Effect of prenatal exposure to ethanol on intestinal development of rat fetuses

BACKGROUND: Chronic alcoholism in pregnant animals and humans lead to general growth impairment in their offspring, which show multiple birth defects and delayed grown (fetal alcohol syndrome). Here we study the maturation of the intestine under the effect of chronic exposure to ethanol in utero together with associated malnutrition. METHODS: Lactase, acid beta-galactosidase, maltase, and alkaline phosphatase activity profiles were monitored in 18-, 19-, 20-, and 21-day-old fetuses from rats kept under three nutritional treatments before and during gestation: alcohol-treated (25% ethanol in drinking water), fiber-treated (50% cellulose-diluted diet) as a control of the malnutrition associated with chronic alcoholism, and control or normal diet. Serum corticosterone determination and lactase immunolocalization were carried out. To detect possible direct effects of ethanol during the period of mucosa development, intestinal explants from 18-, 19-, and 20-day-old control fetuses were cultured either in the basal medium alone or in a medium containing 25 mM ethanol for 72, 48, and 24 h of incubation, respectively. RESULTS: Following chronic ethanol exposure in utero, intestinal weight and brush-border protein content and the specific activities of lactase, acid beta-galactosidase, maltase, and alkaline phosphatase were significantly lower than those of nutritional controls. Organ culture results, under the assay conditions stated, did not show a direct effect of ethanol 25 mM on prenatal mucosal functionality. CONCLUSIONS: All these results suggest that maternal malnutrition is not primarily responsible for the impaired intestinal maturation in rat fetuses from alcohol-treated mothers; indirect effects of ethanol and/or its derivatives throughout embryo-fetal development could be necessary to promote this intestinal delay.     

Interactive effects of prenatal cocaine and nicotine exposure on maternal toxicity, postnatal development and behavior in the rat

Two experiments were performed to investigate the interactive effects of prenatal coadministration of cocaine hydrochloride (C) and nicotine tartrate (N). Experiment I was designed to determine doses of C and N that could be coadministered without altering maternal gestational parameters and/or fetal viability. Exposure of Sprague-Dawley rats to combined high-dose C (20 mg/kg) and high-dose N (5.0 mg/kg) on gestation days 8-21 was not more toxic to dam or fetus that that of exposure to C alone. Experiment II investigated pregnancy outcome, postnatal development, and behavior of the offspring following drug exposure to either high-dose cocaine (20 mg/kg: CS), high-dose nicotine (5.0 mg/kg: NS), or both (NC) on gestation days 8-21. N was administered by osmotic minipump and C by sc injection. Saline-injected dams, fitted with saline-fitted pumps (SS), and untreated dams, pair-fed (PF) to NC females, served as controls. Alterations in maternal variables were limited to a 10-15% decrease in food consumption in NC and CS groups. Pregnancy outcome and birth statistics were unaffected by prenatal treatment, as was offspring body weight during the first four postnatal weeks. However, the development of surface righting was delayed inC CS pups, and only CS offspring were underresponsive to the stimulatory effects of dopamine agonists on activity and stereotypy. Behavioral responses to N challenge were similar in all groups. In addition, only CS offspring showed altered behavioral responses in a spontaneous alternation task. Treatment effects on dopamine D1 and D2 binding in the caudate nucleus were not observed. The combination of N and C did not exacerbate any of the behavioral changes seen in CS offspring. These results support the hypothesis that C is a behavioral teratogen in rodents, and suggest that in the present model, nicotine can mitigate some of the consequences of in utero exposure to cocaine.     

Effects of acute prenatal ethanol exposure on Bergmann glia cells early postnatal development

The effects of acute ethanol exposure during the prenatal phase of Bergmann glia cell (Bgc) generation were evaluated in three postnatal days. Ethanol exposed rats showed Bgc with reduced soma size, decreased number and width of their fibers, and increased fiber length, when compared with control animals. These differences, however, were significant at postnatal day 12. Our results demonstrate that acute, prenatal exposure to ethanol during critical stages of brain development disrupts Bgc early postnatal development.     

