Alcohol Embryopathy Research Articles

The effect of the artichoke leaves extract on the postnatal development of offspring of female rats with the alcoholic placental dysfunction

The experimental research of the artichoke (Cynara scolymus) leaves extract (ALE) influence on the postnatal development of the I st generation rats born by female rats with the ethanol-induced placental dysfunction (PD) has been conducted. It has been found that the therapeutic and preventive regimen of ALE and the reference medicine Solcoseryl from the 14 th to the 19 th day of gestation (on the background of introduction of 40% ethanol solution in the dose of 4 g/kg) reduced the level of death in infant rats: ALE in 2.4 times and Solcoseryl in 1.6 times compared to the untreated control. The medicines studied caused a significant weight gain in rats compared to the control pathology group. From the 1 st to 14 th days of the experiment the weight gain caused by ALE was more significant. The difference in the efficacy of the medicines was not further observed. Introduction of ALE and Solcoseryl also promoted the correction of pathological deviations in the postnatal development of infant rats. Moreover, ALE showed a higher activity compared to Solcoseryl. Therefore, the data obtained allow to recommend ALE for the preventive correction of alcoholic embryopathy developed on the background of PD.

Altered hepatic lipid metabolism in C57BL/6 mice fed alcohol: a targeted lipidomic and gene expression study

Chronic alcohol consumption is associated with fatty liver disease in mammals. The object of this study was to gain an understanding of dysregulated lipid metabolism in alcohol-fed C57BL/6 mice using a targeted lipidomic approach. Liquid chromatography tandem mass spectrometry was used to analyze several lipid classes, including free fatty acids, fatty acyl-CoAs, fatty acid ethyl esters, sphingolipids, ceramides, and endocannabinoids, in plasma and liver samples from control and alcohol-fed mice. The interpretation of lipidomic data was augmented by gene expression analyses for important metabolic enzymes in the lipid pathways studied. Alcohol feeding was associated with i) increased hepatic free fatty acid levels and decreased fatty acyl-CoA levels associated with decreased mitochondrial fatty acid oxidation and decreased fatty acyl-CoA synthesis, respectively; ii) increased hepatic ceramide levels associated with higher levels of the precursor molecules sphingosine and sphinganine; and iii) increased hepatic levels of the endocannabinoid anandamide associated with decreased expression of its catabolic enzyme fatty acid amide hydrolase. The unique combination of lipidomic and gene expression analyses allows for a better mechanistic understanding of dysregulated lipid metabolism in the development of alcoholic fatty liver disease.

Influence of chronic intrauterine exposure to alcohol on structurally normal hearts

Abuse of alcohol during pregnancy is known to cause alcoholic embryopathy and congenital cardiac disease. We sought to establish if there were any cardiac abnormalities to be found in patients known to have alcoholic embryopathy, but with structurally normal hearts. We reviewed the electrocardiograms and echocardiographic data of 347 such patients without congenital cardiac disease. A shortened QT interval was found in half of the cases. The left ventricular diameter was small in one quarter of all patients, independent from age, gender, and the degree of alcoholic embryopathy. We conclude that intrauterine exposure to alcohol as a primary toxin can lead to minor cardiac abnormalities, even in the absence of structural congenital cardiac disease.

Mitogenic effects of phospholipase D and phosphatidic acid in transiently permeabilized astrocytes: effects of ethanol.

Investigations of lipid-mediated signalling pathways are often limited by a lack of methods for the intracellular delivery of lipid messengers. We established a procedure for the transient permeabilization of astrocytes by an oxygen-insensitive mutant of streptolysin-O (SLO) to investigate the participation of the phospholipase D (PLD) signalling pathway in astroglial cell proliferation. Exogenous PLD, when incubated in the presence of SLO, caused an increase in DNA synthesis (measured by thymidine incorporation) which was completely suppressed by ethanol (0.3%, v/v). In parallel experiments, phosphatidic acid also induced a dose-dependent mitogenic response which, however, was not affected by the presence of ethanol. Phosphatidic acid was more effective in this assay than diacylglycerol but its effect was sensitive to the protein kinase inhibitor Ro 31-8220. Our findings provide direct evidence that disruption of the PLD signalling pathway by ethanol is sufficient to suppress astroglial proliferation, an effect that might contribute to the inhibition of brain growth in alcoholic embryopathy.

