Alcohol-exposed Group Research Articles

Altered circadian expression of clock genes and clock-regulatory epigenetic modifiers in saliva of children with fetal alcohol spectrum disorders

Prenatal alcohol-exposed (AE) infants and children often demonstrate disrupted sleep patterns, including more frequent awakenings, reduced total sleep time, and more night-to-night sleep variability. Despite the strong connection between sleep patterns and circadian rhythmicity, relatively little is known about circadian rhythm disruptions in individuals with AE. Recently, several reports demonstrated that evaluating the expression patterns of human clock genes in biological fluids could reveal an individual’s circadian phenotype. Human saliva offers an emerging and easily available physiological sample that can be collected non-invasively for core-clock gene transcript analyses. We compared the expression patterns of core-clock genes and their regulatory genes in salivary samples of children aged 6–10 years-old with and without AE during the light cycle between ZT0-ZT11. We isolated the RNA from the samples and measured the expression patterns of core clock genes and clock regulating genes using the human specific primers with quantitative real-time PCR. Analysis of core clock genes expression levels in saliva samples from AE children indicates significantly altered levels in expression of core-clock BMAL1, CLOCK, PER1-3 and CRY1,2, as compared to those in age-matched control children. We did not find any sex difference in levels of clock genes in AE and control groups. Cosinor analysis was used to evaluate the rhythmic pattern of these clock genes, which identified circadian patterns in the levels of core clock genes in the control group but absent in the AE group. The gene expression profile of a salivary circadian biomarker ARRB1 was rhythmic in saliva of control children but was arhythmic in AE children. Altered expression patterns were also observed in clock regulatory genes: NPAS2, NFL3, NR1D1, DEC1, DEC2, and DBP, as well as chromatin modifiers: MLL1, P300, SIRT1, EZH2, HDAC3, and ZR1D1, known to maintain rhythmic expression of core-clock genes. Overall, these findings provide the first evidence that AE disturbs the circadian patten expression of core clock genes and clock-regulatory chromatin modifiers in saliva.

Deliberative Behaviors and Prefrontal-Hippocampal Coupling are Disrupted in a Rat Model of Fetal Alcohol Spectrum Disorders.

Fetal alcohol spectrum disorders (FASDs) are characterized by a range of physical, cognitive, and behavioral impairments. Determining how temporally specific alcohol exposure (AE) affects neural circuits is crucial to understanding the FASD phenotype. Third trimester AE can be modeled in rats by administering alcohol during the first two postnatal weeks, which damages the medial prefrontal cortex (mPFC), thalamic nucleus reuniens, and hippocampus (HPC), structures whose functional interactions are required for working memory and executive function. Therefore, we hypothesized that AE during this period would impair working memory, disrupt choice behaviors, and alter mPFC-HPC oscillatory synchrony. To test this hypothesis, we recorded local field potentials from the mPFC and dorsal HPC as AE and sham intubated (SI) rats performed a spatial working memory task in adulthood and implemented algorithms to detect vicarious trial and errors (VTEs), behaviors associated with deliberative decision-making. We found that, compared to the SI group, the AE group performed fewer VTEs and demonstrated a disturbed relationship between VTEs and choice outcomes, while spatial working memory was unimpaired. This behavioral disruption was accompanied by alterations to mPFC and HPC oscillatory activity in the theta and beta bands, respectively, and a reduced prevalence of mPFC-HPC synchronous events. When trained on multiple behavioral variables, a machine learning algorithm could accurately predict whether rats were in the AE or SI group, thus characterizing a potential phenotype following third trimester AE. Together, these findings indicate that third trimester AE disrupts mPFC-HPC oscillatory interactions and choice behaviors.

Relationship-based intervention for children who were prenatally alcohol exposed in South Africa

