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Background: Prenatal alcohol exposure (PAE) can negatively affect brain development thereby increasing the risk of cognitive deficits, behavioral challenges, and mental health problems. Brain iron is important for a number of physiological processes for healthy brain development. Animal studies show that PAE reduced brain iron; however, this has not been investigated in human children with PAE. Methods: We studied 20 children and adolescents with PAE and 44 unexposed children and adolescents aged 7.5 to 15 years. All children underwent quantitative susceptibility mapping and T1‐weighted magnetic resonance imaging scans. Susceptibility and volume measurements of the caudate, putamen, pallidum, thalamus, amygdala, hippocampus, and nucleus accumbens were extracted using FreeSurfer. ANCOVAs were used to compare volume and susceptibility between groups for each region of interest, controlling for age and gender. For structures where susceptibility differed by group, we also tested for an association between intelligence quotient (IQ) and susceptibility. Results: There were no significant group differences in susceptibility after multiple comparison correction, though the PAE group had higher susceptibility in the thalamus compared to unexposed participants before correction (p = 0.032, q = 0.230). There was no association between IQ and thalamus susceptibility. The PAE group had significantly lower volume in the bilateral caudate, bilateral pallidum, and left putamen. Conclusions: These findings suggest susceptibility may be altered in children and adolescents with PAE, though more research is needed. Volume reductions are consistent with previous literature and likely underlie cognitive and behavioral deficits associated with PAE. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence that the gut microbiota can be shaped by early‐life experiences/exposures, with long‐term consequences for brain, behavior, and health. Changes in the gut microbiota have also been identified in neurodevelopmental disorders including Autism Spectrum Disorder and schizophrenia. In contrast, no studies to date have investigated whether the gut microbiota is altered in individuals with Fetal Alcohol Spectrum Disorder (FASD), the neurodevelopmental disorder that results from prenatal alcohol exposure (PAE). The current study was designed to assess the impact of PAE on the fecal microbiota. Methods: We used a rodent model in which pregnant Sprague–Dawley rats were provided with an EtOH‐containing diet or a control diet throughout gestation. Fecal samples were collected from adult male and female animals and 16s rRNA sequencing was performed. Results: Overall, PAE rats showed greater richness of bacterial species, with community structure investigations demonstrating distinct clustering by prenatal treatment. In addition, prenatal treatment and sex‐specific alterations were observed for many specific microbes. For example, in males, Bacteroides and Bifidobacterium, and in females, Faecalitalea and Proteus, differed in abundance between PAE and control rats. Conclusions: Taken together, these results show for the first time that PAE has a long‐lasting and sex‐specific impact on the fecal microbiota. Further research is needed that considers fetal microbiota in the development of new interventions in FASD. [ABSTRACT FROM AUTHOR]

For many years, researchers have explored the complex challenges experienced by individuals with fetal alcohol spectrum disorder (FASD). This research has been important for documenting the brain‐ and body‐based impacts of prenatal alcohol exposure and the psychosocial vulnerabilities and environmental adversities frequently associated with FASD. It has also supported advocacy efforts and highlighted the necessity of providing FASD services and supports. However, with the focus on deficits and needs, there is a considerable gap in the literature on the strengths and successes of individuals with FASD. The lack of strengths‐based FASD research has likely perpetuated the stress and stigma experienced by individuals with FASD and their families. Thus, there is a critical need to shift the direction of the field. Here we provide a narrative review of the literature on strengths in FASD. Our goals are to: (1) understand the state of strengths‐based research related to individuals with FASD across the lifespan, and (2) describe positive characteristics, talents, and abilities of individuals with FASD that may be cultivated to promote their fulfillment and well‐being. We identified a total of 19 studies, most of which were conducted to explore the lived experiences of adults with FASD. This preliminary but critical body of evidence highlights the intrinsic strengths of individuals with FASD, including strong self‐awareness, receptiveness to support, capacity for human connection, perseverance through challenges, and hope for the future. Despite the importance of this emerging evidence, appraisal of the literature indicates a need for more intentional, methodologically rigorous, participatory, and theory‐driven research in this area. Findings from this study, including the identified gaps in the literature, can be used to inform research, practice, and policy to meaningfully advance the field of FASD and promote positive outcomes in this population. [ABSTRACT FROM AUTHOR]

Introduction: Fetal alcohol spectrum disorders (FASD) are highly prevalent developmental disabilities associated with prenatal alcohol exposure. In addition to varied strengths and unique talents, people with FASD experience significant challenges, including in adaptive functioning. Adaptive functioning refers to skills related to everyday life such as communication, practical skills, and social skills. For the current review, we aimed to understand how adaptive functioning in FASD compares to that of alcohol nonexposed individuals and those with attention deficit‐hyperactivity disorder (ADHD). Additionally, we investigated how this relationship may change based on IQ, executive functioning, and age. Method: The current review was registered in the International Prospective Register of Systematic Reviews. Studies were eligible for inclusion if they measured adaptive functioning and included an FASD group and at least one eligible comparison group. Articles available in May 2021 in PubMed, PsycInfo, Scopus, and ProQuest Dissertations were searched. Publication bias was assessed using Egger's regression and three‐level random effects models were computed for all domains of adaptive functioning. Possible moderation by IQ, executive functioning, and age were investigated when heterogeneity analyses were significant. A post hoc moderation analysis of recruitment method was also completed. Results: Thirty studies were included. Individuals with FASD had significantly lower adaptive functioning than other groups, with effect sizes ranging from 1.04 to 1.35 compared to alcohol nonexposed groups and from 0.30 to 0.43 compared to ADHD groups. No significant moderating effects were found for IQ or age; executive functioning significantly moderated communication skills in FASD compared to the alcohol nonexposed group. Recruitment method significantly affected this relationship, with larger effect sizes on average found for clinically identified samples than at‐risk or population samples. Conclusions: Individuals with FASD have impairments in adaptive functioning relative to alcohol nonexposed and ADHD groups, regardless of IQ, executive functioning, or age. Limitations of the review include small sample sizes in some comparisons and a limited age range. [ABSTRACT FROM AUTHOR]

Background: The preconception period provides a unique opportunity to optimize the health of women and children. High rates of alcohol use and unintended pregnancies are common across many Western societies, and alcohol‐exposed pregnancies (AEPs) are a possible unintended outcome. The aim of the current study was to evaluate preconception interventions for the prevention of AEPs. Methods: A systematic search of four electronic databases (PubMed, Embase, CINAHL, and PsycINFO) was undertaken for relevant peer‐reviewed articles published from 1970 onward. Studies were included if they enrolled women and/or their support networks during the preconception period. Results: Nineteen studies met the inclusion criteria. The majority of studies (n = 14) evaluated CHOICES‐based interventions, which incorporate motivational interviewing approaches to change alcohol and/or contraceptive behavior. The other five interventions included a range of different approaches and modes of delivery. The majority of interventions were successful in reducing AEP risk. Changes in AEP risk were more often driven by changes in contraceptive behavior, although some approaches led to changes in both alcohol and contraceptive behavior. Conclusions: The review indicated that many interventions were efficacious at reducing AEP risk during the preconception period through preventing unplanned pregnancy. The effectiveness estimated from these clinical trials may be greater than that seen in interventions when implemented in practice where there is a lack of blinding and greater attrition of participants during follow‐up. Further research investigating the real‐world effectiveness of these intervention approaches implemented across a wide range of clinical settings would be beneficial. [ABSTRACT FROM AUTHOR]

