A multi-organ analysis of the role of mTOR in fetal alcohol spectrum disorders.

Alcohol exposure during gestation can lead to fetal alcohol spectrum disorders (FASD), an array of cognitive and physical developmental impairments. Over the past two and a half decades, Mammalian Target of Rapamycin (mTOR) has emerged at the nexus of many fields of study, and has recently been implicated in FASD etiology. mTOR plays an integral role in modulating anabolic and catabolic activities, including protein synthesis and autophagy. These processes are vital for proper development and can have long lasting effects following alcohol exposure, such as impaired hippocampal and synapse formation, reduced brain size, as well as cognitive, behavioral, and memory impairments. We highlight recent advances in the field of FASD, primarily with regard to animal model discoveries and discuss the interaction between alcohol and mTOR in the context of various tissues, including brain, placenta, bone, and muscle, with respect to developmental alcohol exposure paradigms. The current review focuses on novel FASD research within the context of the mTOR signaling and sheds light on mechanistic etiologies at various biological levels including molecular, cellular, and functional, across multiple stages of development and illuminates the dichotomy between the different mTOR complexes and their unique signaling roles.

Impact of alcohol exposure on neural development and network formation in human cortical organoids.

Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.

Maternal background alters the penetrance of growth phenotypes and sex-specific placental adaptation of offspring sired by alcohol-exposed males.

Epigenetic mechanisms of paternal inheritance are an emerging area of interest in our efforts to understand fetal alcohol spectrum disorders. In rodent models examining maternal alcohol exposures, different maternal genetic backgrounds protect or sensitize offspring to alcohol-induced teratogenesis. However, whether maternal background can mitigate sperm-inherited alterations in developmental programming and modify the penetrance of growth defects induced by preconception paternal alcohol exposures remains unaddressed. In our previous studies examining pure C57Bl/6J crosses, the offspring of alcohol-exposed sires exhibited fetal growth restriction, enlarged placentas, and decreased placental efficiency. Here, we find that in contrast to our previous studies, the F1 offspring of alcohol-exposed C57Bl/6J sires and CD-1 dams do not exhibit fetal growth restriction, with male fetuses developing smaller placentas and increased placental efficiencies. However, in these hybrid offspring, preconception paternal alcohol exposure induces sex-specific changes in placental morphology. Specifically, the female offspring of alcohol-exposed sires displayed structural changes in the junctional and labyrinth zones, along with increased placental glycogen content. These changes in placental organization are accompanied by female-specific alterations in the expression of imprinted genes Cdkn1c and H19. Although male placentae do not display overt changes in placental histology, using RNA-sequencing, we identified programmed alterations in genes regulating oxidative phosphorylation, mitochondrial function, and Sirtuin signaling. Collectively, our data reveal that preconception paternal alcohol exposure transmits a stressor to developing offspring, that males and females exhibit distinct patterns of placental adaptation, and that maternal genetic background can modulate the effects of paternal alcohol exposure.

The prevalence of fetal alcohol spectrum disorders in rural communities in South Africa: A third regional sample of child characteristics and maternal risk factors.