BackgroundThis early intervention study investigated the effectiveness of a relationship-based, developmental enhancement process for children who were prenatally exposed to alcohol in the South African context. Methods: Groups were created according to the child’s level of risk for alcohol-related developmental issues based on each mother’s alcohol use during pregnancy as assessed using the Alcohol Use Disorders Identification Test (AUDIT). Primary caregiver/child dyads were the focus of the intervention and child development was monitored by the Ages and Stages Questionnaire (ASQ). Eighteen caregiver/child dyads were in the heavily alcohol-exposed group, and 20 caregiver/child dyads were in the no or light alcohol-exposure group. The Home Observation Measurement of the Environment (HOME) was measured pre and post intervention. Results: The results indicated significant improvements in the home environment (p < .001) post-intervention for the entire cohort. For the total HOME score, there was a statistically significant main effect for time (pre- vs post-test), F(1, 36)= 65.205, p < .001, partial η2 = .64. with 99% confidence limits from .35 to .78. The offspring and parents from both the heavy alcohol exposure group and the no/low alcohol exposure group benefitted from the intervention over the duration of the intervention. Of the HOME domains affected, responsivity was the most improved in the households. The children’s scores on the ASQ varied substantially over the months of the intervention, and the offspring of the heavy exposure group often performed significantly worse than the no/low exposure group. Nevertheless, further analysis revealed that children with the lowest performance at baseline improved their performance on most ASQ domains throughout the intervention and performed significantly better on all ASQ domains over time and at completion of the intervention. Conclusions: This relationship-based, early intervention program for children resulted in benefits to all of the children over time.

The impact of post-encoding alcohol consumption on episodic memory recall and remember-know responses in heavy drinkers.

People often consume alcohol following trauma, particularly in response to distressing memories. To date, little is known about how post-encoding alcohol consumption influences episodic memory recall for negative events. Understanding these effects may help to improve support for trauma victims - for example, witnesses and victims of crimes. We tested 60 participants who self-described as heavy drinkers. After watching an analog trauma film, half were allocated to consuming a moderate dose of alcohol (Alcohol-Exposed group), while half received a placebo drink (Placebo-Control group). Immediately and after a one-week delay, participants recalled the event via free and cued recall tasks. Participants also gave remember-know responses and confidence ratings, elucidating alcohol's effect on experiential memory. Free recall performance was similar for the Alcohol-Exposed group and the Placebo-Control group during Sessions 1 and 2. The Alcohol-Exposed group benefitted more from the delayed repeated retrieval attempt. For the cued recall task, the Alcohol-Exposed group provided more "Do not Know" responses compared to the Placebo-Control group in both sessions. For the Alcohol-Exposed group only "Correct Know" responses increased from Session 1 to 2. Although memory performance improved across sessions, confidence levels decreased from Session 1 to 2 in the Alcohol-Exposed group. Post-encoding alcohol consumption appears to impact immediate episodic memory retrieval; however, this effect is only temporary in nature. No evidence was found that alcohol primarily reduces remembering responses. Much like previous findings focusing on pre-encoding alcohol consumption (Hagsand et al., 2017), current findings suggest that providing individuals who drank alcohol after witnessing an incident with a delayed repeated retrieval attempt can lead to more complete and accurate testimonies.

Repeated alcohol exposure induced dentate gyrus related spatial memory damage

Alcohol is one of the most commonly abused drugs, and it impairs diverse functions of the central nervous system, such as cognition and memorization. The dentate gyrus (DG) region of the hippocampus is crucial for spatial memory coding. However, whether alcohol exposure can affect DG neuron activity and impair spatial memory has not been identified. Here, we discovered hippocampus DG as a key region of alcohol exposure damage. (1) We found repeated alcohol exposure overactivated DG neurons, while this activation was not shown in a single alcohol exposure group. (2) Mice exposed to alcohol repeatedly exhibited obvious spatial memory impairment. In summary, our findings provide convincing evidence that the excessive activation of hippocampus neurons is involved in spatial memory impairment caused by repeated alcohol exposure.

Executive Function After Prenatal Alcohol Exposure in Children in a South African Population: Cross-sectional Study.

BackgroundAlcohol is a teratogen; its consumption during pregnancy can lead to negative birth outcomes, collectively referred to as fetal alcohol spectrum disorders. Neurodevelopmental delays in higher-order cognitive functions that affect development of executive functions are a common feature. Studies on executive function in children have focused on children diagnosed with fetal alcohol spectrum disorder, and there is a lack of information on the impact on children not diagnosed with fetal alcohol spectrum disorder but who had been exposed to alcohol.ObjectiveThe aim of this study was to compare the development of executive function in children between 4 and 6 years of age with and without prenatal exposure to alcohol.MethodsChildren both exposed and not exposed to alcohol were recruited as part of a feasibility RCT evaluating a computer-based cognitive training program for improving executive function development. The study was conducted in a low–socioeconomic status community in South Africa with a high prevalence of fetal alcohol spectrum disorder. Neurodevelopment was assessed in participating children; NEPSY-II standardized scores for executive function domains were compared using a multivariate analysis of variance with group membership as the predictor variable.ResultsNo significant differences in executive functions assessments (P=.39) were found between children in the alcohol-exposed group (n=76) and those in the nonexposed group (n=40). Both groups showed moderate to severe delays in domains. In all but one subtest, the average score for both groups was below the 25th percentile of expected norms.ConclusionsWe expected that alcohol exposure would have a measurable impact on executive function development. The lack of differences highlights the prevalence of developmental delays in low–socioeconomic status communities in South Africa and suggests that children are exposed to various threats to cognitive development.International Registered Report Identifier (IRRID)RR2-10.2196/14489