Background: Despite high levels of prenatal alcohol exposure in the UK, evidence on the prevalence of fetal alcohol spectrum disorders (FASD) is lacking. This paper reports on FASD prevalence in a small sample of children in primary school. Methods: A 2‐phase active case ascertainment study was conducted in 3 mainstream primary schools in Greater Manchester, UK. Schools were located in areas that ranged from relatively deprived to relatively affluent. Initial screening of children aged 8–9 years used prespecified criteria for elevated FASD risk (small for age; special educational needs; currently/previously in care; significant social/emotional/mental health symptoms). Screen‐positive children were invited for detailed ascertainment of FASD using gold standard measures that included medical history, facial dysmorphology, neurological impairment, executive function, and behavioral difficulties. Results: Of 220 eligible children, 50 (23%) screened positive and 12% (26/220) proceeded to Phase 2 assessment. Twenty had a developmental disorder, of whom 4 had FASD and 4 were assessed as possible FASD. The crude prevalence rate of FASD in these schools was 1.8% (95% CI: 1.0%, 3.4%) and when including possible cases was 3.6% (2.1%, 6.3%). None of these children had previously been identified with a developmental diagnosis. Conclusions: FASD was found to be common in these schools and most of these children's needs had not previously been identified. A larger, more definitive study that uses a random sampling technique stratified by deprivation level to select schools is needed to make inferences regarding the population prevalence of FASD. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory‐based network analysis to resting‐state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. Methods: Resting‐state fMRI data were collected from adolescent and young adult participants (ages 12–22) with fetal alcohol syndrome (FAS) or alcohol‐related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures. Results: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS‐IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. Conclusion: Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorder (FASD) is a prevalent neurodevelopmental disorder that is caused by prenatal alcohol exposure (PAE) and associated with a range of cognitive, affective, and health concerns. Although the identification of FASD can facilitate the provision of interventions and support, and plays a protective role against adverse outcomes, there are high rates of missed detection. The identification of FASD via screening may improve its recognition across settings. The current systematic review examined the available evidence on FASD screening tools and approaches across age groups and settings. Methods: A systematic search was carried out for both peer‐reviewed studies and gray literature sources published between January 1990 and May 2020 and was preregistered with PROSPERO (#CRD42019122077). Studies included in the review focused on human applications of FASD screening in children, adolescents, and adults. The quality of the studies was assessed using the QUADAS‐2 and GRADE frameworks. Results: The search yielded 20 screening tools and approaches across 45 studies, broadly characterized in 2 groups. The first group included approaches currently in use that aim to identify individuals at risk of FASD using a range of markers (n = 19) or associated sentinel dysmorphic facial features (n = 6). Another group of studies, characterized as emerging, focused on identifying promising biomarkers of PAE/FASD (n = 20). Overall, we identified limited research supporting the psychometric properties of most screening approaches. The quality review provided evidence of bias due to the common use of case–control designs and lack of adequate reference standards. Conclusions: Although several FASD screening tools and approaches are available for use across a range of age groups and settings, the overall evidence base supporting their psychometric properties is weak, with most studies demonstrating significant risk of bias. Service providers should exercise caution in selecting and implementing FASD screening tools given these limitations. It is critically important to accurately identify individuals with FASD across ages and settings to support healthy outcomes. Thus, there is a pressing need for additional research in this area, particularly validation studies in large and representative samples using robust methodological approaches. [ABSTRACT FROM AUTHOR]

Background: The initial confirmatory factor analysis of the Alcohol Related Neurodevelopmental Disorder Behavioral Checklist (ABC) utilized a population of 203 children. The analysis identified 10 independent measures (executive functioning, attention and concentration, cognition, memory, confabulation, gullibility, communication skills, academic skills, living/social skills, and juvenile justice). The 10 measures differentiated children with FASD from non‐FASD controls. In this study, we present a validity study of the ABC using a different population of children with FASD and non‐FASD controls. Methods: A chart review identified 224 children with ABC checklist scores who had been evaluated for FASD. From this sample, we implemented a case–control study of 76 children diagnosed with FASD and 76 non‐FASD controls who were matched by gender and closest age in years (mean age was 8.5 years). Results: The averages of the total score and individual domain scores were compared between the 2 data sets and then between children with FASD and non‐FASD controls. Children with FASD had significantly higher scores on all 10 measures than the non‐FASD controls. There were very high sensitivity and specificity scores for the total score cutoff and for all 10 of the individual measures. Conclusions: In an independent sample, we found minimal differences between the previous data and the current validation study on measures of average total score cutoffs, scores for the 10 measures and correlations. Combining the 2 samples yielded robust differences in scores between children with FASD and non‐FASD controls. The sensitivity, specificity and accuracy estimates were also very high. The ABC Screen appears to have acceptable epidemiologic performance data to support its use as a screening tool and as an initial step in differentiating children with FASD from those who do not have FASD. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) is linked to a variety of neurodevelopmental challenges, including social functioning (SF) and executive functioning (EF) deficits. These deficits present differently across developmental stages from preschool age to adolescence. Methods: The post hoc analyses described here were conducted on data from 83 preschool‐age children with PAE (early childhood group; ages 2.5 to 5.0) and 95 adolescents (49 with PAE, 46 controls; ages 8 to 16). Each child completed EF tasks as part of several prior studies. Parents completed social and communication inventories about their child's abilities. Thirty‐three participants from the early childhood group returned for a 4‐year follow‐up and completed both SF and EF measures. Results: Both the early childhood and adolescent groups with PAE showed deficits in SF and EF. There was a relationship between SF and EF within the adolescent PAE group that was not present in the adolescent control group or the early childhood PAE group. However, at the 4‐year follow‐up (Mage = 8.45), participants originally in the early childhood PAE group also demonstrated this relationship. Conclusions: These findings support previous research on EF/SF deficits in adolescents with PAE while also addressing a gap in the literature concerning early childhood research on this topic. Additionally, these findings suggest that the relationship between EF and SF deficits may strengthen throughout development. This line of research highlights potential sensitive periods for SF and EF training in children with PAE and suggests that fetal alcohol spectrum disorders programs consider targeting EF training as a component of social skill interventions. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome‐wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. Methods: We investigated 5 DNAm‐based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. Results: Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta‐analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. Conclusions: This study provides novel evidence regarding accelerated epigenetic aging in children with FASD. [ABSTRACT FROM AUTHOR]

