Prenatal Ethanol Exposure Alters Adrenocortical Development of Offspring

Interactive effects of prenatal ethanol and maternal nutritional status on reproductive outcome and maternal and offspring adrenocortical activity were examined. Ethanol was administered to pregnant females in liquid diets (36% ethanol-derived calories) which were marginal or optimal in terms of requirements for pregnancy. Both pair-fed and ad libitum fed control groups were included. Females consuming ethanol from gestation Day 1 through parturition gained less weight, were delayed in parturition, and had fewer and smaller live born young than pair-fed or control females, regardless of whether they consumed marginal or optimal diets. Withdrawing ethanol on Day 21 of gestation attenuated many of ethanol's adverse effects on reproductive outcome. However, prenatal maternal ethanol intake altered adrenocortical activity/responsiveness of the mother, the fetus, and the preweaning offspring, regardless of maternal nutritional status. Relative adrenal weights and basal corticosterone levels were increased in the dam both prenatally and at parturition. Ethanol-exposed fetuses (A) had increased relative adrenal weights but lower basal corticosterone levels than pair-fed (PF) and control (C) fetuses on gestation Day 21. At birth, plasma and adrenal corticosterone levels were increased, while absolute adrenal weights and corticosterone binding globulin (CBG) binding capacity were decreased in A neonates. At 5 days of age, A pups showed reduced plasma corticoid responses to ether at 15 min poststress and to novelty or saline injection at 90-min post stress compared to PF and C pups. CBG binding capacity was also reduced in A pups. At 10 days of age, plasma corticosterone levels were lower overall in A and PF than in C pups following exposure to a number of different acute stressors while at 18 days plasma corticoids were decreased and adrenal corticosterone was increased in A compared to PF and/or C pups. These data support and extend previous studies indicating that in utero ethanol exposure alters postnatal adrenocortical development. This effect is specific to ethanol and unaltered by maternal nutritional status.     

Fetal Exposure to Ethanol Enhances Pituitary-Adrenal and Temperature Responses to Etanol in Adult Rats

Long lasting effects of perinatal ethanol exposure were studied in adult rats who were the offspring of dams fed a 5.0% w/v ethanol-containing liquid diet ad libitum or pair-fed the isocaloric control diet during gestation weeks 2 and 3 or during postnatal week 1. Fetal exposure to ethanol reduced body weight of pups at birth unless the ethanol diet was supplemented with casein; neonatal exposure to the ethanol or pair-fed diets, casein supplemented or not, reduced pup weights until day 21 postnatally when weights of all fetally or neo-natalty exposed pups were normal. Between 52 and 120 days of age females were tested for pituitary-adrenal and temperature responses to a challenge dose of ethanol. Prenatally ethanol-exposed rats showed significantly higher plasma corticosterone titers and developed a greater hypothermia in response to an intraperitoneal injection of ethanol (0.75–1.5 g/kg) than did pair-fed controls. Similar response enhancement did not occur in the postnatally ethanol-exposed rats. Temporal patterns of blood ethanol levels after an intraperitoneal injection of ethanol (1.5 g/kg) were similar in prenatally ethanol-exposed females and their pair-fed controls. The data indicate that exposure to ethanol in utero exerts persistent effects on the offspring, rendering them more responsive to the hypothermic and pituitary-adrenal activating effects of alcohol as adults.     

Effect of Prenatal Ethanol and Stress on Levels of β-Endorphin in Different Brain Regions of the Rat

