Numerous mechanisms likely contribute to the damaging effects of prenatal alcohol exposure on the developing fetus and particularly the developing central nervous system (CNS). The coexistence of a multitude of mechanisms that may act simultaneously or consecutively and differ among various cell types poses particular challenges to researchers. To study alcohol's effects on the fetus more easily, investigators have used animal models and tissue-culture experiments. Such approaches have identified numerous potential mechanisms through which alcohol acts on the fetus, many of which result in cell death by necrosis or apoptosis. Among these mechanisms are increased oxidative stress, damage to the mitochondria, interference with the activity of growth factors, effects on glia cells, impaired development and function of chemical messenger systems involved in neuronal communication, changes in the transport and uptake of the sugar glucose, effects on cell adhesion, and changes in the regulation of gene activity during development.

Mechanisms of alcohol-induced damage to the developing nervous system

Prenatal exposure to alcohol can damage the developing fetus and is the leading preventable cause of birth defects and intellectual and neurodevelopmental disabilities. In 1973, fetal alcohol syndrome was first described as a specific cluster of birth defects resulting from alcohol exposure in utero. Subsequently, research unequivocally revealed that prenatal alcohol exposure causes a broad range of adverse developmental effects. Fetal alcohol spectrum disorder (FASD) is the general term that encompasses the range of adverse effects associated with prenatal alcohol exposure. The diagnostic criteria for fetal alcohol syndrome are specific, and comprehensive efforts are ongoing to establish definitive criteria for diagnosing the other FASDs. A large and growing body of research has led to evidence-based FASD education of professionals and the public, broader prevention initiatives, and recommended treatment approaches based on the following premises: â-a Alcohol-related birth defects and developmental disabilities are completely preventable when pregnant women abstain from alcohol use. â-a Neurocognitive and behavioral problems resulting from prenatal alcohol exposure are lifelong. â-a Early recognition, diagnosis, and therapy for any condition along the FASD continuum can result in improved outcomes. â-a During pregnancy: â-¦no amount of alcohol intake should be considered safe; â-¦there is no safe trimester to drink alcohol; â-¦all forms of alcohol, such as beer, wine, and liquor, pose similar risk; and â-¦binge drinking poses dose-related risk to the developing fetus.

http://depts.washington.edu/fasdpn/pdfs/AAPpeds.2015-3113.full.pdf

Fetal Alcohol Spectrum Disorders.

Prenatal ethanol exposure (PNEE) has been linked to widespread impairments in brain structure and function. There are a number of animal models that are used to study the structural and functional deficits caused by prenatal ethanol exposure, including, but not limited to: invertebrates, fish, rodents and non-human primates. Animal models enable a researcher to control important variables such as the route of ethanol administration, as well as the timing, frequency and amount of ethanol exposure. Each animal model and system of exposure has its place, depending on the research question being undertaken. In this review we will examine the different routes of ethanol administration and the various animal models of FASD that are commonly used in research, emphasizing their strengths and limitations. We will also present an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on behavior across the lifespan, focusing on learning and memory, olfaction, social, executive and motor functions. Special emphasis will be placed where the various animal models best represent deficits observed in the human condition and offer a viable test bed to examine potential therapeutics for humans with FASD.

/pdf/a-comparison-of-the-different-animal-models-of-fetal-alcohol-k8mxufpy29.pdf

A Comparison of the Different Animal Models of Fetal Alcohol Spectrum Disorders and Their Use in Studying Complex Behaviors

Background
Prenatal exposure to ethanol reduces the expression of hypothalamic proopiomelanocortin (POMC) gene, known to control various physiological functions including the organismal stress response. In this study, we determined whether the changes in POMC neuronal functions are associated with altered expressions of histone-modifying and DNA-methylating enzymes in POMC-producing neurons, since these enzymes are known to be involved in regulation of gene expression. In addition, we tested whether gestational choline supplementation prevents the adverse effects of ethanol on these neurons.