Prenatal Alcohol Exposure and the Facial Phenotype in Adolescents: A Study Based on Meconium Ethyl Glucuronide.

Here, we explore the effects of prenatal alcohol exposure (PAE) in adolescence. We investigated associations between meconium ethyl glucoronide (EtG) and facial malformation. For 129 children (66/63 male/female; M = 13.3, SD = 0.32, 12–14 years), PAE was implemented by newborn meconium EtG and maternal self-reports during the third trimester. Cognitive development was operationalized by standardized scores (WISC V). The EtG cut-off values were set at ≥10 ng/g (n = 32, 24.8% EtG10+) and ≥112 ng/g (n = 20, 15.5% EtG112+). The craniofacial shape was measured using FAS Facial Photographic Analysis Software. EtG10+− and EtG112+-affected children exhibited a shorter palpebral fissure length (p = 0.031/p = 0.055). Lip circularity was smaller in EtG112+-affected children (p = 0.026). Maternal self-reports were not associated (p > 0.164). Lip circularity correlated with fluid reasoning (EtG10+ p = 0.031; EtG112+ p = 0.298) and working memory (EtG10+ p = 0.084; EtG112+ p = 0.144). The present study demonstrates visible effects of the facial phenotype in exposed adolescents. Facial malformation was associated with a child’s cognitive performance in the alcohol-exposed group. The EtG biomarker was a better predictor than maternal self-reports.

DNA methylation in the medial prefrontal cortex regulates alcohol-related behavior in rats.

Alcohol abuse causes tissue and organ damage, and may participate neuropsychiatric diseases. Studies have shown that DNA methylation plays an important role in gene expression and behavioral changes induced by alcohol, however the causative neurobiological mechanisms have not been clarified. In this study, 32 healthy adult male SD rats were randomly divided into a drinking water control group (n=16) and a chronic alcohol exposure group (n=16). The alcohol preference and locomotor activity of rats were evaluated by two-bottle choice test (TBCT) and open-field test (OFT). DNA methylation in the medial prefrontal cortex (mPFC) tissue was detected by the reduced representative bisulfite sequencing (RRBS) technology. The methylation differential genes closely related to alcohol abuse were screened. qRT-PCR was used to verify the mRNA expression patterns of differential genes. qRT-PCR and Western blot were used to detect the expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2). Furthermore, the effect of short-term alcohol exposure (7 days) on DNMTs and MeCP2 in the mPFC of rats was tested (n=8/group). The results indicated that the methylation level of promoter region in the mPFC of rats exposed to chronic alcohol was significantly increased. In addition, the increased methylation levels in the promoter of Ntf3 and Ppm1G were accompanied by down-regulated mRNA levels in the chronic alcohol exposure group. The decreased methylation levels in the promoter of Hap1 and DUSP1 were accompanied by up-regulated mRNA levels. Furthermore, chronic alcohol exposure increased the mRNA and protein levels of DNMT3B and MeCP2. However, short term alcohol exposure did not affect their expression. This present study provides evidence that DNA methylation is associated with the development of alcohol abuse, which may be regulated by DNMT3B and MeCP2. The target genes Ntf3, Ppm1G, Hap1, and DUSP1 related to alcohol abuse were discovered as well, providing new insights into the neurobiological mechanism of alcohol abuse and the potential pharmacological targets for the treatment of alcohol abuse.

Executive Functioning Correlates With Communication Ability in Youth With Histories of Heavy Prenatal Alcohol Exposure.