Inhibition of astroglial cell proliferation by alcohols: interference with the protein kinase C-phospholipase D signaling pathway

Ethanol inhibits astroglial cell proliferation, an effect that may contribute to the development of alcoholic embryopathy in humans. In the present study, we investigated inhibitory effects of ethanol and butanol isomers (1-, 2- and t-butanol) on astroglial cell proliferation induced by the strongly mitogenic phorbol ester, 4ß-phorbol-12α,13ß-dibutyrate (PDB). 4ß-Phorbol-12α,13ß-dibutyrate (PDB) induced a 10-fold increase of [3H]thymidine incorporation in cortical astrocytes prepared from newborn rats (EC50: 70 nM) which was blocked by Ro 31-8220, a cell-permeable protein kinase C (PKC) inhibitor. Ethanol blocked PDB-induced astroglial proliferation in a concentration-dependent manner; significant effects were already seen at 0.1% (v/v). Concomitantly, ethanol caused the formation of phosphatidylethanol (PEth) by phospholipase D (PLD) and reduced PLD-mediated formation of phosphatidic acid (PA). The butanols also inhibited the mitogenic action of phorbol ester; the inhibitory potency of the butanols was 1-butanol>2-butanol>t-butanol. The same range of potencies was observed for the inhibitory activity of the butanols towards protein kinase C activity measured in vitro. At 0.3% concentration, 1-butanol potently suppressed the PDB-induced formation of phosphatidic acid while 2- and t-butanol were less active. Taken together, our results suggest that ethanol and 1-butanol exert a specific inhibitory effect on PKC-dependent astroglial cell proliferation by synergistically inhibiting PKC activity and the PLD signaling pathway.

Clinical and electroretinographic findings in fetal alcohol syndrome

Purpose: Fetal exposure to alcohol is a serious public health problem and is associated with anomalies of the eye ground, as well as neurodevelopmental delay, growth delay, and characteristic facial features. Our purpose is to report the incidence of abnormal electroretinogram (ERG) results in children with fetal alcohol syndrome and raise awareness of the diagnosis of fetal alcohol syndrome in ophthalmology. Methods: A retrospective review was performed on the records of 11 children with the diagnosis of fetal alcohol syndrome. The results of the ophthalmologic examination, magnetic resonance imaging, visual acuity test, and ERG are reported. Results: The magnetic resonance imaging results were abnormal in all subjects tested. The ophthalmology examination showed optic nerve hypoplasia in 91% of the subjects. Visual acuity was reduced in all but one subject. The ERG results were abnormal, showing reduced b-wave amplitude, increased a- and b-wave implicit time, reduced Rmax, and increased log (k). The scotopic ERG was more severely affected than the photopic ERG. Conclusions: Prenatal alcohol exposure can lead to changes in retinal function as evidenced by an abnormal ERG response. The ERG can therefore be a tool with which to identify suspected alcohol embryopathy. (J AAPOS 2000;4:200–4)

Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus.

The aim of this paper is to provide a summary of clinical findings regarding the safety of tacrolimus in pregnancy. From 1992 to 1998 data were collected on 100 pregnancies from 84 mothers who received tacrolimus systemically; 83 cases of solid organ transplantation, and 1 case of Behçet's disease. Maternal mean age at conception was 28 years and pregnancy outcome was live birth in 68%, spontaneous abortion in 12%, induced abortion in 12%, stillbirth/perinatal death in 3%, ongoing pregnancy in 2%, and lost to follow up in 3%. Fifty-nine percent of the neonates were delivered prematurely (< 37 weeks of gestation). Birth weight was appropriate for the gestational age in 90% of the cases. Malformations occurred in 4 neonates: case 1, meningocele and urogenital defects; case 2, alcoholic embryopathy; case 3, ear defect, cleft palate and hypospadia; case 4, multicystic dysplastic kidney. There was no consistent pattern of malformations and 2 mothers subsequently delivered a healthy neonate while on tacrolimus therapy. Nearly 70% of pregnancies following systemic tacrolimus administration resulted in a favourable outcome without any significant effect on intrauterine growth. The incidence of malformations was similar to that reported with other immunosuppressants in transplant recipients.

Ethanol inhibits astroglial cell proliferation by disruption of phospholipase D-mediated signaling.