The combination of prenatal ethanol exposure and footshock stress was investigated for its effects on brain β-endorphin levels. Subjects were offspring of rats that received 1 of 3 prenatal dietary treatments: an ethanol-containing liquid diet, a identical liquid diet with ethanol substituted isocalorically with maltose-dextrin (pair-fed group), and standard laboratory rat chow (chow-fed group). Two different stress paradigms were used: a short (30-sec) footshock stress paradigm and a prolonged (180-sec) footshock stress paradigm. Levels of β-endorphin were measured with radioimmunoassay in eight brain regions of unstressed (baseline) rats, and of stressed rats at 3 and 30 min following termination of the stress. Seven brain regions containing high densities of β-endorphin axons and terminals were chosen, as well as the arcuate region of the hypothalamus, the only brain region where bothβ-endorphin perikarya and terminals are located. Following the short footshock stress paradigm, there were no changes in β-endorphin levels, except for a trend toward increased levels in the pair-fed group. After the prolonged stress paradigm, levels of β-endorphin in both the pair-fed and chow-fed groups tended to be decreased in several brain regions, including the arcuate region, at 3 min after termination of the stress. In contrast, for the prenatally ethanol-exposed group, β-endorphin levels were increased significantly in the arcuate region, and moderately increased in the septal/preoptic region and medulla/pons at 3 min after the prolonged stress paradigm. In the hypothalamus, there was a modest decrease in β-endorphin levels in all three treatment groups, and little change in β-endorphin levels at any time after stress in the amygdala, thalamus, and midbrain regions. The decrease in peptide levels in pair-fed and chow-fed rats following stress is interpreted as release of the peptide from terminal stores. The failure of the prenatally ethanol-exposed group to demonstrate this release in the arcuate region, the septal/preoptic region, and the medulla/pons may be related to loss of homeostatic control, seen in behavioral studies of prenatally ethanol-exposed rats, and in human children with the fetal alcohol syndrome.     

Prenatal Alcohol Exposure Alters the Hypothalamic-Pituitary-Adrenal Axis Response of Immature Offspring to Interleukin-1: Is Nitric Oxide Involved?

We have previously shown that following prenatal alcohol exposure, immature offspring showed blunted ACTH released in response to the peripheral administration of interleukin-1β (IL-1β). The present studies were conducted to investigate the role of changes in corticosteroid feedback (measured by altered adrenal responses to ACTH), corticotropin-releasing factor (CRF) content of the median eminence (ME), and the influence of endogenous nitric oxide (NO). The injection of several doses of ACTH failed to indicate measurable differences between the corticosterone responses of offspring born to dams fed ad libitum [control (C)], pair-fed (PF), or fed alcohol [ethanol (EtOH) = E]. CRF content in the ME, taken as an index of the amount of releasable peptide, showed a small, but statistically significant, decrease following prenatal alcohol exposure. A comparable change, however, was also noted in PF rats. As expected, the subcutaneous injection of IL-1β (0.5 μg/kg) induced smaller increases in plasma ACTH levels of E than C pups. The response of PF animals was intermediate between that of E and C rats. Finally, we observed that inhibition of NO formation by the administration of the arginine derivative L_wnitro-L-arginine-methylester significantly augmented ACTH secretion in all three experimental groups, and reversed the decreased corticotrophs' response to IL-1β caused by prenatal alcohol.
Taken together, our results suggest that the ability of prenatal alcohol exposure to alter ACTH released by immature pups in response to blood-borne IL-1β is probably not mediated through changes in adrenal responsiveness. We propose, on the other hand, that endogenous NO levels may be increased by the prenatal treatment, thereby interfering with the release of peptides from nerve terminals in the ME.     

Fetal Ethanol Exposure: Hypothalamic-Pituitary-Adrenal and β-Endorphin Responses to Repeated Stress

Previous studies provide evidence that fetal ethanol exposure induces hypothalamic-pituitary-adrenal (HPA) and pituitary β-endorphin (β-EP) hyperresponsiveness to acute stressors. The present study demonstrates significant effects of in utero ethanol exposure on the parallel response patterns of the HPA axis and the pituitary β-EP system to repeated exposures to a stressor, restraint stress, and indicates sex differences in response. Together, data from the two experiments indicate that, after repeated restraint exposures, fetal ethanol-exposed (E) males and females both show significantly increased plasma levels of adrenocorticotropin (ACTH), and E males also show significantly increased plasma levels of β-endorphin-like immunoreactivity (β-EPLIR), compared with their respective pair-fed and control counterparts. Marginal increases in the corticosterone response of E males and the β-EPLIR response of E females, compared with their controls, were also observed. In addition, delayed or deficient habituation to restraint stress was observed in the β-EPUR response of E males and the ACTH response of E females. These data demonstrate that fetal E-exposed males and females both exhibit hormonal hyperresponsiveness and/or deficits in recovery after repeated exposures to restraint stress, but that the patterns of response may differ depending on the number and duration of restraint exposures, the time course measured, and whether the endpoint measured is corticosterone, ACTH, or β-EPLIR. In addition, the finding that E and pair-fed animals both differed from their respective controls in certain developmental and hormonal measures suggests that prenatal nutritional factors may play a role in mediating some of the changes that are observed.     