Caregivers of youth with heavy prenatal alcohol exposure report impaired communication, which can significantly impact quality of life. Using data collected as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), we examined whether cognitive variables predict communication ability of youth with histories of heavy prenatal alcohol exposure. Subjects (ages 10-16 years) comprised two groups: adolescents with heavy prenatal alcohol exposure (AE) and non-exposed controls (CON). Selected measures of executive function (NEPSY, Delis-Kaplan Executive Function System), working memory (CANTAB), and language were tested in the child, while parents completed communication ratings (Vineland Adaptive Behavior Scales - Second Edition). Separate multiple regression analyses determined which cognitive domains predicted communication ability. A final, global model of communication comprised the three cognitive models. Spatial Working Memory and Inhibition significantly contributed to communication ability across groups. Twenty Questions performance related to communication ability in the CON group only while Word Generation performance related to communication ability in the AE group only. Effects remained significant in the global model, with the exception of Spatial Working Memory. Both groups displayed a relation between communication and Spatial Working Memory and Inhibition. Stronger communication ability related to stronger verbal fluency in the AE group and Twenty Questions performance in the CON group. These findings suggest that alcohol-exposed adolescents may rely more heavily on learned verbal storage or fluency for daily communication while non-exposed adolescents may rely more heavily on abstract thinking and verbal efficiency. Interventions aimed at aspects of executive function may be most effective at improving communication ability of these individuals. (JINS, 2018, 24, 1026-1037).

Association Between Paternal Alcohol Consumption Before Conception and Anogenital Distance of Offspring.

There are limited studies on the effects of paternal alcohol consumption, before conception, on the reproductive development of offspring. Anogenital distance (AGD), the distance from the center of the anus to the genitals, is a sensitive biomarker of reproductive hormone abnormalities during the critical developmental window. The relationship between paternal alcohol consumption and AGD of human offspring has not been studied yet. This cohort study included 1,292 pregnant women recruited in Shanghai. An in-person interview was conducted to collect information on demographic characteristics of couples, and husbands' lifestyles, including drinking habits. AGD (boys, AGD-AP [anus-penis], AGD-AS [anus-scrotum]; girls, AGD-AC [anus-clitoris], AGD-AF [anus-fourchette]) measurements were performed at birth, and at 6 and 12months of age. Multiple linear regression analysis was conducted to determine the association between paternal alcohol consumption before conception, and the AGDs of offspring. Data included AGD measurements of infants at birth (N=980), at 6months (N=592, 60.4%), and at 12months (N=543, 55.4%). Boys in the paternal alcohol-exposed group had shorter AGDs, irrespective of the areas measured (AGD-AP and AGD-AS) and time of measurements, than those in the unexposed group. However, only the differences in AGD-AP at birth and AGD-AS at 6months were statistically significant. For girls, the associations were similar at birth; however, the AGD-AC and AGD-AF were longer in the paternal alcohol-exposed group than the unexposed group at 12months. Our findings provide first, but preliminary evidence, that paternal alcohol consumption within 3months before conception may be associated with shorter AGD in the offspring, especially in boys, which indicates that paternal alcohol drinking may have an adverse effect on their reproductive development. Further studies should be conducted to validate these results.

Alcohol exposure during pregnancy altered childhood developmental trajectories in a rural South African community

This study examined the effects of prenatal alcohol exposure on childhood development trajectories in a rural South African community between 2003 and 2008. We assessed 121 children at 7-12 months (year one) and 5-6 years (year five) using the Griffiths Mental Developmental Scales - Extended Revised, which measures sensorimotor, cognitive and social development, with lower scores indicating developmental delay. We also interviewed their mothers or caregivers. Three groups were identified: 29 with foetal alcohol syndrome (FAS) or partial FAS (pFAS), 57 more who had been exposed to alcohol and 35 controls who had not. The scale's total score was higher in the controls than in the FAS/pFAS group at year one and year five and in the alcohol-exposed group at year five. Many groups' trajectories declined when compared with global norms, but the trajectories in the FAS/pFAS and the alcohol-exposed groups declined more than the controls for eye-hand and performance and total score. Earlier pregnancy recognition in the FAS/pFAS group correlated strongly (r = -0.77) with higher GQ in year five. FAS/pFAS and prenatal alcohol exposure affected the Griffiths scores more than the control group. Efforts are needed to detect pregnancy early and reduce alcohol exposure.

Academic Difficulties in Children with Prenatal Alcohol Exposure: Presence, Profile, and Neural Correlates.

