The present study compares prostaglandin E2 (PGE2), leukotriene C4 (LTC4), and LTB4 release by splenic and resident peritoneal M phi in 89Sr-treated mice and 88Sr controls following in vivo CP and in vitro incubation with zymosan, calcium ionophore A23187, or phorbol ester (PMA). Intraperitoneal administration of CP resulted in the appearance of PGE2- and LTB4-releasing M phi in the spleens of control but not 89Sr mice. The incorporation and quantitative distribution of 3H-arachidonic acid into membrane lipids, however, were comparable in test and control mice. Neither zymosan nor any of the other stimulatory agents was able to effect significant release of PGE2 in vitro. No release of LTC4 by splenic M phi was detectable under experimental or control conditions. In contrast, the capacity of resident peritoneal M phi to release PGE2, LTC4, and LTB4 was apparently unaffected by 89Sr-induced bone marrow and monocyte depletion with virtually no demonstrable elicitation. Resident peritoneal M phi removed after CP in such mice showed a dramatic decrease in PGE2 release when incubated in vitro with zymosan, A23187, or PMA. These results, taken with earlier findings, demonstrate characteristically different phenotypic expression of metabolism of certain eicosanoids by splenic M phi from the spleen and the peritoneal cavity and suggest in addition that the induction of PGE2-synthesizing M phi in the spleen by CP is dependent on either an immigrant cell originating in the bone marrow or a regulatory agent derived from a bone marrow cell.

Animals↗