Effects of Maternal Ethanol Consumption on the Subsequent Development of Immunity to Trichinella spiralis in Rat Neonates

The immune response of rat pups to the intestinal parasite Trichinella spiralis was studied to determine if maternal pre-and/or postnatal ethanol consumption affected neonatal immune responses. Female rats were fed ethanol-containing (36% of calories) or pair-fed control liquid diets and include groups that were maintained on ethanol as follows: group 1, from day 1 of pregnancy through weaning and whose pups were then placed on ethanol to sacrifice; group 2, from day 1 of pregnancy through lactation; group 3, from day 1 of pregnancy through pup delivery; and group 4, from day 1 of lactation through weaning. A parallel group of animals was pair-fed isocaloric control diet until sacrifice. The pups of all litters were immunized orally with 500 L₁ (T. spiralis) larva 5 days after weaning. To examine the effects of maternal ethanol on primary immune responses, one-fourth of the pups from each litter were sacrificed on days 10 and 20 after immunization. To examine the effects on neonatal secondary immune responses, the remaining pups were challenged with 1,000 larva 30 days after the initial immunization and sacrificed either 3 or 8 days after challenge. At the time of sacrifice, blood samples were collected, the intestine removed to determine T. spiralis worm burdens, and suspensions of mesenteric lymph node (MLN) cells prepared. Intestinal worm counts and serum levels of anti-T. spiralis IgM and IgG antibodies, interleukin-2 (IL-2), and tumor necrosis factor (TNF) were determined. In vitro proliferation responses of MLN cells to T. spiralis antigen and to the mitogen concanavalin A (Con A) were also examined. Pups from groups 1 to 3 demonstrated significantly higher intestinal worm counts (decreased immunity) than the pair-fed controls at the day 20 primary immune response sacrifice, and pups from group 1 had significantly higher worm counts at day 3 after a secondary immune challenge. Pups of dams from groups 1, 3, and 4 had significantly lower IgM antibody titers at the day 20 primary immune response sacrifice. All experimental ethanol groups (1 to 4) demonstrated significantly lower IgG antibody titers than that observed in pair-fed control pups at the 20-day sacrifice. IgM antibody titers showed significant reductions for ethanol-treated groups at 3 and 8 days after T. spiralis secondary challenge. In addition, IgG antibody titers were also significantly reduced for all alcohol groups at 3 and 8 days during the secondary immune response. Serum IL-2 and TNF levels were significantly lower in all experimental ethanol groups (1 to 4) relative to pair-fed controls at day 20 during a primary immune response, and IL-2 levels at 3 days postchallenge were lower in groups 2 to 4 after a secondary immune challenge. MLN proliferation responses to antigen and Con A were significantly reduced in ethanol groups 1 to 3 and to Con A in group 4 at day 10 after a primary immune challenge. Ethanol group 3 pups also demonstrated a reduced response to antigen at day 20. For animals undergoing a secondary immune response, ethanol group 2 demonstrated a reduced response to antigen at day 3, whereas groups 2 and 4 showed increased reactivity to antigen at days 3 and 8 postchallenge. These results show that maternal ethanol consumption diminishes the capacity of neonates to respond to T. spiralis antigen and that the depressed immune response involves T-and B-cell–mediated reactions and also affects the production of certain cytokines. These results also suggest that the diminished immune responses are increased with longer periods of maternal and neonatal exposure to ethanol.     