BACKGROUND: This study is the ninth cross-sectional community study of fetal alcohol spectrum disorders (FASD) conducted by the multidisciplinary Fetal Alcohol Syndrome Epidemiology Research team in the Western Cape Province of South Africa. It is the third comprehensive study of FASD in a rural, agricultural region of South Africa. METHODS: Population-based, active case ascertainment methods were employed among a school-based cohort to assess child physical and neurobehavioral traits, and maternal risk factor interviews were conducted to identify all children with FASD to determine its prevalence. RESULTS: Consent was obtained for 76.7% of 1158 children attending first grade in the region's public schools. Case-control results are presented for 95 with fetal alcohol syndrome (FAS), 64 with partial fetal alcohol syndrome (PFAS), 77 with alcohol-related neurodevelopmental disorder (ARND), 2 with alcohol-related birth defects (ARBD), and 213 randomly-selected controls. Four techniques estimating FASD prevalence from in-person examinations and testing yielded a range of total FASD prevalence of 206-366 per 1000. The final weighted, estimated prevalence of FAS was 104.5 per 1000, PFAS was 77.7 per 1000, ARND was 125.2 per 1000, and total FASD prevalence was 310 per 1000 (95% CI = 283.4-336.7). Expressed as a percentage, 31% had FASD. Although the rate of total FASD remained steady over 9 years, the proportion of children within the FASD group has changed significantly: FAS trended down and ARND trended up. A detailed evaluation is presented of the specific child physical and neurobehavioral traits integral to assessing the full continuum of FASD. The diagnosis of a child with FASD was significantly associated with maternal proximal risk factors such as: co-morbid prenatal use of alcohol and tobacco (OR = 19.1); maternal drinking of two (OR = 5.9), three (OR = 5.9), four (OR = 38.3), or more alcoholic drinks per drinking day; and drinking in the first trimester (OR = 8.4), first and second trimesters (OR = 17.7), or throughout pregnancy (OR = 18.6). Distal maternal risk factors included the following: slight or small physical status (height, weight, and head circumference), lower BMI, less formal education, late recognition of pregnancy, and higher gravidity, parity, and older age during the index pregnancy. CONCLUSION: The prevalence of FASD remained a significant problem in this region, but the severity of physical traits and anomalies within the continuum of FASD is trending downwards.

Effects of prenatal alcohol exposure on cognitive and behavioral development: Findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts.

BACKGROUND: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. METHODS: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. RESULTS: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. CONCLUSIONS: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

Sex-specific effect of prenatal alcohol exposure on N-methyl-D-aspartate receptor function in orbitofrontal cortex pyramidal neurons of mice.

BACKGROUND: Alcohol consumption during pregnancy can produce behavioral and cognitive deficits that persist into adulthood. These include impairments in executive functions, learning, planning, and cognitive flexibility. We have previously shown that moderate prenatal alcohol exposure (PAE) significantly impairs reversal learning, a measure of flexibility mediated across species by different brain areas that include the orbital frontal cortex (OFC). Reversal learning is likewise impaired by genetic or pharmacological inactivation of GluN2B subunit-containing N-methyl-D-aspartate receptors (NMDARs). In the current study, we tested the hypothesis that moderate PAE persistently alters the number and function of GluN2B subunit-containing NMDARs in OFC pyramidal neurons of adult mice. METHODS: We used a rodent model of fetal alcohol spectrum disorders and left offspring undisturbed until adulthood. Using whole-cell, patch-clamp recordings, we assessed NMDAR function in slices from 90- to 100-day-old male and female PAE and control mice. Pharmacologically isolated NMDA receptor-mediated evoked excitatory postsynaptic currents (NMDA-eEPSCs) were recorded in the absence and presence of the GluN2B antagonist, Ro25-6981(1 µM). In a subset of littermates, we evaluated the level of GluN2B protein expression in the synaptic fraction using Western blotting technique. RESULTS: Our results indicate that PAE females show significantly larger (~23%) NMDA-eEPSC amplitudes than controls, while PAE induced a significant decrease (~17%) in NMDA-eEPSC current density of pyramidal neurons recorded in slices from male mice. NMDA-eEPSC decay time was not affected in PAE-exposed mice from either sex. The contribution of GluN2B subunit-containing NMDARs to the eEPSCs was not significantly altered by PAE. Moreover, there were no significant changes in protein expression in the synaptic fraction of either PAE males or females. CONCLUSIONS: These findings suggest that low-to-moderate PAE modulates NMDAR function in pyramidal neurons in a sex-specific manner, although we did not find evidence that the effect is mediated by dysfunction of synaptic GluN2B subunit-containing NMDARs.

Maternal psycho-social risk factors associated with maternal alcohol consumption and Fetal Alcohol Spectrum Disorder: a systematic review.

