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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Developmental neurotoxicity can be ascribed to in utero exposure to exogenous substances or to exposure of the fetus to endogenous compounds that accumulate because of genetic mutations. One of the best recognized human neuroteratogens is ethanol. The Fetal Alcohol Syndrome (FAS) is characterized by growth deficiency, particular facial features, and central nervous system (CNS) dysfunctions (mental retardation, microencephaly and brain malformations). Abuse of toluene by pregnant women can lead to an embryopathy (fetal solvent syndrome, (FSS)) whose characteristics are similar to FAS. Phenylketonuria (PKU) is a genetic defect in phenylalanine (Phe) metabolism. Offspring of phenylketonuric mothers not under strict dietary control are born with maternal PKU (mPKU), a syndrome with similar characteristics as FAS and FSS. While ethanol has been shown to cause neuronal death, no such evidence is available for toluene or Phe and/or its metabolites. On the other hand, alterations in astrocyte proliferation and maturation have been found, mostly in in vitro studies, which may represent a potential common mode of action for at least some of the CNS effects found in FAS, mPKU, and FSS. Further in vivo and in vitro studies should validate this hypothesis and elucidate possible molecular targets.
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PMID:Developmental neurotoxicity: do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria. 1205 59

The complex relationship between alcohol use and pregnancy involves socioeconomic, biomedical, psychological, and ethical factors. In recent years alcohol abuse on the part of women of childbearing age has been increasing steadily. Currently, a significant segment of the American population is at risk for an alcoholic pregnancy. Discussion includes a review of the literature concerning alcohol and pregnancy and covers the following: the symptomatology of fetal alcohol syndrome; prospective and epidemiologic human studies; animal models; etiology of fetal alcohol syndrome (FAS); maternal aspects of alcoholism and pregnancy and associated risk factors; paternal drinking and the theory of germ cell damage; use of ethanol in obstetrics; prevention of FAS; and questions to be answered in the future. The Fetal Alcohol Study Group of the Research Society of Alcoholism has promulgated a list of minimal criteria that must be met before a diagnosis of fetal alcohol syndrome (FAS) can be made. These criteria include prenatal and postnatal growth retardation and at least 2 of the following characteristic facial features: microcephaly, microopthalmia, and/or short palpebral fissures; and midfacial hypoplasia (defined as absent or rudimentary philtrum, thin vermilion border of upper lip, hypoplastic maxilla). The label "possible FAS" also is recommended if the criteria are not met, but congenital damage due to alcohol still is suspected. Virtually all infants with FAS have very low birth weights for their gestational age, usually at or below the third percentile. Body length and head circumference also are reduced to a similar degree. Mental retardation is the most debilitating and tragic aspect of this syndrome. Hyperactivity, hyperresponsiveness, hyperacusis, hypotonia, and tremulousness also are commonly described in FAS infants. Numerous studies involving large numbers of pregnant women have provided important data concerning the epidemiology and symptomatology of maternal alcohol use. All of these studies have been based on self reported use of alcohol, and the relationship of these reports to actual intake probably varies. Available prospective studies permit the estimation of the incidence of FAS in general and clarify to some extent the magnitude of risks an alcoholic woman has for giving birth to a defective child. Animal studies are very important in the study of alcohol and pregnancy because they provide an opportunity to control for variables that are seldom accounted for in human beings. One can control dosage and timing of ethanol administration, nutritional factors via pair feeding, and environment, and one can consider individual variation through cross strain comparisons.
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PMID:Pregnancy and alcohol. 1233 10

Fetal alcohol exposure is the most common nonhereditary cause of mental retardation in the western world. Rats prenatally treated with ethanol liquid diet exhibit extensive defects in the brain that accurately model those observed in humans. To analyze the ethanol effects on gene expression during brain development, we performed mRNA differential display and two-dimensional electrophoresis on gestational day (G) 13 and G 16 brain from rats treated with ethanol liquid diet. Using mRNA differential display followed by a variety of quantitative analyses, three genes were confirmed to be ethanol-responsive. Among them was Neuroendocrine-Specific Protein-A (NSP-A), which is known to be affected by thyroid hormone in the cortex at this developmental time. However, two additional genes known to be thyroid hormone-responsive were unaffected by ethanol, indicating that interference with thyroid hormone action may not be a predominant pathway by which alcohol induces damage in the fetal brain. The observation that interferon-inducible protein-10 (IP-10) is up-regulated in ethanol-treated fetal brain may indicate the presence of a disease process recruiting CD8+ T-cells capable of interfering with myelination. The result of two-dimensional (2D) electrophoresis and Western analyses demonstrated that few changes in the abundance of individual proteins or the phosphorylation of proteins at threonine and tyrosine were induced by prenatal ethanol exposure. A critical analysis of the approaches used in the present study may be important for future studies in this field.
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PMID:Differential display identifies neuroendocrine-specific protein-A (NSP-A) and interferon-inducible protein 10 (IP-10) as ethanol-responsive genes in the fetal rat brain. 1235 40