Prenatal Ethanol Exposure Alters Steroidogenic Enzyme Activity in Newborn Rat Testes

We have examined the in utero effects of ethanol exposure on testicular steroidogenesis in newborn male pups. Pregnant Sprague-Dawley rats were fed a liquid ethanol diet (35% ethanol-derived calories), a pair-fed isocaloric liquid diet, or a standard laboratory rat chow and water diet beginning on Day 12 of gestation and continuing through parturition. Although there were no significant differences in the enzymatic activity of 5-ene-3 beta-hydroxysteroid dehydrogenase/isomerase or C17,20-lyase, the enzymatic activity of 17 alpha-hydroxylase was significantly (p less than 0.01) reduced (i.e., approximately 36%) in the ethanol-exposed pups compared to those from the pair-fed and chow treatment groups. This lesion in testicular steroidogenic enzyme activity in newborn male pups exposed to alcohol in utero was transient as 17 alpha-hydroxylase activity from the ethanol-exposed animals returned to control levels by postnatal Day 20 and remained at control levels through adulthood (postnatal Day 60). These data suggest that the suppression of the perinatal testosterone surge in male rats exposed to alcohol in utero and the associated long term demasculinizing effects of prenatal ethanol exposure might be the result of reduced testicular steroidogenic enzyme activity in the perinatal animal.     

Effects of prenatal ethanol exposure on hypothalamic-pituitary-adrenal responses to chronic cold stress in rats

Animals prenatally exposed to ethanol typically exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. In contrast to previous studies that have investigated effects of prenatal ethanol exposure on HPA responses to acute or intermittent stressors, our study investigated HPA responses to a chronic continuous stressor, cold stress (4 degrees C for 0, 1, or 3 days). We tested the hypothesis that prenatal ethanol exposure would result in increased plasma corticosterone (CORT) and adrenocorticotropin (ACTH) responses and increased peptide [corticotropin-releasing factor and vasopressin] mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus compared to that in control animals. In addition, CORT and ACTH responses were measured after exposure to an acute stressor (i.p. isotonic saline injection), superimposed during chronic cold exposure, to examine possible sensitization of the HPA response to the acute stress. Thus, blood samples were collected at the end of each of the three periods of cold exposure, either before (0 min) or 15 min after acute stress. The subjects were adult male and female Sprague-Dawley rat offspring from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) treatment groups. Exposure to cold stress resulted in significant body weight loss in E males at 1 day and in both males and females of all prenatal treatment groups by 3 days of cold stress. Males in all prenatal groups also exhibited significant increases in adrenal weight:body weight ratios. Cold stress alone (0 min condition) increased CORT levels in E males and overall ACTH levels in E males and females compared to controls. ACTH levels were also higher overall in E compared to control males after acute stress (15 min condition). Sensitization of the CORT response to acute stress was observed in males but not females across all prenatal treatment groups. Corticotropin-releasing factor and vasopressin mRNA levels in the PVN were not significantly affected by prenatal treatment or chronic cold stress in either males or females. In contrast, both males and females displayed increases in PVN thyrotropin-releasing hormone (TRH) mRNA levels after cold stress. These data support and extend previous work demonstrating differential effects of prenatal ethanol exposure on HPA responsiveness of male and female offspring, and suggest that E males may be more vulnerable to the effects of chronic cold stress than E females.     

Effects of mineralocorticoid and glucocorticoid receptor blockade on hypothalamic-pituitary-adrenal function in female rats prenatally exposed to ethanol