PURPOSE: Fetal Alcohol Spectrum Disorder (FASD) is a preventable range of neurocognitive disorders associated with the biological mother's consumption of alcohol during pregnancy. However, on average, 45% of Australian women continue to consume alcohol during pregnancy resulting in a high rate of alcohol-exposed pregnancies and risk of FASD. This level of exposure is higher than the estimated global average of alcohol-exposed pregnancies (9.8%). This systematic literature review aims to identify demographic, health and psycho-social variables associated with alcohol consumption during pregnancy which may lead to FASD. METHODS: Using PRISMA principles, this systematic literature review reports on psycho-social factors which increase the risk of alcohol consumption during pregnancy thereby increasing the risk of FASD. RESULTS: Fourteen studies were accepted into this review. Studies were conducted across several countries and included a total of 386,067 cases. Seven studies were case-controlled and seven were cross-sectional design. Multiple studies identified the significance of prior mental illness, anxiety, depression, exposure to abuse and/or domestic violence and alcohol consumption behaviours of partners and family members as strong predictors of risky alcohol consumption during pregnancy and therefore associated risk of FASD. CONCLUSION: Clinical services may be able to use the evidence-based findings from this review to improve assessment and treatment services for vulnerable women to reduce alcohol-exposed pregnancies.

Epigallocatechin Gallate Ameliorates the Effects of Prenatal Alcohol Exposure in a Fetal Alcohol Spectrum Disorder-Like Mouse Model.

Fetal alcohol spectrum disorder is the main preventable cause of intellectual disability in the Western world. Although binge drinking is the most studied prenatal alcohol exposure pattern, other types of exposure, such as the Mediterranean, are common in specific geographic areas. In this study, we analyze the effects of prenatal alcohol exposure in binge and Mediterranean human drinking patterns on placenta and brain development in C57BL/6J mice. We also assess the impact of prenatal treatment with the epigallocatechin-3-gallate antioxidant in both groups. Study experimental groups for Mediterranean or binge patterns: (1) control; (2) ethanol; (3) ethanol + epigallocatechin-3-gallate. Brain and placental tissue were collected on gestational Day 19. The molecular pathways studied were fetal and placental growth, placental angiogenesis (VEGF-A, PLGF, VEGF-R), oxidative stress (Nrf2), and neurodevelopmental processes including maturation (NeuN, DCX), differentiation (GFAP) and neural plasticity (BDNF). Prenatal alcohol exposure resulted in fetal growth restriction and produced imbalances of placental angiogenic factors. Moreover, prenatal alcohol exposure increased oxidative stress and caused significant alterations in neuronal maturation and astrocyte differentiation. Epigallocatechin-3-gallate therapy ameliorated fetal growth restriction, attenuated alcohol-induced changes in placental angiogenic factors, and partially rescued neuronal nuclear antigen (NeuN), (doublecortin) DCX, and (glial fibrillary acidic protein) GFAP levels. Any alcohol consumption (Mediterranean or binge) during pregnancy may generate a fetal alcohol spectrum disorder phenotype and the consequences may be partially attenuated by a prenatal treatment with epigallocatechin-3-gallate.

[ALCOHOL DRINKING DURING PREGNANCY AND ITS EFFECTS ON THE FETUS AND THE NEWBORN].

INTRODUCTION: Alcohol consumption during pregnancy has become a prevalent phenomenon worldwide in general, as well as in Israel in particular. This habit is associated with an increase in various complications during pregnancy - mainly fetal alcohol syndrome and post-natal fetal alcohol spectrum disorder. There is no "safe limit" for alcohol consumption during pregnancy and alcohol drinking may be detrimental to the fetus or to the newborn when consumed at any stage of the pregnancy. The negative effects of alcohol consumption during pregnancy are also related to a shortage of key nutritional elements due to this habit. The main negative results of this habit are fetal alcohol syndrome and fetal alcohol spectrum disorders. Pregnant women after infertility treatment are also not deterred from drinking alcohol. Education of pregnant women is currently regarded as the best treatment.

Ocular measurements in fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non-FASD individuals. We compared ocular measurement centiles in children with FASD to non-FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non-FASD children who had various forms of growth deficiency (microcephaly, short-stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.