Academic achievement was evaluated in children with heavy prenatal alcohol exposure to determine potential strengths and weaknesses, evaluate the utility of different definitions for identifying low academic performance, and explore the neural correlates that may underlie academic performance. Children (8 to 16years) were assessed using the WIAT-II. Patterns of performance were examined in 2 subject groups: children with heavy prenatal alcohol exposure (n=67) and controls (n=61). A repeated-measures MANCOVA examining group differences on academic domain (reading, spelling, math) scores was conducted. Post hoc comparisons examined within-group profiles. Numbers and percentage of children with low achievement were calculated using several criteria. In a subsample (n=42), neural correlates were analyzed using FreeSurfer v5.3 to examine relations between cortical structure (thickness and surface area) and performance. The alcohol-exposed group performed worse than controls on all domains and had a unique academic profile, supported by a significant group×academic domain interaction (p<0.001). For the alcohol-exposed group, math reasoning was significantly lower than numerical operations, which was significantly lower than spelling and word reading. Over half of the alcohol-exposed group (58.2%) demonstrated low achievement on 1 or more academic domains. The number and percentage of children meeting criteria for low achievement varied based on the domain and definition used. The imaging analysis identified several surface area clusters that were differentially related to math (L superior parietal and R lateral/middle occipital) and spelling (bilateral inferior and medial temporal) performance by group, with no relations for the other academic domains. Generally, scores improved as surface area decreased in controls, whereas no relation or a positive relation was observed in the alcohol-exposed group. Alcohol-exposed children demonstrated deficits in academic performance across domains and definitions, with a relative weakness in math functioning. Atypical brain development may contribute to these impairments in academic achievement. Understanding academic difficulties can assist in advocating effectively for alcohol-exposed children.

An ERP Study of Response Inhibition in the Auditory Domain in Children with Fetal Alcohol Spectrum Disorders.

Previous event-related potential (ERP) studies of response inhibition in children with fetal alcohol spectrum disorder (FASD) have used a visual Go/NoGo task to study the impact of prenatal alcohol exposure on response inhibition. No studies exist using auditory versions of the task; thus, it is unclear how the deficits observed in visual tasks translate into the auditory domain. This study examined ERPs using an auditory Go/NoGo paradigm in a sample of 35 school-age children-18 with heavy prenatal alcohol exposure and 17 normally developing controls. Alcohol-exposed children performed as well as controls in terms of inhibiting their responses; however, their reaction times were significantly slower under the Go condition. As in the ERP visual Go/NoGo task previously administered to these children, group differences were seen in early perceptual processing, specifically related to stimulus discrimination, with a decrease in P2 amplitude in the alcohol-exposed group. The control group exhibited greater N2 amplitude in the NoGo compared to the Go condition while the alcohol-exposed group did not, suggesting a group difference in the neural substrates underlying conflict monitoring. The alcohol-exposed group demonstrated longer latency P3 with reduced amplitude, suggesting poorer allocation of attention. The alcohol-exposed group also exhibited a late positive component (LPC) similar to the one observed in the previous visual ERP study. This LPC may indicate compensatory neurophysiological function related to resetting of attentional control networks in preparation for the next trial. None of the ERP outcomes in this study were related to potential confounders which included cognitive and socioeconomic measures as well as ADHD diagnosis. The observed ERP group differences point to elements of perceptual and attentional processing likely to be involved in the performance deficits often observed in children with FASD. We also observed changes in ERPs related to conflict monitoring/response inhibition, highlighting fetal alcohol-related effects on how the brain responds when there is need to identify and respond to environmental cues by switching away from a prepotent motor response to an inhibited state.

Placental Morphology in Fetal Alcohol Spectrum Disorders.