Effects of prenatal exposure to N-methylpyrrolidone on postnatal development and behavior in rats

Pregnant rats (Mol:WIST) were exposed to 150 ppm N-methylpyrrolidone for 6 hours per day on gestation days 7-20. The dose level was selected so as not to induce maternal toxicity or decrease viability of offspring. In the preweaning period, the exposed offspring had a lower body weight and their physical development was delayed. Neurobehavioral evaluation of the male pups revealed no effects on basal functions of the central nervous system. The animals appeared normal and motor function (rotarod), activity level (open field), and performance in learning tasks with a low grade of complexity were similar in the two groups. However, in more difficult tasks such as the reversal procedure in Morris water maze and operant delayed spatial alternation (Skinner boxes), performance was impaired in exposed offspring.     

Enduring effects of prenatal cocaine exposure on attention and reaction to errors.

Rats exposed to cocaine prenatally were administered a series of 3-choice visual attention tasks, with the most pronounced deficits seen in a task in which the onset time, location, and duration of a visual cue varied unpredictably between trials. The cocaine-exposed rats were less accurate than controls but did not differ in the rate of premature responses or omission errors. The pattern of errors, coupled with response latency data, implicated deficits in the ability to rapidly engage attention and maintain a high level of alertness to the task. The cocaine-exposed rats also exhibited a blunted reaction to an error on the previous trial, possibly reflecting an alteration in emotional regulation and/or error monitoring. Implications for underlying neuropathology are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Developmental and behavioral effects of prenatal primidone exposure in the rat

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.     

Influence of prenatal exposure to low levels of lead on the neuro-behavioral development of neonates

OBJECTIVES: To study the effects on the neuro-behavioral development of neonates exposed to low levels of lead in utero. METHODS: 131 neonates were selected and their umbilical blood lead level was determined by Atomic Absorption Spectrometer. The neurobehavioral-cognitive performance of neonates was evaluated by Neonatal Behavioral Neurological Assessment (NBNA). RESULTS: NBNA scores in neonates with blood lead levels greater than or equal to 0.29 mumol/L were markedly lower than those with less than 0.14 mumol/L, and the difference was highly significant. CONCLUSION: Blood lead levels of less than 0.48 mumol/L could still have harmful effects on the development of children.     

Growth-inhibitory effects of transforming growth factor-beta 1 on myeloid leukemia cell lines

Transforming growth factor-beta1 is a pleiotropic cytokine involved in a variety of biological processes in both transformed and normal cells, including regulation of cellular proliferation and differentiation; its predominant action on hematopoietic cells is to inhibit cell growth. We used growth factor-dependent cell lines to assess TGF-beta1 effects on human myeloid leukemia cell growth. While four lines were completely or predominantly resistant, TGF-beta1 inhibited effectively, albeit to various extents, the growth of 12 other cell lines. This effect was dose dependent and specific, because a neutralizing anti-TGF-beta1 antibody prevented TGF-beta1-induced growth suppression. In the present system, basic fibroblast growth factor, known as an antagonist of TGF-beta1 counteracting its inhibitory effects, did not abrogate the suppressive effects of TGF-beta1. Other growth-stimulatory cytokines negated the TGF-beta1-induced inhibition in several cell lines, again to various extents. When proliferation was enhanced by growth-promoting cytokines (e.g. granulocyte-macrophage colony-stimulating factor, GM-CSF, stem cell factor, SCF, or PIXY-321), some previously TGF-beta1-sensitive cell lines acquired cellular resistance toward TGF-beta1-mediated growth suppression, whereas four other cell lines remained susceptible to TGF-beta1 growth inhibition despite possible counteraction by other cytokines. Thus, three growth response patterns to TGF-beta1 were seen: (1) constitutive resistance; (2) factor-dependent relative resistance; and (3) sensitivity to growth inhibition indifferent to counteracting cytokines. In the latter case, TGF-beta1 did not downregulate expression of one specific growth factor receptor. These studies indicate that human myeloid leukemia cells, represented here by leukemia cell lines as model systems, exhibit heterogeneous growth responses to TGF-beta1; its inhibitory effects can be modulated or completely alleviated by positive antagonistic cytokines. The availability of TGF-beta1-susceptible and -refractory cell lines allows for detailed investigations on the mechanisms of these regulatory pathways, the nature of TGF-beta1-resistance, and the possible contribution of acquired TGF-beta1-resistance to disease progression.     