Individuals with fetal alcohol spectrum disorder (FASD) experience remarkably high rates of mental health and substance use challenges, beginning early in life and extending throughout adulthood. Proactive intervention can help to mitigate some of these negative experiences. Although the literature on FASD intervention is growing, there is currently a lack of consolidated evidence on interventions that may improve mental health and substance use outcomes in this population. Informed by a life course perspective, we undertook a systematic review of the literature to identify interventions that improve mental wellness through all developmental stages for people with prenatal alcohol exposure (PAE) and FASD. A total of 33 articles were identified, most of which were focused on building skills or strategies that underlie the well‐being of children with PAE and FASD and their families. Other interventions were geared toward supporting child and family wellness and responding to risk or reducing harm. There was a notable lack of interventions that directly targeted mental health and substance use challenges, and a major gap was also noted in terms of interventions for adolescents and adults. Combined, these studies provide preliminary and emerging evidence for a range of intervention approaches that may support positive outcomes for individuals with FASD across the life course. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) is associated with a variety of structural abnormalities in the brain, including several within the para‐limbic system. Children with PAE have higher rates of internalizing disorders, including depression and anxiety, which may be related to underlying limbic system anomalies. Methods: Children aged 8 to 16 with PAE (n = 41) or without PAE (n = 36) underwent an magnetic resonance imaging of the brain and parents completed behavioral questionnaires about their children. Semi‐automated procedures (FreeSurfer) were used to derive para‐limbic volumes from T1‐weighted anatomical images. Results: There were significant group differences (PAE vs. nonexposed controls) in the caudate, hippocampus, and the putamen; children with PAE had smaller volumes in these regions even after controlling for total intracranial volume. A trend‐level association was seen between caudate volume and internalizing symptoms in children with PAE; smaller caudate volumes (presumably reflecting less optimal neurodevelopment) were associated with higher levels of anxiety and depression symptoms in these children. Conclusions: Caudate structure may be disproportionately affected by PAE and may be associated with the later development of internalizing symptoms in those affected by PAE. [ABSTRACT FROM AUTHOR]

Background: Individuals with fetal alcohol spectrum disorder (FASD) experience a range of problems in their cognitive, affective, and physical functioning following prenatal alcohol exposure (PAE), in addition to multiple complex difficulties in daily living that impact well‐being. Using the Canadian National FASD Database, we sought to profile a range of difficulties in daily living, along with risk factors, in a large cross‐sectional cohort of adolescents, transition‐aged youth, and adults with PAE, of which a subset was ultimately diagnosed with FASD. Methods: We summarized data for 9 current difficulties in daily living reported at the time of diagnostic assessment for 726 individuals with PAE assessed at 26 FASD diagnostic clinics across Canada, including 443 adolescents (12 to 17 years), 135 transition‐aged youth (18 to 24 years), and 148 adults (25 to 60 years). Difficulties included problems related to school disruption, employment, independent living needs, supportive or sheltered housing, legal problems with victimization, legal problems with offending, incarceration, alcohol misuse, and other substance misuse. Risk factors included age, gender, living placement, postnatal trauma, and neurodevelopmental impairment. Results: Across the full PAE sample, adolescents, transition‐aged youth, and adults presented with high rates of difficulties in daily living, including independent living support needs (63%), alcohol misuse (38%), other substance misuse (46%), employment problems (37%), legal problems with offending (30%), assisted or sheltered housing (21%), school disruption (18%), legal problems with victimization (4%), and incarceration (3%). Difficulty rates were similar for those with FASD irrespective of diagnosis (e.g., with or without sentinel facial features), but rates greater for adults, and those with low overall intellectual functioning (IQ < 70). Controlling for age and IQ, cumulative difficulty was independently associated with gender, living placement, and neurodevelopmental impairment. Conclusions: Adolescents, transition‐aged youth, and adults with FASD experienced a range of substantial and complex difficulties at the time of their diagnostic assessment, signaling a high level of service needs. These findings underscore the importance of developmentally informed assessment continued through childhood, as well as ongoing functional and needs‐based service provision as youth with FASD transition to adulthood and beyond. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorder (FASD) is a diagnosis relating to neurocognitive impairments associated with prenatal alcohol exposure. A key aspect of improving FASD diagnostic processes and management is understanding the demographic and neurocognitive profile of those living with FASD. The aim of this study was to describe the demographic and neurocognitive profile of the first 199 individuals diagnosed with FASD in PATCHES Paediatrics clinics. Methods: A retrospective cross‐sectional descriptive study design was conducted with individuals diagnosed with FASD between 2013 and 2018 through a multidisciplinary team according to the Australian FASD Diagnostic Guidelines. Results: Participants were primarily male 133 (66.8%) and Aboriginal Australian 147 (73.9%), aged 2 to 31 (mean 10.5), with 94 (47.3%) from remote or very remote parts of Western Australia. Participants came from low 119 (59.8%), medium 48 (24.1%), and high 32 (16.1%) socioeconomic (SE) backgrounds. Low SE background was found to be a predictor of number of sentinel facial features (Wald χ2 (1) = 4.03, p < 0.05). Most received a diagnosis of FASD with <3 sentinel features 165 (82.9%). Participants either had 6 or more 46 (23.1%), 5 44 (22.1%), 4 55 (27.6%), or 3 (27.1%) neurodevelopmental domains impaired. Executive functioning was the most commonly impaired neurodevelopmental domain 158 (79.4%), and 31 (61%) reported sleep disturbance. ADHD was the most observed comorbid condition (41.7%). Conclusions: This study improves our current understanding of neurocognitive and demographic profiles in individuals with FASD that have been clinically referred for diagnosis within Western Australia and the Northern Territory, and highlights the importance of prevention and early assessment/diagnosis as well as guidance regarding more targeted interventions. FASD affects individuals from all cultural and SE backgrounds. Individuals from middle to higher SE groups are at risk of FASD with prevention efforts needing to target these sectors of society. Suggestions for future research directions are also provided. [ABSTRACT FROM AUTHOR]

Evidence suggests that children with fetal alcohol spectrum disorder (FASD) experience challenges across many areas of their daily lives and often require interprofessional supports. Recent studies have emphasized the need for an integrated system of care for children with FASD, incorporating medical, allied health, and education services, to facilitate open communication and support for the complex needs that many children experience. To develop such a system of care, it is important to first understand the impact of FASD on children's functioning during daily activities in different environmental contexts. A critical review of existing research was conducted using a critical interpretive synthesis approach. Results revealed that while many studies discussed impacts at the body functions and structures level of children with FASD, they often did not consider the activity, participation, and environmental factors also contributing to the daily functioning of this population. Several studies discussed caregiver experiences and challenges raising a child with FASD; however, no studies investigated the lived experiences relating to impacts across activities and environments from children's perspectives. In addition, the focus on deficits overshadowed investigation into the strengths of children with FASD, leaving a gap in the picture of their daily lives. Further research is required to determine the strengths that children with FASD demonstrate and the challenges impacting their daily functioning within different environmental contexts. Insights gleaned from such research would support intervention practices to become more holistic and interprofessional. [ABSTRACT FROM AUTHOR]