/pdf/gestational-choline-supplementation-normalized-fetal-alcohol-ocjq38tfcf.pdf

Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus.

Prenatal exposure to alcohol has profound effects on many aspects of fetal development. Although alterations of somatic growth and specific minor malformations of facial structure are most characteristic, the effects of alcohol on brain development are most significant in that they lead to substantial problems with neurobehavioral development. Since the initial recognition of the fetal alcohol syndrome (FAS), a number of important observations have been made from studies involving both humans and animals. Of particular importance, a number of maternal risk factors have been identified, which may well be of relevance relative to the development of strategies for prevention of the FAS as well as intervention for those who have been affected. These include maternal age >30 years, ethnic group, lower socioeconomic status, having had a previously affected child, maternal under-nutrition, and genetic background. The purpose of this review is to discuss these issues as well as to set forth a number of questions that have not adequately been addressed relative to alcohol's effect on fetal development. Of particular importance is the critical need to identify the full spectrum of structural defects associated with the prenatal effects of alcohol as well as to establish a neurobehavioral phenotype. Appreciation of both of these issues is necessary to understand the full impact of alcohol on fetal development.

http://www.ppsmodena.it/flex/cm/pages/ServeAttachment.php/L/IT/D/9%252Fb%252Fa%252FD.1aa00a09c446e33f7c81/P/BLOB%3AID%3D1228/E/pdf

The effects of alcohol on fetal development.

BACKGROUND
Prenatal alcohol exposure can alter physical and behavioral development, leading to a range of fetal alcohol spectrum disorders (FASD). Despite warning labels, pregnant women continue to drink alcohol, creating a need to identify effective interventions to reduce the severity of alcohol’s teratogenic effects. Choline is an essential nutrient that influences brain and behavioral development. Recent studies indicate that choline supplementation can reduce the teratogenic effects of developmental alcohol exposure. The present study examined whether choline supplementation during prenatal ethanol treatment could mitigate the adverse effects of ethanol on behavioral development.

Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats

Dietary choline levels modify the effects of prenatal alcohol exposure in rats.

Background: Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N-methylD-aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK-801) during withdrawal can attenuate ethanol’s teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol-related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Methods: Sprague–Dawley pups were exposed to 6.0 g ⁄ kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty-four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg ⁄ kg memantine, totaling doses of 0, 20, or 30 mg ⁄ kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Results: Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol-associated motor deficits and cerebellar cell loss in a dose-dependent manner. Conclusions: Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum

/pdf/administration-of-memantine-during-ethanol-withdrawal-in-4ie4sg3wyq.pdf

Administration of Memantine During Ethanol Withdrawal in Neonatal Rats: Effects on Long-Term Ethanol-Induced Motor Incoordination and Cerebellar Purkinje Cell Loss

Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure.

Despite the known damaging effects of prenatal alcohol exposure, women continue to drink during pregnancy, creating a need for effective interventions and treatments for fetal alcohol spectrum disorders (FASD). Experimental models can be useful in identifying potential treatments, and this article describes the spectrum of experimental therapeutics that currently are being investigated, including pharmacological, nutritional, and environmental/behavioral interventions. Some treatments target the underlying mechanisms that contribute to alcohol-induced damage, protecting against alcohol's teratogenic effects, whereas other treatments may enhance central nervous system plasticity either during alcohol exposure or long after alcohol exposure has ceased. The insights gained to date from experimental models offer several candidates for attenuating the deficits associated with FASD.

Nirelia M. Idrus

Papers

Prenatal choline supplementation mitigates behavioral alterations associated with prenatal alcohol exposure in rats

Dietary choline levels modify the effects of prenatal alcohol exposure in rats.

Administration of Memantine During Ethanol Withdrawal in Neonatal Rats: Effects on Long-Term Ethanol-Induced Motor Incoordination and Cerebellar Purkinje Cell Loss

Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure.

Fetal alcohol spectrum disorders: experimental treatments and strategies for intervention.