In utero exposure to ethanol is deleterious to fetal brain development. Children born with the fetal alcohol syndrome (FAS) display a number of abnormalities, the most significant of which are central nervous system (CNS) dysfunctions, such as microencephaly and mental retardation. An interaction of ethanol with glial cells, particularly astrocytes, has been suggested to contribute to the developmental neurotoxicity of this alcohol. At low concentrations (10-100 mM) ethanol inhibits the proliferation of astroglial cells in vitro, particularly when stimulated by acetycholine through muscarinic M3 receptors. Of the several signal transduction pathways activated by these receptors in astrocytes or astrocytoma cells, which are involved in mitogenic signaling, only some (e.g. protein kinase C (PKC) zeta, p70S6 kinase) appear to be targeted by ethanol at the same low concentrations which effectively inhibit proliferation. Inhibition of astroglial proliferation by ethanol may contribute to the microencephaly seen in FAS.
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PMID:Inhibition of muscarinic receptor-induced proliferation of astroglial cells by ethanol: mechanisms and implications for the fetal alcohol syndrome. 1252 Jul 58

Foetal alcohol syndrome is a known cause of mental retardation. It has been suggested that the anatomical and functional alterations observed in the cerebral cortex could be mediated by an interference of ethanol with developmental processes modulated by neurotrophins and/or their receptors. We have studied by immunohistochemistry the expression of the p75 neurotrophin receptor (p75 NTR) in the sensori-motor cortex of P10 and P20 rats exposed to the inhalation of ethanol during the first week of postnatal life. At both the studied ages, the number of p75 NTR immunoreactive neurons was higher in ethanol treated animals compared to controls. The increase of immunoreactive elements was relatively more marked in the motor than in the somatosensory cortex. The involvement of p75 NTR in ethanol-induced apoptosis and neural plasticity is discussed.
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PMID:Overexpression of the p75 neurotrophin receptor in the sensori-motor cortex of rats exposed to ethanol during early postnatal life. 1272 25

Clinical and experimental evidence has demonstrated that ethanol is a teratogen, and that its consumption during pregnancy induces harmful effects on the developing foetus that leads to foetal alcohol syndrome (FAS). Central nervous system dysfunctions are the most severe and permanent consequence of maternal alcohol intake and can occur in absence of gross morphological defects associated with FAS. Mental retardation and long-term cognitive and behavioural deficits are some of the problems commonly found in children of women who were moderate or heavy drinkers during pregnancy. Experimental evidence demonstrates that alcohol interferes with many molecular, neurochemical and cellular events occurring during the normal development of the brain. Some brain areas are more affected than others and, even within a given region, some cell populations are more vulnerable than others. The neocortex, hippocampus and cerebellum are especially susceptible to alcohol and have been associated with the behavioural deficits. For example, alcohol exposure during the development of neocortex increases natural apoptosis and induces cell necrosis. These effects may be associated with ethanol-induced alterations in both neurotrophic support, and the expression of cell adhesion molecules, which may affect cell-cell interactions and cell survival. Experimental evidence also shows that alcohol disrupts radial glial and astroglial development which may lead to alterations in cell migration and neuronal survival and differentiation. Impairment of several neurotransmitter systems and/or their receptors, as well as changes in the endocrine environment during brain development, are also important factors involved in the neurodevelopmental liabilities observed after in utero alcohol exposure.
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PMID:Mechanisms involved in central nervous system dysfunctions induced by prenatal ethanol exposure. 1282 22