Fetal alcohol spectrum disorder among pre-adopted and foster children.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a leading cause of neurodevelopmental disorders. Children in foster care or domestically adopted are at greater risk for FASD. The aim of this study was to determine the prevalence or risk for FASD in a selected population of foster and adopted children. METHODS: Children between 2 and 12 years who were candidates for adoption in foster care were evaluated for clinical manifestations and historical features of fetal alcohol spectrum disorder based on established criteria for FASD. RESULTS: Of the 89 children evaluated, 18 had mothers with a confirmed history of alcohol consumption during pregnancy. Two children had fetal alcohol syndrome and one had partial fetal alcohol syndrome. In addition, five had alcohol-related neurodevelopmental disorder, one had alcohol-related birth defects, and a single child had manifestations of both. Of the 71 children in which fetal alcohol exposure could not be confirmed, many had manifestations that would have established a diagnosis of FASD were a history of maternal alcohol consumption obtained. CONCLUSIONS: In a population of high-risk children seen in an adoption clinic, many had manifestations associated with FASD especially where prenatal alcohol exposure was established. The reported prevalence in this study is higher than that reported in our previous study of younger children. This is most likely due to the higher number of children diagnosed with alcohol-related neurodevelopmental disorders that typically manifest at an older age.

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder.

Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith-Magenis, Matthew-Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

Quantifying fetal alcohol exposure by meconium fatty acid ethyl esters (FAEE); association with adverse fetal outcomes and population estimates of fetal alcohol exposure.

Fetal Alcohol Spectrum Disorder (FASD) describes the wide range of adverse physical, behavioral and cognitive effects resulting from ethanol exposure during embryonic and fetal development. Identification of children suffering from FASD is often difficult, as abuse of ethanol during pregnancy is a heavily stigmatized behavior that receives little prenatal screening attention in routine care. Over the last 3 decades, measurement of the ethanol metabolites fatty acid ethyl esters (FAEE) has emerged as a useful tool to detect in the neonatal period fetal alcohol exposure starting from mid gestation. This review aims at updating clinicians and researchers on the validity and utility of this biological marker in two aspects: The association with adverse fetal outcomes and in generating population estimates of fetal alcohol exposure.

Quantifying harms to others due to alcohol consumption in Germany: a register-based study.

BACKGROUND: The consumption of alcohol increases the risk of drinkers harming others. The extent of alcohol's morbidity and mortality harms to others in Germany in 2014 was estimated for (1) fetal alcohol syndrome (FAS) or fetal alcohol spectrum disorders (FASD) among newborns, (2) road traffic fatalities, and (3) interpersonal violence-related deaths. METHODS: The incidences of FAS and FASD were estimated by means of a meta-analytical approach, combining data on alcohol use during pregnancy and the risk relationship between alcohol consumption during pregnancy and FAS/FASD. In order to estimate alcohol-attributable road traffic fatalities and interpersonal violence due to the drinking of others, an attributable fraction methodology was applied to cause-of-death statistics for road traffic and interpersonal violence-related deaths. RESULTS: For 2014, the incidences of FAS and FASD were estimated at 41 children per 10,000 live births (95% CI 24; 63) and 177 children per 10,000 live births (95% CI 135; 320), or 2930 (95% CI 1720; 4500) and 12,650 (95% CI 9650; 23,310) children, respectively. Furthermore, alcohol was estimated to be responsible for 1214 (95% CI 1141; 1287) third-party road traffic fatalities and 55 (95% CI 46; 64) deaths from interpersonal violence, representing 45.1% of all third-party road traffic fatalities and 14.9% of all interpersonal violence deaths. CONCLUSION: These study's estimates indicate there is a substantial degree of health harm to third parties caused by alcohol in Germany. While more research on harms to others caused by alcohol is needed to provide comprehensive estimates, the results indicate a need for effective prevention.

Hippocampal deficits in neurodevelopmental disorders.

Neurodevelopmental disorders result from impaired development or maturation of the central nervous system. Both genetic and environmental factors can contribute to the pathogenesis of these disorders; however, the exact causes are frequently complex and unclear. Individuals with neurodevelopmental disorders may have deficits with diverse manifestations, including challenges with sensory function, motor function, learning, memory, executive function, emotion, anxiety, and social ability. Although these functions are mediated by multiple brain regions, many of them are dependent on the hippocampus. Extensive research supports important roles of the mammalian hippocampus in learning and cognition. In addition, with its high levels of activity-dependent synaptic plasticity and lifelong neurogenesis, the hippocampus is sensitive to experience and exposure and susceptible to disease and injury. In this review, we first summarize hippocampal deficits seen in several human neurodevelopmental disorders, and then discuss hippocampal impairment including hippocampus-dependent behavioral deficits found in animal models of these neurodevelopmental disorders.