Aims Maternal alcohol drinking adversely affects pregnancy outcome. Although fetal health and development are highly dependent upon the integrity of placentation, little is known about placental morphology following gestational exposure to alcohol in humans. Methods In this clinical study, subjects were recruited between 2010 and 2013 from an outpatient substance abuse and mental health treatment center for women. Data collected included maternal age, substance abuse history, comorbidities, pregnancy outcomes, gestational age at delivery, birth weight and placental weight. Placental histopathological lesions associated with uteroplacental malperfusion (UPM) were scored under code. Villous cytotrophoblasts reflecting another measure of UPM were immunostained with E-cadherin and quantified using stereology. Inter-group comparisons were made using univariate or multivariate analysis. Results Of the 92 women enrolled in the study, 61 (66%) had histories of alcohol use during the pregnancy while the remaining 31 served as controls. The alcohol-exposed group significantly differed from controls based on (a) higher rates of smoking and polydrug use during pregnancy, (b) lower mean gestational age and birth weight of their infants, (c) elevated UPM scores, (d) increased densities of villous cytotrophoblastic cells and (e) more extensive chorangiosis in placenta. Logistic regression analysis demonstrated alcohol to be the only significant predictor of these outcomes and responses. Conclusions Gestational alcohol exposure is significantly associated with UPM, which could account for the higher rates of preterm delivery and reduced mean birth weights. Since chorangiosis reflects altered placental oxygen dynamics, the greater abundance of this abnormality could represent a compensatory response to UPM. Short Summary In this clinical study, we assessed the effects of maternal alcohol drinking on placental morphology. Applying a cumulative scoring system, we determined that gestational alcohol exposure is significantly associated with uteroplacental malperfusion, which could account for the higher rates of preterm delivery and reduced mean birth weights.

Pituitary lacks sexual dimorphism and displays reduced signal intensity on T1-weighted MRI in adolescents with histories of heavy prenatal alcohol exposure

Prenatal alcohol exposure can interfere with endocrine function and have sex-specific effects on behavior. Disrupted development of the pituitary gland, which has been observed in rodent studies, may account for some of these effects. To determine if gestational exposure to alcohol produces measureable changes in the pituitary in human adolescents, we manually traced the pituitary in T1-weighted structural magnetic resonance images (MRI) from adolescents with (15 males, 11 females) and without (16 males, 11 females) heavy prenatal alcohol exposure. Pituitary gland volume and maximum signal intensity were examined for group differences. Control female adolescents presented with significantly greater pituitary volume compared to males, as has been previously reported. However, this sexual dimorphism was absent in adolescents with histories of prenatal alcohol exposure. Alcohol-exposed adolescents, regardless of sex, demonstrated reduced pituitary maximum signal intensity compared to controls. The lack of a sex difference in pituitary volumes within the alcohol-exposed group suggests such exposure may interfere with adolescent typical sexual dimorphism of the pituitary. Signal intensity in the posterior pituitary may reflect vasopressin storage. Our findings suggest vasopressin activity should be evaluated in alcohol-exposed adolescents.

Neurobehavioral Deficits Consistent Across Age and Sex in Youth with Prenatal Alcohol Exposure.

Neurobehavioral consequences of heavy prenatal alcohol exposure are well documented; however, the role of age or sex in these effects has not been studied. The current study examined the effects of prenatal alcohol exposure, sex, and age on neurobehavioral functioning in children. Subjects were 407 youth with prenatal alcohol exposure (n=192) and controls (n=215). Two age groups (child [5 to 7years] or adolescent [10 to 16years]) and both sexes were included. All subjects completed standardized neuropsychological testing, and caregivers completed parent-report measures of psychopathology and adaptive behavior. Neuropsychological functioning, psychopathology, and adaptive behavior were analyzed with separate 2 (exposure history)×2 (sex)×2 (age) multivariate analyses of variance (MANOVAs). Significant effects were followed by univariate analyses. No 3-way or 2-way interactions were significant. The main effect of group was significant in all 3 MANOVAs, with the control group performing better than the alcohol-exposed group on all measures. The main effect of age was significant for neuropsychological performance and adaptive functioning across exposure groups with younger children performing better than older children on 3 measures (language, communication, socialization). Older children performed better than younger children on a different language measure. The main effect of sex was significant for neuropsychological performance and psychopathology; across exposure groups, males had stronger language and visual spatial scores and fewer somatic complaints than females. Prenatal alcohol exposure resulted in impaired neuropsychological and behavioral functioning. Although adolescents with prenatal alcohol exposure may perform more poorly than younger exposed children, the same was true for nonexposed children. Thus, these cross-sectional data indicate that the developmental trajectory for neuropsychological and behavioral performance is not altered by prenatal alcohol exposure, but rather, deficits are consistent across the 2 age groups tested. Similarly, observed sex differences on specific measures were consistent across the groups and do not support sexually dimorphic effects in these domains.

Relationships between Head Circumference, Brain Volume and Cognition in Children with Prenatal Alcohol Exposure.

Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5–19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.