BACKGROUND: Rats prenatally exposed to ethanol (E) exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness, demonstrated by increased and/or prolonged elevations of adrenocorticotropic hormone (ACTH) and/or corticosterone (CORT) in response to stressors. The present study examined the possible role of CORT feedback deficits in mediating this hyperresponsiveness by examining HPA function following mineralocorticoid (MR) and glucocorticoid (GR) receptor blockade. METHODS: Adult female Sprague-Dawley offspring from E, pair-fed (PF), and control (C) groups were injected subcutaneously with the MR antagonist spironolactone (SPIRO; 30 mg/kg bw), the GR antagonist RU38486 (120 mg/kg bw), or vehicle. One hour postinjection, blood samples (0 minutes) were taken via jugular cannulae to obtain a measure of prestress ACTH and CORT levels. Rats were then loosely restrained for 1 hour, and samples were taken during (15, 30, and 60 minutes) and then 1 hour following stress, for determination of plasma ACTH and CORT levels. RESULTS: Both SPIRO and RU38486 significantly increased prestress ACTH levels in E compared with both PF and C females. In contrast, RU38486 significantly increased ACTH levels in C compared with PF females during stress and in C compared with E females during recovery. CORT levels were increased during stress in E females in response to SPIRO, and RU38486 increased the CORT response during stress in PF and during recovery in E and PF females compared with vehicle. CONCLUSIONS: E females showed enhanced HPA responses to both MR and GR blockade compared with PF and C before restraint as well as a different pattern of responsivity during and following restraint. While receptor blockade had some effect on CORT responses in PF females, changes in ACTH appear specific to ethanol. These findings suggest that the balance between HPA drive and feedback may be altered in E compared with C females.     

A Morphometric Study of the Effects of Ethanol Consumption on Lactating Mammary Glands of Rats

Morphometric procedures were used to quantitate changes induced by ethanol in tissue components of rat mammary gland. Rats were pair-fed ethanol-containing or isocaloric control liquid diets formulated for pregnant or lactating animals, or maintained on regular laboratory chow. Short term animals were pair-fed ethanol or control diets from Day 1 of pregnancy through lactation Days 2 or 10. Long term animals were pair-fed ethanol or control diets for 25 days prior to mating, and then through pregnancy to lactation Days 2 or 10. Point counting was used to determine the volume fractions (vf) of alveolar epithelium, lumen, and connective tissue in the mammary glands. In chow-fed animals the percentage of alveolar epithelium remained constant from late pregnancy through lactation, while the amount of connective tissue decreased and that of alveolar lumen increased. This indicates the sensitivity of this procedure to detect changes in tissue volume fractions during mammary proliferation. No changes from the normal controls were found in any tissue component in short term ethanol or pair-fed animals. At lactation Day 2, long term ethanol-treated animals demonstrated a significant decrease in the percentage of alveolar epithelium and a significant increase in the percentage of total connective tissue as compared to pair-fed and chow-fed control animals. However, by Day 10 of lactation, no changes were found in any of the tissue components in long-term ethanol-fed versus control animals. These results indicate that ethanol consumption can alter mammary gland structure during the early stages of lactation, even when adequate levels of dietary protein are maintained.     

Effect of Prenatal Exposure to Ethanol on Body Growth and the Pituitary β-Endorphin

Pregnant rats were fed an ethanol diet from the first day of pregnancy until parturition. Control rats were either pair fed with an isocaloric sucrose diet, or fed with standard lab chow (basic control group). Rats fed with the ethanol diet and their pair-fed controls showed a similar increase in body weight during pregnancy, which was lower than the increase observed in the basic control group. At 10 days after ethanol withdrawal all three groups presented similar body weights. A lower body growth was exhibited by the offspring of both the ethanol and the sucrose pair-fed rats, implicating a prenatal nutritional factor on the postnatal growth. Furthermore, the rate of body growth was lower in the offspring of the ethanol-treated animals than in the offspring of both their pair-fed and the basic control rats, indicating the presence of an additional ethanol-associated factor. On day 4 of development, the concentration of beta-endorphin peptides (pmol/mg protein) in the pituitary gland and the anterior lobe, of the offspring of the ethanol-treated animals and their sucrose pair-fed controls, was significantly higher than that of the offspring of the basic control animals. However, a lower content of beta-endorphin-like peptides was noticed in the whole pituitary gland, the anterior lobe, and the intermediate lobe of the offspring of the ethanol-treated rats and their pair-fed controls on days 8, 14, and 22 postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperresponsiveness to Stress: Differential Effects of Prenatal Ethanol on Males and Females