Background: The adult hippocampal dentate is comprised of both developmentally generated dentate granule cells (dDGCs) and adult‐generated dentate granule cells (aDGCs), which play distinct roles in hippocampal information processing and network function. EtOH exposure throughout gestation in mouse impairs the neurogenic response to enriched environment (EE) in adulthood, although the basal rate of adult neurogenesis under standard housing (SH) is unaffected. Here, we tested whether the production and/or survival of either dDGCs or aDGCs are selectively impaired following exposure of mice to EtOH vapors during early postnatal development (human third trimester‐equivalent), and whether this exposure paradigm leads to impairment of EE‐mediated dentate neurogenesis in adulthood. Methods: All experiments were performed using NestinCreERT2:tdTomato bitransgenic mice, which harbor a tamoxifen‐inducible tdTomato (tdTom) reporter for indelible labeling of newborn hippocampal DGCs. We exposed all mice to EtOH vapor or room air (Control) for 4 h/d from postnatal day (PND) 3 through PND 15. This paradigm resulted in a mean daily postexposure blood EtOH concentration of ~160 mg/dl. One cohort of neonatal mice received a single injection of tamoxifen at PND 2 and was sacrificed at either PND 16 or PND 50 to assess the impact of EtOH exposure on the production and long‐term survival of dDGCs born during the early postnatal period. A second cohort of mice received daily injections of tamoxifen at PND 35 to 39 to label aDGCs and was exposed to SH or EE for 6 weeks prior to sacrifice. Results: Early postnatal EtOH exposure had no statistically significant effect on the production or survival of tdTom+ dDGCs, as assessed at PND 16 or PND 50. Early postnatal EtOH exposure also had no effect on the number of tdTom+ aDGCs under SH conditions. Furthermore, early postnatal EtOH exposure had no significant impact on the adult neurogenic response to EE. Conclusions: Both early postnatal dentate neurogenesis and adult dentate neurogenesis, as well as the adult neurogenic response to EE, are surprisingly resistant to early postnatal EtOH vapor exposure in mice. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) causes long‐term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron‐fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production—EPO/BMP6/SMAD and IL‐6/JAK2/STAT3. Methods: Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron‐sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5. Results: PAE did not affect Epo or Bmp6 expression, but reduced p‐SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.01). In contrast, PAE stimulated maternal hepatic expression of Il‐6 (p = 0.03) and elevated p‐STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.02). PAE modestly elevated maternal Il‐1β, Tnf‐α, and Ifn‐γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il‐6 (p = 0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il‐6 expression in response to PAE, with IF driving a 150‐fold decrease (p < 0.001) in maternal liver and a 10‐fold decrease (p < 0.01) in fetal liver. The IF diet also normalized p‐STAT3/STAT3 ratios in both maternal and fetal liver. Conclusions: These findings suggest that alcohol‐driven stimulation of the IL‐6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL‐6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) is linked to alterations of cerebral white matter, including volume and nonspecific diffusion magnetic resonance imaging (MRI) indices of microstructure in humans. Some animal models of PAE have demonstrated myelination deficiencies, but myelin levels have not yet been evaluated in individuals with PAE. Multiecho T2MRI offers a quantitative method to estimate myelin water fraction (MWF; related to myelin content) noninvasively, which was used here to evaluate brain myelination in children with PAE. Methods: Participants with PAE (n = 10, 6 females, mean age 13.9 years, range 7 to 18 years) and controls (n = 14, 11 females, mean age 13.2 years, range 9 to 16 years) underwent 3T MRI of the brain. T2 images (15 minutes acquisition for 32 echoes) were used to create MWF maps from which mean MWF was measured in 12 regions of interest (ROIs) including 8 in white matter and 4 in deep gray matter. Results: As expected, across the combined sample, MWF was highest for major white matter tracts such as the internal capsule and genu/splenium of the corpus callosum (10 to 18%) while the caudate and putamen had MWF less than 5%. Mean MWF was similar across 11/12 brain white and gray matter regions for the PAE and control groups (L/R internal capsule, major forceps, putamen, caudate nucleus, L minor forceps, genu and splenium of corpus callosum). In the PAE group, MWF was positively correlated with age in the genu of corpus callosum and right minor forceps, notably 2 frontal tracts. Conclusions: Given comparable MRI‐derived myelination fraction measures in PAE relative to controls, white matter alterations shown in other imaging studies, such as diffusion tensor imaging, may reflect microstructural anomalies related to axon caliber and density. [ABSTRACT FROM AUTHOR]

Background: Gestational ethanol (EtOH) exposure is associated with multiple developmental abnormalities, collectively termed fetal alcohol spectrum disorder (FASD). While the majority of women abstain from EtOH following knowledge of pregnancy, one contributing factor to the high FASD prevalence is that pregnancy is not detected until 4 to 6 weeks. Thus, EtOH consumption continues during the initial stages of fetal development. Methods: An experimental protocol is described in which rhesus macaques self‐administer 1.5 g/kg/d EtOH (or isocaloric maltose dextrin) prior to pregnancy and through the first 60 days of a 168‐day gestation term. Menstrual cycles were monitored, including measurements of circulating estradiol and progesterone levels. The latency to consume 1.5 g/kg EtOH and blood EtOH concentration (BEC) was measured. Results: Twenty‐eight fetuses (14 EtOH and 14 controls) were generated in this study. EtOH did not affect menstrual cycles or the probability of successful breeding. No EtOH‐induced gross adverse effects on pregnancy were observed. Individual variability in latency to complete drinking translated into variability in BEC, measured 90 minutes following session start. Drinking latencies in controls and EtOH drinkers were longer in the second gestational month than in the first. All pregnancies reached the planned experimental time point of G85, G110, or G135, when in utero MRIs were performed, fetuses were delivered by caesarean section, and brains were evaluated with ex vivo procedures, including slice electrophysiology. Fetal tissues have been deposited to the Monkey Alcohol Tissue Research Resource. Conclusions: This FASD model takes advantage of the similarities between humans and rhesus macaques in gestational length relative to brain development, as well as similarities in EtOH self‐administration and metabolism. The daily 1.5 g/kg dose of EtOH through the first trimester does not influence pregnancy success rates. However, pregnancy influences drinking behavior during the second month of pregnancy. Future publications using this model will describe the effect of early‐gestation EtOH exposure on anatomical and functional brain development at subsequent gestational ages. A nonhuman primate model of FASD, induced by early‐gestation oral ethanol self‐administration, has been developed. This animal model will be used to assess the ability of in utero MRI procedures to identify ethanol‐induced abnormalities in brain development during the second half of gestation. A mid‐gestation image is shown, which facilitates construction of a 3D brain model (inset). Electrophysiological recordings from tissue slices are obtained from the striatum immediately following MRI to validate the functional significance of abnormalities identified by MRI. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) can result in permanent disability, including physical, neurodevelopmental, and cognitive impairments, known as fetal alcohol spectrum disorder (FASD). Individuals with FASD are more likely to engage with the law, including being placed in detention, than individuals without FASD. Young people who were sentenced to detention participated in a FASD prevalence study in Western Australia. The diagnosis of FASD requires a multidisciplinary assessment and confirmation of maternal alcohol consumption during pregnancy. Obtaining accurate assessment of PAE for young people participating in the study was challenging. Methods: An interview with the birth mother or other responsible adult for young people sentenced to detention in Western Australia was conducted as part of the FASD assessment. The Alcohol Use Disorders Identification Test consumption subset (AUDIT‐C), other relevant questions, and documentary evidence were used to assess PAE. PAE was categorized according to the Australian Guide to the Diagnosis of FASD: no PAE reported, confirmed or confirmed high‐risk, or unknown. Results: Among the 101 participants, information on PAE was unable to be obtained for 13 (13%) young people. Of the remaining 88 participants with information of PAE, 41 reported no PAE and 47 had confirmed PAE. Conclusions: Accurately assessing prenatal alcohol consumption is challenging in any setting, but it is exceptionally challenging when assessed 13 to 17 years retrospectively as part of a FASD assessment for a young person sentenced to detention. Recording and recoding detailed qualitative responses was required to provide an accurate assessment of PAE using the AUDIT‐C. Standardized recording of PAE in antenatal and birth records would facilitate later assessments for FASD and provide opportunities for advice and support for women who continue to drink during pregnancy. This study discusses the challenges of assessing prenatal alcohol exposure (PAE) as part of a fetal alcohol spectrum disorder assessment for young people sentenced to detention in Western Australia. PAE was assessed using the AUDIT‐C with the birth mother or another responsible adult who was present during the mother's pregnancy. Recording and recoding detailed qualitative responses was required to provide an accurate assessment of PAE, as recalling prenatal alcohol consumption retrospectively, 13 to 17 years post‐pregnancy, is challenging. [ABSTRACT FROM AUTHOR]