Atypical cortical gyrification in adolescents with histories of heavy prenatal alcohol exposure

Prenatal alcohol exposure can adversely affect brain development, although little is known about the effects of prenatal alcohol exposure on gyrification. Gyrification reflects cortical folding complexity and is a process by which the surface of the brain creates sulci and gyri. Prior studies have shown that prenatal alcohol exposure is associated with reduced gyrification in childhood, but no studies have examined adolescents. Subjects (12–16 years) comprised two age-equivalent groups: 30 adolescents with histories of heavy prenatal alcohol exposure (AE) and 19 non-exposed controls (CON). A T1-weighted image was obtained for all participants. Local gyrification index (LGI) was estimated using FreeSurfer. General linear models were used to determine between group differences in LGI controlling for age and sex. Age-by-group interactions were also investigated while controlling for sex. The AE group displayed reduced LGI relative to CON in the bilateral superior parietal region, right postcentral region, and left precentral and lateral occipital regions (ps<.001). Significant age-by-group interactions were observed in the right precentral and lateral occipital regions, and in the left pars opercularis and inferior parietal regions (ps<.01). The AE group showed age-related reductions in gyrification in all regions whereas the CON group showed increased gyrification with age in the lateral occipital region only. While cross-sectional, the age-related reduction in gyrification observed in the AE group suggests alterations in cortical development throughout adolescence and provides further insight into the pathophysiology and brain maturation of adolescents prenatally exposed to alcohol.

Plasma IL‐6 Levels are Elevated During the Third Trimester in Alcohol‐Exposed Women with Children Diagnosed with Fetal Alcohol Spectrum Disorder (FASD) Compared to Alcohol–Exposed Women with Normally Developed Children

Elevated plasma IL‐6 concentrations during pregnancy are associated with certain neurological disorders (e.g. autism and schizophrenia) in offspring. We investigated the hypothesis that IL‐6 is a risk factor in women who gave birth to a child with FASD. Alcohol‐exposed and control women were recruited during mid pregnancy (mean gestational age 20.4±7.0 wk). A subset of blood samples were obtained from women in the third trimester and analyzed for plasma cytokines. Children were examined at 6 and 12 months and were classified as having FASD if they presented with both physical features and one Bayley Score of Infant Development test below 85. There were no differences in IL‐10 or TNF‐α concentrations among the groups. In contrast, alcohol‐exposed women with children displaying features of FASD had significantly higher plasma IL‐6 levels (n=26, ‐0.21±0.07 log pg/mL) compared to alcohol‐exposed women who bore children with no features of FASD (n=25, ‐0.48±0.07 log pg/mL, p=0.007) when controlled for smoking and socioeconomic status. There were no differences in IL‐6 levels in the control women (n=13, ‐0.26±0.09 log pg/mL) compared to either alcohol‐exposed group. These data suggest that IL‐6 can be a contributor in FASD and further investigation is warranted.

Prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing histone H3K14 acetylation in C57 BL/6 mice

Prenatal alcohol exposure leads to congenital heart abnormal development, its mechanisms are still unknown. Recent reports have associated alcohol exposure with histone H3 acetylation. In the present study, we have performed the experiments to test the hypothesis that histone H3K14 acetylation is the key role in the fetal heart leads to over-expression of cardiac specific genes DHAND and EHAND caused by prenatal alcohol exposure. Seventy pregnant C57BL/6 mice were divided randomly into seven groups (n=10). They were the untreated group, dimethyl sulfoxide group, alcohol exposure group, curcumin treatment group, both alcohol and curcumin treatment group, SAHA treatment group, both alcohol and SAHA treatment group. Fetal mouse hearts were collected on embryonic day 14.5. The changes of HATs activities, the acetylation levels of histone H3K14 (H3K14ac), the expression levels of cardiac specific genes DHAND and EHAND, and structure of chromatin were determined. Our data indicates that curcumin and SAHA significantly reduces and increases the activities of HATs and the levels of histone H3K14ac in fetal hearts, respectively. The expression of DHAND and EHAND is significantly down-regulated and up-regulated in the groups treated with curcumin and SAHA. Furthermore, our results from ChIP assays have shown that the histone H3K14ac connects with the DHAND and EHAND genes are significantly inhibited by curcumin and simulated by SAHA. Our study suggests that prenatal alcohol exposure causes the over-expression of DHAND and EHAND by increasing H3K14ac in mice.