In this study we investigated the hypothesis that pituitary-adrenal response inhibition is compromised in animals prenatally exposed to ethanol. In the first experiment, we examined whether opportunity to perform a consummatory response reduces the adrenocortical response to a novel test cage. Animals were water deprived for 24 hr and tested in one of three conditions: (a) removed from home cage, blood sample obtained immediately; (b) placed into empty novel cage, blood sample obtained 30 min later; (c) placed into novel cage with water available, blood sample obtained 30 min later. All animals showed an increase in corticoids over basal levels following 24-hr water deprivation, and placement into a novel cage produced a further significant increase in corticosterone. Opportunity to drink reduced the corticosterone response to novelty for all males. However, fetal ethanol-exposed females showed significantly less attenuation of their corticosterone response to novelty than both pair-fed and control females. In the second experiment, we examined adrenocortical habituation to a stressful stimulus. Animals were restrained in plastic tubes which restricted movement, and blood samples were obtained following 30 or 60 min of restraint. All animals showed significant corticoid elevations at 30 min. Males showed no change in corticoids from 30 to 60 min while both pair-fed and control females showed a corticoid decrease at 60 min. Fetal ethanol-exposed females, however, showed no significant corticoid decrease at 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Prenatal Ethanol Exposure on Hypothalamic-Pituitary-Adrenal Regulation After Adrenalectomy and Corticosterone Replacement

BACKGROUND: Previous studies have demonstrated that rats prenatally exposed to ethanol (E) exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness, demonstrated by increased and/or prolonged elevations of adrenocorticotropin (ACTH) and/or corticosterone (CORT) after stress. This study investigated possible mechanisms of HPA hyperresponsiveness in E rats by manipulating CORT feedback regulation of HPA activity via adrenalectomy (ADX) with or without CORT replacement. METHODS: Male Sprague-Dawley rat offspring from prenatal E, pair-fed (PF) and ad libitum-fed control (C) groups were tested at 90 to 120 days of age. Rats were either sham-operated or underwent ADX, with or without CORT replacement. CORT (25 microg/ml) was replaced via the drinking water to achieve basal plasma CORT levels and maintain a phasic CORT signal. Seven days after surgery, animals were decapitated at the diurnal peak either under basal conditions or after a 15-min restraint stress, and trunk blood was collected. RESULTS: After ADX, loss of the CORT feedback signal resulted in increased plasma ACTH in all groups compared with those in sham animals. In addition, under basal conditions, ADX E rats had significantly greater plasma ACTH levels than both PF and C rats. However, no differences were seen in ADX rats after stress. CORT replacement after ADX was partially effective in normalizing ACTH levels under both basal and stress conditions, with no differences among E, PF, and C animals. CONCLUSIONS: These results suggest that E males may exhibit enhanced stimulatory inputs to the hypothalamus, increased pituitary sensitivity to secretagogues, or both, which may be revealed after ADX. In contrast, E animals seem similar to controls in their ability to use an exogenous CORT signal to regulate HPA activity.     

Lack of Prenatal Testosterone Surge in Fetal Rats Exposed to Alcohol: Alterations in Testicular Morphology and Physiology

Pregnant Sprague-Dawley rats were administered a liquid alcohol diet (35% ethanol-derived calories), a pair-fed isocaloric diet, or dry food pellets beginning on Day 14 of gestation and continuing until parturition. Testosterone levels in male fetuses were measured on Days 17 through 20 of gestation. The normal surge of testosterone on Days 18 and 19 was present in controls, but notably absent in male fetuses exposed to alcohol. Light microscopic examination of the testes at birth revealed a reduction in the number of leydig cells in the alcohol exposed group and the presence of a large number of vacuoles in the seminiferous tubules. In vitro studies of fetal testes at 18 and 22 days of gestation revealed that this in utero alcohol exposure regimen produced a marked insensitivity to rat LH (10 ng/ml) stimulation of testosterone secretion compared to controls. The response to ethanol (160 mg/dl) in alcohol exposed testes was characterized by a long-lasting suppression of testosterone compared to a large increase observed in control testes. No differences in anogenital distance were observed among the groups. Together, these data may explain some of the long-term feminizing and demasculinizing effects on reproductive and nonreproductive sexually dimorphic behaviors observed in adult males prenatally exposed to alcohol.     