L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis.

Ethanol causes fetal alcohol spectrum disorders (FASDs) partly by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Ethanol interacts with an alcohol binding pocket in the L1 extracellular domain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.-Dou, X., Menkari, C., Mitsuyama, R., Foroud, T., Wetherill, L., Hammond, P., Suttie, M., Chen, X., Chen, S.-Y., Charness, M. E., Collaborative Initiative on Fetal Alcohol Spectrum Disorders. L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis.

Prenatal alcohol use as a risk for attention-deficit/hyperactivity disorder.

The objective of the study was to investigate the association between alcohol use during pregnancy and mental disorders in childhood, controlling for confounding risk factors by a longitudinal study of pregnant women and their offspring. The initial cohort comprised pregnant women attending an obstetric service. From the initial sample of 449 pregnant women, 81 mother-child pairs agreed to participate. After 12 years, mother-child pairs were assessed through self-administered questionnaires and semi-structured interviews. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) was used to assess the presence of any mental disorders in the children. The mothers were assessed by the Self-Reporting Questionnaire (SRQ) and the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, data on the mother's alcohol use collected during pregnancy were analysed. A logistic regression tested the influence of alcohol consumption in all trimesters and binge drinking on the occurrence of attention-deficit/hyperactivity disorder (ADHD), controlling for covariates. Binge drinking at any time during pregnancy or low-moderate alcohol consumption in all trimesters of pregnancy was associated with a fivefold increased odds of child ADHD. The combination of both patterns of alcohol use added an increase of 19% in the variance of ADHD's occurrence. The episodic use of at least four drinks or the regular use of low-moderate alcohol doses during pregnancy was associated with significantly increased odds of subsequent child ADHD. Reducing binge drinking and regular alcohol use of pregnant women may lead to a significant decrease in their children developing ADHD.

Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD.

Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrß and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health.

A Brief History of Awareness of the Link Between Alcohol and Fetal Alcohol Spectrum Disorder.

OBJECTIVE: Fetal alcohol spectrum disorder (FASD) is a medical term used to describe a range of mental and physical disabilities caused by maternal alcohol consumption. The role of alcohol as a teratogen and its effects on the cellular growth of the embryo and the fetus were not determined on scientific grounds until the late 1960s. However, the link between alcohol use during pregnancy and its harms to offspring might have been observed frequently over the many thousands of years during which alcohol has been available and used for social and other reasons. METHODS AND RESULTS: Using sources ranging from the biblical Book of Judges (pre-1700) up until the first public health bulletin (1977), we seek to provide an overview of the academic debate around early historical accounts ostensibly attributed to the awareness of alcohol as a prenatal teratogen as well as to describe the social and political influences that sculpted developments leading to the public recognition of FASD. CONCLUSIONS: Our analysis provides a brief overview of the discourse regarding historical awareness of the detrimental effects of prenatal alcohol exposure on fetal development leading to the formal recognition of FASD as a distinct clinical entity. Further research will be required to fully appreciate the scientific, medical, and societal ills associated with prenatal alcohol exposure.

Alcohol Use in Pregnancy.

Alcohol exposure during pregnancy results in impaired growth, stillbirth, and fetal alcohol spectrum disorder. Fetal alcohol deficits are lifelong issues with no current treatment or established diagnostic or therapeutic tools to prevent and/or ameliorate some of these adverse outcomes. Despite the recommendation to abstain, almost half of the women consume alcohol in pregnancy in the United States. This review focuses on the trends in prenatal alcohol exposure, implications for maternal and fetal health, and evidence suggesting that preconception and the prenatal period provide a window of opportunity to intervene, mitigate, and ideally curtail the lifetime effects of fetal alcohol spectrum disorder.