Long-term effects of prenatal exposure to low levels of gamma rays on open-field activity in male mice

The open-field activity of first-generation (F1) hybrid male C57BL/6 x C3H mice irradiated with gamma rays on day 14 of gestation was studied at the following ages: 6-7 months (young), 12-13 months (adult) and 19-20 months (old). Doses were 0.5 Gy or 1.0 Gy. Open-field activity was recorded with a camera. The camera output signal was recorded every second through an A/D converter to a personal computer. The field was divided into 25 8-cm2 units. All recordings were continuous for 60 min. The walking speed of the 1.0-Gy group recorded at 19-20 months was higher than that for the comparably aged control group. The time which the irradiated group, recorded at 19-20 months, spent in the corner fields was high in comparison with the control group at the same age. Conversely, the time spent by the irradiated group in the middle fields when recorded at 19-20 months was shorter than in the comparably aged control group. No effect of radiation was shown for any of the behaviors observed and recorded at 6-7 and 12-13 months. The results demonstrate that such exposure to gamma rays on day 14 of gestation results in behavioral changes which occur at 19-20 months but not at 6-7 or 12-13 months.     

Neonatal exposure to bFGF exerts NGF-like effects on mouse behavioral development

Metabolic products secreted by the fungal mycelia of Hirsutella thompsonii var. thompsonii (CBS 556.77D) in a defined culture broth in shake culture were tested for toxicity to Galleria mellonella larvae and Drosophila melanogaster adults via injection and per os application, respectively. In addition, the toxic effect of broth filtrate was observed in vitro in a cell line of Bombyx mori. Czapek-Dox broth fortified with 1% yeast extract stimulated more rapid mycelial growth and correspondingly more toxin production in time. At 25-30 degrees C, metabolic toxin(s) was detected in broth via bioassay at about 4-5 days postinoculation when mycelial biomass reached 5 mg/ml (dry wt). At these temperatures, biological activity of the filtrate peaked at about 8-10 days when mycelial growth reached a maximum (10 mg/ml, dry wt). This suggests a positive relationship between toxic metabolite and mycelial production. After 10 days, the toxicity of the filtrate appeared to decline gradually. Pathogenicity symptoms of the metabolites developed slowly in both G. mellonella and D. melanogaster. Early signs of lethargy appeared at 4 days postinjection and cumulative mortality of G. mellonella larvae was low after 1 week; however, the percentage of mortality reached 98-100% after 14 days. At death, G. mellonella larvae displayed small dark spots on a brownish cuticle. Histopathological effects were observed in the larval midgut, malpighian tubules, hypodermis, fat body, hemocytes, muscle, and silk glands. Cellular change consisted of pycnosis of the nucleus and a reduction in cytoplasm density. Highest mortality (78.8%) to adult D. melanogaster occurred after 10 days post-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adverse consequences of prenatal illicit drug exposure

Our appreciation of the impact on health of illicit drug use is growing. Once considered a maternal risk, prenatal drug exposure may target fetal neurobehavior, affecting attention and learning as the child grows into adulthood. Cocaine, opiates, marijuana, and amphetamines have each been scrutinized for adverse actions on placental transport, fetal behavior states, newborn withdrawal, and childhood learning and attentive skills. Neurotransmitter analysis in the animal model after prenatal drug exposure now provides biological support for these clinical findings. The increasing prevalence of drug use by pregnant women, the effect of illicit drug use on transmission of the human immunodeficiency virus, and the maternal and fetal consequences of illicit drug exposure make illicit drug use in pregnancy a central challenge in maternal-fetal medicine and a need-to-know field in general obstetrics.     