The activation of phospholipase D (PLD) is a common response to mitogenic stimuli in various cell types. As PLD-mediated signaling is known to be disrupted in the presence of ethanol, we tested whether PLD is involved in the ethanol-induced inhibition of cell proliferation in rat cortical primary astrocytes. Readdition of fetal calf serum (FCS) to serum-deprived astroglial cultures caused a rapid, threefold increase of PLD activity and a strong mitogenic response; both effects were dependent on tyrosine kinases but not on protein kinase C. Ethanol (0.1-2%) suppressed the FCS-induced, PLD-mediated formation of phosphatidic acid (PA) as well as astroglial cell proliferation in a concentration-dependent manner. Moreover, exogenous bacterial PLD increased astroglial proliferation in an ethanol-sensitive manner, whereas exogenous PA or lysophosphatidic acid was less effective. Formation of PA and astroglial proliferation were strongly inhibited by 1-butanol (0.1-1%), a substrate of PLD, but were unaffected by t-butanol, a non-substrate; 2-butanol had intermediate effects. Platelet-derived growth factor and endothelin-1 mimicked the mitogenic effect of FCS; their effects were also inhibited by the butanols in the potency order 1-butanol > 2-butanol > tert-butanol. Our results, in particular, the differential effects of 1-, 2-, and tert-butanol with respect to PA formation and astroglial proliferation, strongly suggest that the antiproliferative effects of ethanol in glial cells are due to the disruption of the PLD signaling pathway. This mechanism may also contribute to the inhibition of astroglial growth and brain development observed in alcoholic embryopathy.

Pregnancies following liver transplantation – how safe are they?

The number of pregnancies following liver transplantation is increasing due to better patient and graft survival and quality of life. Out of 156 women of a reproductive age, there were 19 pregnancies in 16 women, 12 on CSA and seven on tacrolimus, which occurred between 7/92 and 1/97. The median age of the women was 27.9 yr, median time after transplantation 33 months. There were four spontaneous and two induced abortions in the first trimenon. Ten women delivered ten healthy babies; three newborns had problems (alcoholic embryopathy due to recurrent alcohol abuse of his mother, pneumonia, weight 2000 g). In eight women mostly mild complications were observed, such as hypertension (n = 5), nonspecific elevation of liver enzymes (n = 2), infection (n = 3) and premature labor (n = 1). Mean gestational age was 39 wk and mean birth weight 2900 g. One case of prematurity and three cases of growth retardation occurred. Cesarean sections were performed in 7 patients (54%) for maternal hypertension (n = 2), presumed fetal hypoxia (n = 4) and breech position (n = 1). All children are normally developed, the oldest being 5 yr old. Although experience with tacrolimus is limited, pregnancies following liver transplantation carry an acceptable risk if carefully monitored by an experienced team of transplant surgeons and obstetricians.

Stippled epiphyses in fetal alcohol syndrome

We report on punctate epiphyseal calcifications (stippled epiphyses) in the fetal alcohol syndrome and present the differential diagnosis of chondrodysplasia punctata. A literature survey shows that epiphyseal calcifications accompanying alcoholic embryopathy are regularly located in the lower limbs and rarely found in the upper extremities.

Malformation patterns in children with congenital heart disease.

We prospectively examined 1016 infants and children with congenital heart disease (CHD) to detect additional malformation patterns. They were divided into two major groups. In the first group (n = 881), the CHD either occurred alone or was accompanied by a major extracardiac malformation (n = 68, 7.7%). In the second group (n = 135, 13.3%), the CHD was part of a malformation syndrome, embryopathy, association, or complex. In one fourth of the 56 chromosomal syndromes, the underlying cytogenetic anomaly differed from trisomy 21. Fourteen of the 30 children with non-chromosomal malformation syndromes had Noonan's syndrome. Thirteen of the 27 embryopathies were due to rubella infection, but alcohol embryopathy occurred nearly as often (n = 10). In those children with malformation associations (n = 16) seven showed cardiofacial association. Three of the five children with malformation complexes had Ivemark disease. In this study, underlying disorders were found in one of eight children with CHD, a considerably higher percentage than that reported in earlier studies.

The effect of ethanol on the growth of rat embryos: the role of stage dependency and hyperosmolality.