Background: Alcohol exposure during pregnancy can kill developing neurons and lead to fetal alcohol spectrum disorder (FASD). However, affected individuals differ in their regional patterns of alcohol‐induced neuropathology. Because neuroprotective genes are expressed in spatially selective ways, their mutation could increase the vulnerability of some brain regions, but not others, to alcohol teratogenicity. The objective of this study was to determine whether a null mutation of neuronal nitric oxide synthase (nNOS) can increase the vulnerability of some brain regions, but not others, to alcohol‐induced neuronal losses. Methods: Immunohistochemistry identified brain regions in which nNOS is present or absent throughout postnatal development. Mice genetically deficient for nNOS (nNOS−/−) and wild‐type controls received alcohol (0.0, 2.2, or 4.4 mg/g/d) over postnatal days (PD) 4 to 9. Mice were sacrificed in adulthood (~PD 115), and surviving neurons in the olfactory bulb granular layer and brain stem facial nucleus were quantified stereologically. Results: nNOS was expressed throughout postnatal development in olfactory bulb granule cells but was never expressed in the facial nucleus. In wild‐type mice, alcohol reduced neuronal survival to similar degrees in both cell populations. However, null mutation of nNOS more than doubled alcohol‐induced cell death in the olfactory bulb granule cells, while the mutation had no effect on the facial nucleus neurons. As a result, in nNOS−/− mice, alcohol caused substantially more cell loss in the olfactory bulb than in the facial nucleus. Conclusions: Mutation of the nNOS gene substantially increases vulnerability to alcohol‐induced cell loss in a brain region where the gene is expressed (olfactory bulb), but not in a separate brain region, where the gene is not expressed (facial nucleus). Thus, differences in genotype may explain why some individuals are vulnerable to FASD, while others are not, and may determine the specific patterns of neuropathology in children with FASD. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure results in cognitive, behavioral, and neurological deficits in offspring. There is an urgent need for safe and effective treatments to overcome these effects. Maternal choline supplementation has been identified as a potential intervention. Our objective was to review preclinical and clinical studies using choline supplementation in known cases of fetal alcohol exposure to determine its effectiveness in ameliorating deficits in offspring. A systematic search of 6 electronic databases was conducted and studies selected by reviewing titles/abstracts against specific inclusion/exclusion criteria. Study characteristics, population demographics, alcohol exposure, and intervention methods were tabulated, and quality of reporting was assessed. Data on cognitive, behavioral, and neurological outcomes were extracted and tabulated. Quantitative analysis was performed to determine treatment effects for individual study outcomes. A total of 189 studies were retrieved following duplicate removal. Of these, 22 studies (2 randomized controlled trials, 2 prospective cohort studies, and 18 preclinical studies) met the full inclusion/exclusion criteria. Choline interventions were administered at different times relative to alcohol exposure, impacting on their success to prevent deficits for specific outcomes. Only 1 clinical study showed significant improvements in information processing in 6‐month‐old infants from mothers treated with choline during pregnancy. Preclinical studies showed significant amelioration of deficits due to prenatal alcohol exposure across a wide variety of outcomes, including epigenetic/molecular changes, gross motor, memory, and executive function. This review suggests that choline supplementation has the potential to ameliorate specific behavioral, neurological, and cognitive deficits in offspring caused by fetal alcohol exposure, at least in preclinical studies. As only 1 clinical study has shown benefit, we recommend more clinical trials be undertaken to assess the effectiveness of choline in preventing deficits across a wider range of cognitive domains in children. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) can be associated with significant difficulties in self‐regulatory abilities. As such, interventions have been developed that focus on improving varying aspects of self‐regulation for this population. The application of a multilevel theoretical framework that describes the development of self‐regulation during early childhood could further advance the field. First, this framework could assist in elucidating mechanisms in the trajectories of early adjustment problems in this population and, second, informing the development of more precise assessment and interventions for those affected by PAE. The aims of the current review were to provide an overview of the self‐regulatory framework proposed by Calkins and colleagues (e.g., Calkins, 2007; Calkins and Fox, 2002); examine the self‐regulatory difficulties that are commonly experienced during infancy (i.e., 0 to 2 years) and early childhood (i.e., 3 to 8 years) in children with PAE in the context of the developmental framework; and describe how the framework can inform the development of future assessment and intervention provision for young children with PAE. The application of a developmental framework, such as proposed by Calkins and colleagues, allows for a systematic and theoretically driven approach to assessment and intervention programs for young children with PAE. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) causes neurodevelopmental disability. Clinical and animal studies show gestational iron deficiency (ID) exacerbates PAE's behavioral and growth deficits. In rat, PAE manifests an inability to establish iron homeostasis, increasing hepcidin (maternal and fetal), and fetal liver iron while decreasing brain iron and promoting anemia. Here, we hypothesize dietary iron fortification during pregnancy may mitigate alcohol's disruption of fetal iron homeostasis. Methods: Pregnant Long‐Evans rats, fed iron‐sufficient (100 ppm iron) or iron‐fortified (IF; 500 ppm iron) diets, received either 5 g/kg alcohol (PAE) or isocaloric maltodextrin daily on gestational days (GD) 13.5 through 19.5. Maternal and fetal outcomes were evaluated on GD20.5. Results: PAE reduced mean fetal weight (p < 0.001) regardless of maternal iron status, suggesting iron fortification did not improve fetal growth. Both PAE (p < 0.01) and IF (p = 0.035) increased fetal liver iron. In fetal brain, PAE (p = 0.015) affected total (p < 0.001) and nonheme iron (p < 0.001) such that iron fortification normalized (p = 0.99) the alcohol‐mediated reductions in brain iron and nonheme iron. Iron fortification also improved fetal hematologic indices in PAE including hemoglobin, hematocrit, and mean cell volume (ps<0.001). Iron fortification also normalized hepcidin expression in alcohol‐exposed maternal and fetal liver. Neither diet nor PAE affected transferrin (Tf) and ferritin (FTN) content in fetal liver, nor Tf or transferrin receptor in fetal brain. However, IF‐PAE fetal brains trended to less FTN content (p = 0.074), suggesting greater availability of nonstorage iron. In PAE, hepcidin levels were linearly related to increased liver iron stores and decreased red blood cell count and brain iron. Conclusions: Maternal oral iron fortification mitigated PAE's disruption of fetal iron homeostasis and improved brain iron content, hematologic indices, and hepcidin production in this rat PAE model. Clinical studies show maternal ID substantially enhances fetal vulnerability to PAE, and our work supports increased maternal dietary iron intake may improve fetal iron status in alcohol‐exposed pregnancies. [ABSTRACT FROM AUTHOR]