Effects of Prenatal Ethanol Exposure on Brain Region NMDA-Mediated Increase in Intracellular Calcium and the NMDAR1 Subunit in Forebrain

The effects of prenatal ethanol exposure on N -methyl-d-aspartate (NMDA)-mediated calcium entry into neonatal dissociated neurons from hippocampus, forebrain, and cerebellum were investigated. Dissociated cells were isolated from less than 1-day-old pups of prenatally exposed, pair-fed control and ad libitum control groups and loaded with fura-2. Prenatal ethanol exposure significantly reduced the NMDA-stimulated increase in intracellular calcium in all three brain regions compared to the two control groups. These findings are very similar to those previously observed in neonatal dissociated whole brain neurons using the same ethanol exposure protocol. Studies were also conducted using forebrain to determine if prenatal ethanol exposure alters NMDAR1 subunit protein expression in this major brain area; however, the results indicated no significant differences between ethanol-exposed and control groups.     

Aluminum absorption and excretion following sucralfate therapy in chronic renal insufficiency.

PURPOSE: To measure serum aluminum levels and urinary aluminum excretion in patients with chronic renal insufficiency (CRF) receiving therapeutic doses of sucralfate. PATIENTS: Six patients with CRF were enrolled in the study. Creatinine clearances ranged from 0.2 to 0.9 mL/second (mean +/- SD 0.40 +/- 0.25 mL/second). Seven subjects with normal renal function were also studied. METHODS: Each subject received sucralfate 1 g four times daily for 21 days. Serum and urine samples (serum only) were collected on baseline and on Days 2, (3), 8, 15, 22, (23, 24), 29, and 36. Samples were assayed by graphite furnace atomic absorption spectrophotometry. RESULTS: In CRF, serum aluminum levels (mumol/L) increased by Day 2 and remained elevated to Day 24. Urinary aluminum excretion (mumol/day) was elevated throughout the study. The elimination half-life of serum aluminum after therapeutic dosing of sucralfate was 13.1 +/- 3.1 days. In subjects with normal renal function, baseline serum aluminum levels were similar to those in CRF (0.12 +/- 0.12 versus 0.11 +/- 0.12 mumol/L), but serum aluminum levels were higher at the end of the study in CRF (Day 22, 0.24 +/- 0.17 versus 0.83 +/- 0.48 mumol/L). CONCLUSIONS: After therapeutic doses of sucralfate, significant elevations of serum aluminum levels occurred in CRF. Serum aluminum levels were higher in patients with CRF than in normal subjects. Long courses of sucralfate should be used with caution or avoided in CRF.     

Endocrine Effects of Maternal Alcoholization: Plasma and Brain Testosterone, Dihydrotestosterone, Estradiol, and Corticosterone

Maternal ethanol consumption was associated with reduced levels of dihydrotestosterone in the brains of 1–2-day-old male rats when compared to those of sex-matched pups obtained from dames that were fed sucrose. In contrast, brain levels of corticosterone were increased significantly in the pups of ethanol-fed animals when compared to those from sucrose-fed controls. Brain and plasma estradiol did not differ between groups. These results suggest that maternal ethanol consumption may influence the central nervous system and plasma levels6000 of certain steroidal hormones in the offspring.     

Ontogeny of the beta-endorphin response to stress in the rat: role of the pituitary and the hypothalamus