Effects of prenatal cocaine exposure on embryonic expression of sonic hedgehog

PURPOSE: To estimate the impact of visual impairment in older Australians on the use of community support services. METHODS: In the Blue Mountains Eye Study, 3654 people aged 49 or older were examined- 82.4% of eligible residents in an area west of Sydney, Australia. Presenting and best-corrected visual acuities were measured using a LogMAR chart. Subjects were categorized as having visual impairment if their better eye read 40 or fewer letters (20/40 or worse). Interview data included marital and other socioeconomic status measures, living status (alone or with spouse or other person), use of community support services, reliance on regular help from nonspouse family members or friends, and perceived ability to go out alone. RESULTS: After adjusting for age, gender, education, living status, walking disability, and health-related factors, for each one-line (five-letter) decrease in best-corrected visual acuity, there was a corresponding increase in reliance on community support services (odds ratio [OR], 1.17; 95% confidence interval, [CI] 1.07-1.28) or combined community and family support (OR 1.22; 95% CI, 1.12-1.32). Visually impaired persons were three times as likely to use regular support services provided by the municipality (OR 3.1; 95% CI, 1.8-5.1). A similar increased reliance on regular help from community, nonspouse family members, or friends was found. Visually impaired persons were also much more likely to state that they thought they were unable to go out alone (OR 6.2; 95% CI, 2.6-14.3). The findings were similar when presenting visual acuity was used to define visual impairment or after subjects with walking disabilities were excluded. Visual impairment seemed to have a greater effect on use of community support services in women than in men. CONCLUSIONS: After adjustment was made for confounding factors, visual impairment was found to affect significantly and negatively the independence of elderly people, particularly older women. Presenting visual acuity closely approximated best-corrected visual acuity in its impact on the use of community support services.     

Gene-environment interactions across development: Exploring DRD2 genotype and prenatal smoking effects on self-regulation.

Genetic factors dynamically interact with both pre- and postnatal environmental influences to shape development. Considerable attention has been devoted to gene-environment interactions (G × E) on important outcomes (A. Caspi & T. E. Moffitt, 2006). It is also important to consider the possibility that these G × E effects may vary across development, particularly for constructs like self-regulation that emerge slowly, depend on brain regions that change qualitatively in different developmental periods, and thus may be manifested differently. To illustrate one approach to exploring such developmental patterns, the relation between variation in the TaqIA polymorphism, related to D2 dopamine receptor expression and availability, and prenatal exposure to tobacco was examined in two exploratory studies. First, in 4-week-old neonates, genotype-exposure interactions were observed for attention and irritable reactivity, but not for stress dysregulation. Second, in preschool children, genotype was related to Preschool Trail Making Test (K. A. Espy and M. F. Cwik, 2004) task performance on conditions requiring executive control; children with both the A1+ genotype and a history of prenatal tobacco exposure displayed disproportionately poor performance. Despite study limitations, these results illustrate the importance of examining the interplay between genetic and prenatal environmental factors across development. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of prenatal diazepam exposure on TNF-alpha production by rat splenocytes

Prenatal exposure to diazepam and other benzodiazepines (BDZ) has been found to result in a marked reduction of T-lymphocyte proliferation during postnatal development of rats. In search for pathogenic changes underlying this effect, we investigated the mitogen lipopolysaccharide (LPS) and concanavalin A (ConA) stimulated release of tumour necrosis factor (TNF)-alpha by mixed splenocytes of male offspring from Long Evans rats treated with 1.25 mg/kg per day diazepam from gestational day 14 to 20. In response to LPS, TNF-alpha release was found to be significantly lower in mixed splenocytes of two- and four-week-old treated than in control offspring. However, at eight weeks of age, prenatally diazepam-treated animals showed a significantly higher LPS-induced TNF-alpha release than control rats. Since monocytes/macrophages represent a major source of TNF-alpha, additional experiments were performed on purified spleen macrophages and lymphocytes stimulated with LPS. TNF-alpha release was only detectable in supernatants of adherent spleen macrophages and not in supernatants of lymphocytes. Thus, our data indicate that a disturbance in TNF-alpha release from macrophages is involved in the deficient immune response of prenatally diazepam-exposed rats.     