Background: We have reported that prenatal alcohol exposure (PAE)‐induced deficits in dentate gyrus, long‐term potentiation (LTP), and memory are ameliorated by the histamine H3 receptor inverse agonist ABT‐239. Curiously, ABT‐239 did not enhance LTP or memory in control offspring. Here, we initiated an investigation of how PAE alters histaminergic neurotransmission in the dentate gyrus and other brain regions employing combined radiohistochemical and electrophysiological approaches in vitro to examine histamine H3 receptor number and function. Methods: Long‐Evans rat dams voluntarily consumed either a 0% or 5% ethanol solution 4 hours each day throughout gestation. This pattern of drinking, which produces a mean peak maternal serum ethanol concentration of 60.8 ± 5.8 mg/dl, did not affect maternal weight gain, litter size, or offspring birthweight. Results: Radiohistochemical studies in adult offspring revealed that specific [3H]‐A349821 binding to histamine H3 receptors was not different in PAE rats compared to controls. However, H3 receptor‐mediated Gi/Go protein–effector coupling, as measured by methimepip‐stimulated [35S]‐GTPγS binding, was significantly increased in cerebral cortex, cerebellum, and dentate gyrus of PAE rats compared to control. A LIGAND analysis of detailed methimepip concentration–response curves in dentate gyrus indicated that PAE significantly elevates receptor–effector coupling by a lower affinity H3 receptor population without significantly altering the affinities of H3 receptor subpopulations. In agreement with the [35S]‐GTPγS studies, a similar range of methimepip concentrations also inhibited electrically evoked field excitatory postsynaptic potential responses and increased paired‐pulse ratio, a measure of decreased glutamate release, to a significantly greater extent in dentate gyrus slices from PAE rats than in controls. Conclusions: These results suggest that a PAE‐induced elevation in H3 receptor‐mediated inhibition of glutamate release from perforant path terminals as 1 mechanism contributing the LTP deficits previously observed in the dentate gyrus of PAE rats, as well as providing a mechanistic basis for the efficacy of H3 receptor inverse agonists for ameliorating these deficits. [ABSTRACT FROM AUTHOR]

Background Maternal alcohol abuse leading to fetal alcohol spectrum disorder ( FASD) includes fetal growth restriction ( FGR). Ethanol (EtOH) induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD. EtOH facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca2+. We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca2+. Therefore, nifedipine, a Ca2+ channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol. Methods Human first-trimester chorionic villous explants and the human trophoblast cell line HTR-8/ SVneo (HTR) were pretreated with 12.5 to 50 nM of the Ca2+ channel blocker nifedipine for 1 hour before exposure to 50 mM EtOH for an additional hour. Intracellular Ca2+ concentrations were monitored in real time by epifluorescence microscopy, using fluo-4- AM. Apoptosis was assessed by terminal deoxynucleotidyl transferase d UTP nick end labeling ( TUNEL), accumulation of cytoplasmic cytochrome c, and cleavage rates of caspase 3 and caspase 9. Results The increase in intracellular Ca2+ upon exposure to EtOH in both villous explants and HTR cells was completely blocked ( p < 0.05) when pretreated with nifedipine, accompanied by inhibition of EtOH-induced release of cytochrome c, caspase activities, and TUNEL. Conclusions This study indicates that nifedipine can interrupt the apoptotic pathway downstream of EtOH exposure and could provide a novel strategy for future interventions in women with fetuses at risk for FASD. [ABSTRACT FROM AUTHOR]

Background Impaired motor function in children with histories of prenatal exposure to alcohol has been previously reported but, to date, no studies using quantitatively based analyses have been performed to assess gait in these children. Methods Gait of children with ( n = 18) or without ( n = 26) prenatal alcohol exposure was assessed using an electronically instrumented walkway. Children completed blocks of trials traversing the walkway with different combinations of walking condition (increased, self-paced, and decreased cadence) and direction (forward and backward). Gait velocity, cadence, stride length, step width, foot angle, and double support time, as well as the variability of these temporal-spatial markers, were used to assess gait. Results Results indicated that, in comparison with typically developing children, alcohol-exposed children produced exaggerated foot angle and increased step width. Additionally, alcohol-exposed children produced greater intrasubject variability of gait velocity and walking cadence while walking forward and backward, and greater variability in step width when walking backward and for all 3 walking conditions. Conclusions The results indicate that selected gait markers are adversely affected by prenatal exposure to alcohol. Clinicians and front-line personnel (e.g., teachers) should provide movement enriched experiences to help ameliorate these alcohol-related deficits. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy can cause adverse effects to the fetus, because it interferes with fetal development, leading to later physical and mental impairment. The most common clinical tool to determine fetal alcohol exposure is maternal self-reporting. However, a more objective and useful method is based on the use of biomarkers in biological specimens alone or in combination with maternal self-reporting. This review reports on clinically relevant biomarkers for detection of prenatal alcohol exposure (PAE). A systematic search was performed to ensure a proper overview in existing literature. Studies were selected to give an overview on clinically relevant neonatal and maternal biomarkers. The direct biomarkers fatty acid ethyl esters (FAEEs), ethyl glucuronide (EtG), ethyl sulfate, and phosphatidylethanol (PEth) were found to be the most appropriate biomarkers in relation to detection of PAE. To review each biomarker in a clinical context, we have compared the advantages and disadvantages of each biomarker, in relation to its window of detectability, ease of collection, and the ease and cost of analysis of each biomarker. The biomarkers PEth, FAEEs, and EtG were found to be applicable for detection of even low levels of alcohol exposure. Meconium is an accessible matrix for determination of FAEEs and EtG, and blood an accessible matrix for determination of PEth. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure ( PAE) in animal models results in excitatory-inhibitory (E/I) imbalance in neocortex due to alterations in the GABAergic interneuron ( IN) differentiation and migration. Thus, E/I imbalance is a potential cause for intellectual disability in individuals with fetal alcohol spectrum disorder ( FASD), but whether ethanol (Et OH) changes glutamatergic and GABAergic IN specification during human development remains unknown. Here, we created a human cellular model of PAE/ FASD and tested the hypothesis that Et OH exposure during differentiation of human pluripotent stem cell-derived neurons ( hPSNs) would cause the aberrant production of glutamatergic and GABAergic neurons, resulting in E/I imbalance. Methods We applied 50 mM Et OH daily to differentiating hPSNs for 50 days to model chronic first-trimester exposure. We used quantitative polymerase chain reaction, immunocytochemical, and electrophysiological analysis to examine the effects of Et OH on hPSN specification and functional E/I balance. Results We found that Et OH did not alter neural induction nor general forebrain patterning and had no effect on the expression of markers of excitatory cortical pyramidal neurons. In contrast, our data revealed highly significant changes to levels of transcripts involved with IN precursor development (e.g., GSX2, DLX1/ 2/ 5/ 6, NR2F2) as well as mature IN specification (e.g., SST, NPY). Interestingly, Et OH did not affect the number of GABAergic neurons generated nor the frequency or amplitude of miniature excitatory and inhibitory postsynaptic currents. Conclusions Similar to in vivo rodent studies, Et OH significantly and specifically altered the expression of genes involved with IN specification from hPSNs, but did not cause imbalances of synaptic excitation-inhibition. Thus, our findings corroborate previous studies pointing to aberrant neuronal differentiation as an underlying mechanism of intellectual disability in FASD. However, in contrast to rodent binge models, our chronic exposure model suggests possible compensatory mechanisms that may cause more subtle defects of network processing rather than gross alterations in total E/I balance. [ABSTRACT FROM AUTHOR]