Clinical studies and experimental research have established the teratological rela­tionship between constant ethanol consumption throughout pregnancy, and the occurrence of alcohol embryopathy (AE) in the offspring of alcoholics (as re­viewed by Abel, 1982). The implication of social or “binge” drinking is of specific interest because confusion exists concerning advice given to pregnant women about their drinking habits.

Alterations of myocardial function and structure in a model of alcohol embryopathy

Alterations of myocardial function and structure in a model of alcohol embryopathy

Anomalies of the Kidneys and Genitourinary Tract in Alcohol Embryopathy

In addition to the well known major signs of growth retardation, microcephaly, mental retardation and typical craniofacial dysmorphism, malformations of the urinary tract were found in 9 of 110 patients with alcohol embryopathy. Of the 110 patients 21 have been examined adequately. An extensive urologic investigation of children with alcohol embryopathy and symptoms suggesting kidney or genitourinary tract disease is essential for early diagnosis and correction of malformations. Awareness of alcohol embryopathy in a child referred for correction of urinary tract anomalies may help to establish the diagnosis and prevent it in further offspring.

Alcohol embryo- and fetopathy: Neuropathology of 3 children and 3 fetuses

Maternal chronic ethanol abuse during pregnancy causes malformations of the offspring. Three children (aged 6 months, 9 months, 4 1 2 years) and 3 fetuses (17th, 18th, and 20th gestational week) showed a wide spectrum of disorders ranging from severe dysraphic state, arhinencephaly, porencephaly, agenesis of corpus callosum, a range from hydranencephaly to microdysplasias (p.e. reduced gyration of dentate nucleus and inferior olives), and a range from gastrochisis or congenital heart defects to craniofacial dysmorphogenesis and palmar crease anomalies. The patterns of the cerebral malformations were not as uniform as the clinical phenotype of the alcohol embryopathy. The observations did not support the assumption that there exists a specific period for alcohol teratogenicity.

Furrows and dermal ridges of the hand in patients with alcohol embryopathy.

Palmar creases and dermal ridge patterns of 34 patients with alcohol embryopathy are compared with 470 healthy individuals. In alcohol embryopathy several typical deviations were noted. Palmar Creases. The interdigital part of the distal palmar crease is generally sharply bent, the proximal transverse crease is hypoplastic or missing, the thenar crease is commonly well marked. Simian creases and bridged palmar creases are more common in patients with alcohol embryopathy than in healthy individuals. Ridge Patterns of the Palm. The main line D coming from triradius d in patients with alcohol embryopathy mostly shows a low type of ending in the fourth interdigital area; in this area loops are twice as common as in healthy individuals. Patterns of the Fingertips. No deviations were noted in the distribution of whorls and loops, but virtually no arches were observed in patients with alcohol embryopathy. These anomalies suggest embryonic damage in the twelfth week of gestation.

No elevation of exchange type aberrations in lymphocytes of children with alcohol embryopathy.

The lymphocyte chromosomes from 23 children with the 'fetal alcohol syndrome' or 'alcohol embryopathy' (AE) were analyzed with respect to exchange type aberrations. These aberrations were not more frequent in AE than in controls. The possibility that AE results from unspecific suppression of RNA and consequently of protein synthesis in the developing embryo is discussed.

The influences of alcohol on the fetus.

The dual role of alcohol as a drug on one hand anddepending on the amount consumed-as stimulant or poison on the other hand, has been considered and documented by man for Centimes. Only in this Century has the initial importance of alcohol as almost a panacea been replaced by the development of therapeutic agents with more specific indications. Only folk medicine still accords a certain role to alcohol. Although certain physical and psychological characteristics have always been related to the consumption of alcohol, it was onyl at the turn of this Century that certain diseases were recognized a& consequences of the direct or indirect toxicity of alcohol. The world-wide problem of increasing alcoholism has consequences for many aspects of life, but it is remarkable that alcohol as a potential embryotoxic agent has been recognized only in the last few years. Currently the consequences of alcohol are considered one of the most common causes of Problems in infancy [35]. A review of the literature shows that only the chronic matemal alcohol abuse during early pregnancy has a etiological role for the symptom complex of alcoholic embryopathy. Generally, it is impossible to allocate specific single Symptoms to the intrauterine exposure to alcohol because conditions associated with alcoholism may also substantially influence the intrauterine development. Therefore, this review will attempt to identify that fetal damage specifically related to alcohol and to pursue the question whether social drinking or