基于农村社区人群的心血管危险因素相对效应和性别差异的分层研究

目的:调查北京市房山区农村人群心血管疾病及其相关危险因素的分布,并探讨该人群中主要危险因素与心血管疾病的关联强度.方法:采用普查的方法,对青龙湖镇32个行政村40岁以上人群进行横断面研究;通过问卷调查、体格检查和生化检测收集心血管疾病患病及其相关危险因素的资料,采用分层分析和多因素logistic回归模型进行统计学分析.结果:共计7 577名研究对象中冠心病、脑卒中、糖尿病、高血压、血脂紊乱、超重和肥胖的患病率分别为6.5%、4.1%、10.7%、39.5%、56.7%、44.0%和13.6%.采用多因素logistic回归模型调整变量后比较危险因素对脑卒中/冠心病的现患比值比(prevalence odds ratio,POR),发现高血压与脑卒中的关联更强(POR=2.780,95%CI:2.146～3.602),而糖尿病与冠心病的关联更强(POR=2.671,95%CI:2.121～3.363);按性别分层后各危险因素及数量性状指标与脑卒中的关联存在明显差异,在女性中主要是超重/肥胖(POR=1.652,95%CI:1.122～2.433)、体重指数(POR=1.048,95%CI:1.002～1.096)、收缩压(POR=1.017,95%CI:1.005～1.030)和血糖水平(POR=1.093,95%CI:1.048～1.140),而在男性中主要是血脂紊乱(POR=1.615,95%CI:1.124～2.319)、总胆固醇(POR=3.932,95%CI:1.533～10.086)和HDL-C水平(POR=0.072,95%CI:0.022～0.236).结论:本研究人群中心血管危险因素的聚集影响脑卒中和冠心病的高患病率,不同危险因素对脑卒中和冠心病的影响程度以及在不同性别人群中的影响存在差异.     

Selective effects on CRF neurons and catecholamine terminals in two stress-responsive regions of adult rat brain after prenatal exposure to diazepam

Earlier work demonstrated that prenatal exposure to diazepam (DZ) selectively affected the noradrenergic (NE) terminals in the hypothalamus, leading to decreased basal NE levels, turnover rate, and release in adult offspring as well as altered responses to stressors in these NE projections. The exposure also affected plasma hormonal responses to stressors. In the present work, we used immunocytochemistry to study the effects of prenatal DZ exposure on NE terminals and on corticotropin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. DZ exposure (2.5 or 10 mg/kg over gestational days 14-20) led to a decrease in dopamine-beta-hydroxylase (DBH)-immunoreactivity (-ir) and a decrease in CRF-ir containing cells within the PVN of adult rats. The exposure also decreased DBH-ir in the ventral portion of the bed nucleus of the stria terminalis (BNST) but did not affect CRF-ir in the oval nucleus of BNST. Therefore, this study provides anatomic evidence that targeting benzodiazepine binding sites prenatally affects two neurotransmitter systems involved in responses to stressors.     

Behavioral and neuroanatomical effects of prenatal, postnatal, or combined exposure to ethanol in weanling rats.

Separate and combined effects of prenatal and postnatal exposure to ethanol on activity, emotionality, learning, and hippocampal neuroanatomy were examined in infant rats. Neonatal rats from mothers that were fed either a liquid ethanol (E) or control (C) diet were artificially reared on either 3% ethanol (E) or isocaloric maltose/dextrin (C). Pups in 4 treatment groups (EE, EC, CE, and CC) were compared. Differences in activity and emotionality were slight. Ethanol affected both the partial reinforcement acquisition effect and the partial reinforcement extinction effect. Hippocampal cell density (compared with Group CC) showed a 12% reduction in CA1 pyramidal cells and an 11% reduction in mature granule cells in Groups EC and EE; the CA4 area (compared with Group CC) was significantly larger after postnatal exposure (Groups CE and EE). Significant positive correlations were found between rate of extinction after partial reinforcement (PRF) training and CA1 pyramidal cell density in Groups CC and CE. A significant negative correlation was found between extinction rate after PRF training and CA4 area in Group EE. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of prenatal exposure to cocaine on the dopaminergic cells in the rat retina. An immunocytochemical and neurochemical study