Background Saccades are rapid eye movements that bring an image of interest onto the retina. Previous research has found that in healthy individuals performing eye movement tasks, the location of a previous visual target can influence performance of the saccade on the next trial. This rapid behavioral adaptation represents a form of immediate neural plasticity within the saccadic circuitry. Our studies have shown that children with fetal alcohol spectrum disorder ( FASD) are impaired on multiple saccade measures. We therefore investigated these previous trial effects in typically developing children and children with FASD to measure sensory neural plasticity and how these effects vary with age and pathology. Methods Both typically developing control children ( n = 102; mean age = 10.54 ± 3.25; 48 males) and children with FASD ( n = 66; mean age = 11.85 ± 3.42; 35 males) were recruited from 5 sites across Canada. Each child performed a visually guided saccade task. Reaction time and saccade amplitude were analyzed and then assessed based on the previous trial. Results There was a robust previous trial effect for both reaction time and amplitude, with both the control and FASD groups displaying faster reaction times and smaller saccades during alternation trials (visual target presented on the opposite side to the previous trial). Children with FASD exhibited smaller overall mean amplitude and smaller amplitude selectively on alternation trials compared with controls. The effect of the previous trial on reaction time and amplitude did not differ across childhood and adolescent development. Conclusions Children with FASD did not display any significant reaction time differences, despite exhibiting numerous deficits in motor and higher level cognitive control over saccades in other studies. These results suggest that this form of immediate neural plasticity in response to sensory information before saccade initiation remains intact in children with FASD. In contrast, the previous trial effect on amplitude suggests that the motor component of saccades may be affected, signifying differential vulnerability to prenatal alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Although screening and brief intervention ( SBI) for unhealthy alcohol use has demonstrated efficacy in some trials, its implementation has been limited. Technology-delivered approaches are a promising alternative, particularly during pregnancy when the importance of alcohol use is amplified. The present trial evaluated the feasibility and acceptability of an interactive, empathic, video-enhanced, and computer-delivered SBI (e- SBI) plus 3 tailored mailings, and estimated intervention effects. Methods We recruited 48 pregnant women who screened positive for alcohol risk at an urban prenatal care clinic. Participants were randomly assigned to the e- SBI plus mailings or to a control session on infant nutrition, and were re-evaluated during their postpartum hospitalization. The primary outcome was 90-day period prevalence abstinence as measured by timeline follow-back interview. Results Participants rated the intervention as easy to use and helpful (4.7 to 5.0 on a 5-point scale). Blinded follow-up evaluation at childbirth revealed medium-size intervention effects on 90-day period prevalence abstinence ( OR = 3.4); similarly, intervention effects on a combined healthy pregnancy outcome variable (live birth, normal birthweight, and no neonatal intensive care unit stay) were also of moderate magnitude in favor of e- SBI participants ( OR = 3.3). As expected in this intentionally underpowered pilot trial, these effects were nonsignificant ( p = 0.19 and 0.09, respectively). Conclusions This pilot trial demonstrated the acceptability and preliminary efficacy of e- SBI plus tailored mailings for alcohol use in pregnancy. These findings mirror the promising results of other trials using a similar approach and should be confirmed in a fully powered trial. [ABSTRACT FROM AUTHOR]

Background Fetal alcohol spectrum disorders ( FASD) result from fetal exposure to alcohol and are the leading cause of mental retardation in the United States. There is currently no effective treatment that targets the causes of these disorders. Thus, novel therapies are critically needed to limit the neurodevelopmental and neurodegenerative pathologies associated with FASD. Methods A neonatal mouse FASD model was used to examine the role of the neuroimmune system in ethanol (EtOH)-induced neuropathology. Neonatal C57 BL/6 mice were treated with EtOH, with or without pioglitazone, on postnatal days 4 through 9, and tissue was harvested 1 day post treatment. Pioglitazone is a peroxisome proliferator-activated receptor ( PPAR)- γ agonist that exhibits anti-inflammatory activity and is neuroprotective. We compared the effects of EtOH with or without pioglitazone on cytokine and chemokine expression and microglial morphology in the hippocampus, cerebellum, and cerebral cortex. Results In EtOH-treated animals compared with controls, cytokines interleukin-1 β and tumor necrosis factor- α mRNA levels were increased significantly in the hippocampus, cerebellum, and cerebral cortex. Chemokine CCL2 mRNA was increased significantly in the hippocampus and cerebellum. Pioglitazone effectively blocked the EtOH-induced increase in the cytokines and chemokine in all tissues to the level expressed in handled-only and vehicle-treated control animals. EtOH also produced a change in microglial morphology in all brain regions that was indicative of microglial activation, and pioglitazone blocked this EtOH-induced morphological change. Conclusions These studies indicate that EtOH activates microglia to a pro-inflammatory stage and also increases the expression of neuroinflammatory cytokines and chemokines in diverse regions of the developing brain. Further, the anti-inflammatory and neuroprotective PPAR- γ agonist pioglitazone blocked these effects. It is proposed that microglial activation and inflammatory molecules expressed as a result of EtOH treatment during brain development contribute to the sequelae associated with FASD. Thus, pioglitazone and anti-inflammatory pharmaceuticals more broadly have potential as novel therapeutics for FASD. [ABSTRACT FROM AUTHOR]

Background Fetal alcohol spectrum disorder, the leading known cause of mental retardation, is caused by alcohol exposure during pregnancy. One mechanism of ethanol (EtOH) teratogenicity is the disruption of the functions of L1 cell adhesion molecule (L1). These functions include enhancement of neurite outgrowth, trafficking through lipid rafts, and signal transduction. Recent data have shown that choline supplementation of rat pups reduces the effects of EtOH on neurobehavior. We sought to determine whether choline could prevent the effect of EtOH on L1 function using a simple experimental system. Methods Cerebellar granule neurons ( CGN) from postnatal day 6 rat pups were cultured with and without supplemental choline, and the effects on L1 signaling, lipid raft distribution, and neurite outgrowth were measured in the presence or absence of EtOH. Results Choline significantly reduced the effect of EtOH on L1 signaling, the distribution of L1 in lipid rafts and L1-mediated neurite outgrowth. However, choline supplemented EtOH-exposed cultures remained significantly different than controls. Conclusions Choline pretreatment of CGN significantly reduces the disruption of L1 function by EtOH, but does not completely return L1 function to baseline. This experimental system will enable discovery of the mechanism of the neuroprotective effect of choline. [ABSTRACT FROM AUTHOR]