Exposure to ethanol during pregnancy is detrimental to fetal development, and individuals affected by the fetal alcohol syndrome present a number of CN system dysfunctions including microencephaly and mental retardation. Recently, it has been suggested that ethanol-induced inhibition of glial cell proliferation may be relevant in the causation of microencephaly. In this study, we measured the developmental changes of MAPK (ERKl/2) and p70S6 kinase, which are considered to play a prominent role in cell proliferation, and their phosphorylated proteins in rat brain, and examined the effects of in vivo ethanol administration. MAPK and phospho-MAPK increased gradually after birth, and reached adult levels on postnatal day 21. In contrast, levels of both p70S6 kinase and phospho-p70S6 kinase decreased after birth. Exposure to ethanol (2-6 g/kg, from postnatal day 4 to 7) had no effects on MAPK or p70S6 kinase levels, but caused a dose-dependent decrease of both phosphoproteins. These results suggest that phosphorylation of MAPK and p70S6 kinase may represent relevant targets for the developmental neurotoxicity of ethanol, and may be involved in microencephaly.
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PMID:In vivo ethanol decreases phosphorylated MAPK and p70S6 kinase in the developing rat brain. 1287 81

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder due to an inborn error of cholesterol metabolism, characterized by congenital malformations, dysmorphism of multiple organs, mental retardation and delayed neuropsychomotor development resulting from cholesterol biosynthesis deficiency. A defect in 3 -hydroxysteroid-delta7-reductase (delta7-sterol-reductase), responsible for the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol, causes an increase in 7-DHC and frequently reduces plasma cholesterol levels. The clinical diagnosis of SLOS cannot always be conclusive because of the remarkable variability of clinical expression of the disorder. Thus, confirmation by the measurement of plasma 7-DHC levels is needed. In the present study, we used a simple, fast, and selective method based on ultraviolet spectrophotometry to measure 7-DHC in order to diagnose SLOS. 7-DHC was extracted serially from 200 l plasma with ethanol and n-hexane and the absorbance at 234 and 282 nm was determined. The method was applied to negative control plasma samples from 23 normal individuals and from 6 cases of suspected SLOS. The method was adequate and reliable and 2 SLOS cases were diagnosed.
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PMID:Diagnosis of Smith-Lemli-Opitz syndrome by ultraviolet spectrophotometry. 1450 64

Central nervous system dysfunctions (most notably microencephaly and mental retardation) are among the most significant effects of in utero exposure to ethanol. Ethanol causes alterations of both neuronal and glial cells. In particular, ethanol has been shown to inhibit proliferation of astroglial cells stimulated by certain, but not all mitogens. Here, we review evidence that acetylcholine, by activating the M(3) subtype of muscarinic receptors, increases DNA synthesis in rat and human astroglial cells and that this effect is inhibited by low ethanol concentrations (10-100mM). Of the several signal transduction pathways activated by these receptors in astrocytes or astrocytoma cells, ethanol appears to target activation of phospholipase D, leading to a decrease in phosphatidic acid, a decreased activation of the atypical protein kinase C zeta and decreased down-stream activation of p70S6 kinase and of nuclear factor-kappaB. Inhibition of this pathway by ethanol occurs at the same concentrations which effectively inhibit proliferation. Inhibition of astroglial cell proliferation by ethanol may contribute to the microencephaly present in most children diagnosed with the fetal alcohol syndrome.
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PMID:Signal transduction mechanisms involved in the antiproliferative effects of ethanol in glial cells. 1509 50

While excess cholesterol may have deleterious consequences, as in the case of atherosclerosis, too little cholesterol may endanger the development of the brain. Different degrees of mental retardation are often observed in inborn errors of cholesterol synthesis, such as the Smith-Lemli-Opitz syndrome or in maternal phenylketonuria, where the metabolite of accumulating phenylalanine, phenylacetate, is an inhibitor of cholesterol synthesis. Lack of cholesterol during brain development as a consequence of these genetic defects leads to severe brain damage, microencephaly and mental retardation, which are also hallmarks of the fetal alcohol syndrome (FAS). The brain relies on the in situ synthesis of cholesterol, which occurs mostly in astrocytes. Astrocyte-produced cholesterol is utilized for cell proliferation, or is released, via astrocyte-secreted high density lipoprotein-like particles containing apolipoprotein E, outside the cell, where it is taken up and utilized by neurons for dendrite outgrowth and to form synapses. We propose the hypothesis that ethanol may disrupt cholesterol homeostasis during brain development, and that this effect may be responsible, at least in part, for the central nervous system dysfunctions observed in the FAS, which include altered astrocyte proliferation, neuronal death and diminished synaptic contacts.
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PMID:Disruption of cholesterol homeostasis in the developing brain as a potential mechanism contributing to the developmental neurotoxicity of ethanol: an hypothesis. 1561 67


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