5-Hydroxytryptamine1A (5-HT1A) receptors have been visualized at the electron microscopic level in selected areas (dorsal raphe nucleus, hippocampus, septum) of the rat brain using specific anti-peptide antibodies. 5-HT1A receptor immunoreactivity was found almost exclusively in the somatodendritic compartment of neurons and was very rarely observed within processes possibly belonging to glial cells. The immunoenzymatic reaction product was associated exclusively with dendritic spines in the dorsal hippocampus, whereas in the dorsal raphe nucleus and the septal complex, immunoreactivity was found in both dendritic processes and somata. Although some immunolabeling was observed within the cytoplasm of cell bodies, 5-HT1A receptor immunoreactivity was essentially confined to the plasma membrane where it was unevenly distributed. It was frequently associated with synapses (except in the dorsal raphe nucleus), but was also found extrasynaptically in both somata and dendrites. These data suggest that the action of serotonin via 5-HT1A receptor could occur through junctional as well as nonjunctional transmission.     

Effects of prenatal PCB exposure on cognitive processing efficiency and sustained attention.

Assesses 4-yr-old children exposed prenatally to polychlorinated biphenyls (PCBs; an environmental toxin) on 3 tasks: 2 designed to evaluate cognitive processing efficiency and 1 to evaluate sustained attention. When compared with standardized IQ tests, these tasks provided greater specificity in identifying cognitive deficits. Adapted for 4-yr-old children in the present study, these paradigms demonstrated moderate levels of test–retest reliability. Prenatal exposure to PCBs was associated with less efficient visual discrimination processing and more errors in short-term memory scanning but not with sustained attention. Although much larger quantities of these contaminants are transferred postnatally via breastfeeding than prenatally across the placenta, postnatal exposure was unrelated to cognitive performance. The data link intrauterine PCB exposure to 2 dimensions of cognitive functioning fundamental to learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The interference effects of hexadecylphosphocholine on proliferation and membrane phospholipid metabolism in human myeloid leukemia cell lines

Membrane phospholipids are important regulators of cellular function. The phospholipid activities, such as lipid composition and transportation, contribute to cellular homeostasis in the lifespan of cells. Alterations in phospholipids result in the movement of bilayer lipids and the initiation of coagulation, recognition and internalization. Hexadecylphosphocholine (HePC) exerts antitumor potencies and represents a new class of antitumor agents targeted to the cellular membrane. Human myeloid leukemia cell lines HL-60 and K562 employed in this study were inhibited by HePC in vitro. The results indicate that the HL-60 cell line was sensitive, while K562 was resistant to HePC. Synthetic HePC is an alkyllysophospholipid analog which interacted with the cell membrane, thereby altering lipid composition and metabolism of membrane phospholipids and modulating intracellular calcium in human myeloid leukemia HL-60 and K562 cell lines. The contents of membrane phospholipids, including phosphatidylinositol (PI), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE), were determined quantitatively with high performance liquid chromatography. The sensitivity of myeloid leukemia HL-60 and K562 cell lines to HePC probably depends on the different distribution of these four phospholipids in the cellular membrane, or on the response of these phospholipids to HePC. The cytosolic free calcium ([Ca++]i) concentration increased by HePC confirmed that [Ca++]i was released from the intracellular calcium pool and is associated with cell differentiation and apoptosis. We investigated the hypothesis that the antiproliferative effect of HePC was mediated through the interference with cellular membrane phospholipids, including choline-containing phospholipids (PC), aminophospholipids (PE and PS) and PI, in eukaryotic cells.