Neonatal rats show a period of diminished adrenocorticotropin responsiveness to stress during the first 2 weeks of life. To test whether beta-endorphin-like peptides (beta-EPLPs) follow the same pattern of hyporesponsiveness to stress during this period, we examined the ontogeny of the beta-EPLPs response to two different types of stressors (ether vapors and cold) during the early postnatal period. The content of beta-EPLPs was estimated in the serum, the pituitary gland and the hypothalamus prior to and 5 min following exposure to stressful stimuli. Furthermore, to determine the relationship between the responsiveness of beta-EPLPs to stress and that of the hypothalamic-pituitary-adrenal axis in the developing rat, the content of hypothalamic corticotropin-releasing factor (CRF) and serum corticosterone was estimated prior to and following stress. Results indicated that stress induced an increase in the serum corticosterone levels at all ages tested (days 1-22), however, the stress-induced elevations of serum corticosterone were significantly greater on days 1 and 22 than on days 3-14. Significant stress-induced elevations of serum immunoreactive beta-endorphin (ir-beta-EP) were observed on days 14 and 22 of life, while changes on days 1, 3, 8 and 10 were either nonexistent or not statistically significant. Gel filtration analysis revealed that the increases in serum ir-beta-EP following stress on days 14 and 22 resulted primarily from increases in the beta-lipotropin component with lesser increases in the beta-endorphin component. Pituitary content of beta-EPLPs was not affected by stress before day 10, but was markedly reduced in the 10- and 14-day-old rats, following stress. A similar, although not statistically significant decrease was observed in the pituitary content of beta-EPLPs of the 22-day-old rats after exposure to stress. Furthermore, exposure to cold stress in the 14-day-old rats induced more pronounced changes in the serum ir-beta-EP and corticosterone levels as well as in the pituitary ir-beta-EP content than it did with ether stress. Despite variations in serum corticosterone as well as serum and pituitary content of beta-EPLPs, no changes in the hypothalamic ir-beta-EP content were seen in rats after subjection to stress, while small, not statistically significant reductions in the hypothalamic CRF content were observed at 5 min after the onset of stress in the 14-and 22-day-old rats. Thus, during the first 2 weeks of life neonatal rats exhibit a reduced capacity to secrete beta-EPLPs in response to stress.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cerebral Cortical Morphology and Behavior in Rats Following Acute Prenatal Ethanol Exposure

Cerebral cortical morphology and early motor development were evaluated in offspring from ethanol-exposed mothers, pairfed control mothers and ad libitum control rats. Ethanol-exposed rats received a total dose of 18 g/kg of ethanol by intubation on gestational Days 14 and 15, a critical period of development of the cerebral cortex. Pairfed control mothers received isocaloric sucrose on gestational Days 14 and 15 and were pairfed to ethanol-exposed animals from gestational Day 12 through gestational Day 20. Ethanol-exposed offspring weighed significantly less than control offspring from postnatal Day 7 through postnatal Day 28. Ethanol-exposed offspring also showed significant delays in reflex suspension (time an animal maintained its grip on a crossbar) and continuous corridor (number of turns in 5 min). The thickness of the cerebral cortex of ethanol-exposed offspring was significantly different from ad libitum and pairfed control offspring on postnatal Day 1. However, only Layer V and total cortical thickness were affected in ethanol-exposed offspring on postnatal Day 28. The results of this study indicate that ethanol exposure during a critical period of development causes alterations in central nervous system development and developmental delays.     

Effect of ether stress on growth hormone during development in the neonatal rat.

Stress in adult rats causes an inhibition of growth hormone (GH) secretion which might be mediated by corticotropin-releasing factor (CRF). The response of neonates to stress differs from that observed in adults, including changes in GH secretion that are independent of CRF. The present study examines the effects of ether exposure, a stress known to elicit CRF release, on serum GH in the neonatal period. Preliminary experiments indicated that ether elicits increases in serum adrenocorticotropic hormone and corticosterone, and that the latter response is blocked by pretreatment with dexamethasone. Corticosterone was measured as an indicator of hypothalamo-pituitary-adrenal (HPA) axis stimulation for subsequent studies. Rat pups of 5, 8, 10, 15, 18 or 30 days were divided into three groups. Baseline animals were taken for decapitation directly from the mother. Ether animals were exposed to ether fumes for 1 min, returned to the mother after a brief recovery period, and killed 30 min later. Handled control animals were removed from the mother briefly, returned, and similarly killed at 30 min. Blood was assayed for GH and corticosterone. Handling itself stimulated both GH and corticosterone on postnatal days 10 and 15 and suppressed GH and corticosterone on days 5 and 30. Ether significantly lowered GH and increased corticosterone when compared to this handling control from day 8 to 18, but values in ether-treated animals were different from baseline animals only at 5 and 30 days of age. These results indicate that ether stress produces a mild decrease in GH by day 5 postnatally and throughout the neonatal period which is only apparent in relation to 'handled' controls.(ABSTRACT TRUNCATED AT 250 WORDS)