Background Due to its profound impact on human development, ethanol (EtOH) teratogenicity is a field of intense study. The complexity of variables that influence the outcomes of embryonic or prenatal EtOH exposure compels the use of animal models in which these variables can be isolated. Methods Numerous model systems have been used in these studies. The zebrafish is a powerful model system, which has seen a recent increase in usage for EtOH studies. Results Those using zebrafish for alcohol studies often face 2 questions: (i) How physiologically relevant are the doses of EtOH administered to zebrafish embryos? and (ii) Will the mechanisms of EtOH teratogenesis be conserved to other model systems and human? Conclusions The current article by Flentke and colleagues () helps to shed important light on these questions and clearly demonstrates that the zebrafish will be a valuable model system with which to understand EtOH teratogenicity. [ABSTRACT FROM AUTHOR]

Background We previously reported that prenatal alcohol-induced deficits in dentate gyrus ( DG) long-term potentiation ( LTP) are ameliorated by the histamine H3 receptor inverse agonist ABT-239. ABT-239 did not enhance LTP in control rats, suggesting that the possibility of a heightened H3 receptor-mediated inhibition of LTP in prenatal alcohol-exposed ( PAE) offspring. Methods To further investigate this mechanism, we examined the effect of methimepip, a selective histamine H3 receptor agonist, on DG granule cell responses and LTP in saccharin control and PAE rats. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 hours each day throughout gestation. Adult male offspring from these dams were anesthetized with urethane and electrodes implanted into the entorhinal cortical perforant path and the DG. Results In control offspring, methimepip reduced the coupling of fast excitatory postsynaptic field potentials to population spikes ( E- S coupling), the probability of glutamate release, as measured by paired-pulse ratio ( PPR) and diminished DG LTP. Similar reductions in E- S coupling and LTP were observed in saline-treated PAE offspring. In contrast to the control group, methimepip did not exacerbate PAE-induced reductions in E- S coupling or LTP. Conclusions While the effects of methimepip in control offspring were consistent with speculation of a PAE-induced enhancement of H3 receptor-mediated inhibition of E- S coupling and LTP, the absence of an added effect of methimepip in PAE offspring could indicate either an inability to further inhibit these responses with methimepip in PAE rats or the presence of more complex regulatory neural interactions with in vivo recordings in PAE rats. Follow-up studies of H3 receptor-mediated responses in DG slice preparations are under way to provide clearer insights into the role of the H3 receptor regulation of excitatory transmission in PAE rats. [ABSTRACT FROM AUTHOR]

Background The first trimester of human development and the equivalent developmental period in animal models is a time when teratogenic ethanol (EtOH) exposure induces the major structural birth defects that fall within fetal alcohol spectrum disorder ( FASD). Previous FASD research employing an acute high dose maternal intraperitoneal EtOH treatment paradigm has identified sensitive periods for a number of these defects. Extending this work, this investigation utilized high resolution magnetic resonance microscopy ( MRM)-based analyses to examine the dysmorphology resulting from maternal dietary EtOH intake occurring during selected first trimester-equivalent time periods. Methods Female C57Bl/6J mice were acclimated to a liquid 4.8% EtOH (v/v)-containing diet, then bred while on standard chow. Dams were again provided the EtOH-containing liquid diet for a period that extended either from the beginning of gestational day ( GD) 7 to the end of GD 11 or from the beginning of GD 12 to the end of GD 16. On GD 17, a subset of fetuses was selected for MRM-based analyses. Group comparisons were made for litter characteristics and gross dysmorphology, as well as whole and regional brain volumes. Results EtOH-induced stage of exposure-dependent structural brain abnormalities were observed. The GD 7 to 11 EtOH-exposed group presented with a significant decrease in cerebellar volume and an increase in septal volume, while GD 12 to 16 EtOH treatment resulted in a reduction in right hippocampal volume accompanied by enlarged pituitaries. Additionally, the GD 12 to 16 EtOH exposure caused a high incidence of edema/fetal hydrops. Conclusions These results illustrate the teratogenic impact of maternal dietary EtOH intake occurring at time periods approximately equivalent to weeks 3 through 6 ( GD 7 to 11 in mice) and weeks 7 through 12 ( GD 12 to 16 in mice) of human gestation, further documenting EtOH's stage of exposure-dependent neuroteratogenic end points and highlighting the vulnerability of selected brain regions during the first trimester. Additionally they suggest that clinical attention should be paid to fetal hydrops as a likely component of FASD. [ABSTRACT FROM AUTHOR]

Background Animal models have demonstrated fetal alcohol-related disruptions in neuroendocrine function in the hypothalamic-pituitary-gonadal axis and downstream effects on pubertal development and sexual behavior in males and females, but little is known about these effects in humans. This study examined whether prenatal alcohol exposure is associated with alterations in testosterone during adolescence and whether it affects timing of pubertal development. Methods The sample consisted of 265 African American adolescents from the Detroit Longitudinal Cohort Study for whom testosterone and/or pubertal development data were available. Subjects were offspring of women recruited at their first prenatal clinic visit to over represent moderate-to-heavy alcohol use, including a 5% random sample of low-level drinkers/abstainers. Mothers were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach and about their smoking and drug use and sociodemographic factors. At age 14 years, adolescents provided salivary samples, which were analyzed for testosterone (pg/ml), self-reported Tanner stages for pubertal development, and age at menarche (females). Results Prenatal alcohol exposure was related to elevated testosterone concentrations for males and females but not to changes in Tanner stages or age at menarche, after controlling for confounders. In regression models stratified by alcohol exposure, the expected relation between testosterone and pubic hair development was seen among males with light-to-no prenatal alcohol exposure, but not among those with moderate-to-heavy prenatal alcohol exposure. This interaction between testosterone and prenatal alcohol exposure was confirmed in multivariable models including an alcohol exposure group × testosterone interaction term and potential confounders. Conclusions This study is the first to show a relation between prenatal alcohol exposure and increased testosterone during adolescence and evidence of decreased testosterone responsiveness in tissues related to pubertal development in humans. Further studies examining androgen receptor expression and other hormonal and cellular factors affecting pubertal development may reveal important mechanisms underlying these teratogenic effects of alcohol exposure. [ABSTRACT FROM AUTHOR]

Background Apoptosis is induced by ethanol (EtOH) in human placental trophoblast cells, possibly disrupting placentation and contributing to intrauterine growth restriction in fetal alcohol spectrum disorder ( FASD). EtOH induces programmed cell death in several embryonic tissues by raising intracellular Ca2+. Therefore, the role of Ca2+ signaling in EtOH-induced apoptosis was examined using human first trimester cytotrophoblast cell lines, examining the hypothesis that apoptosis is dependent on intracellular Ca2+ signaling. Methods Using HTR-8/ SVneo and SW.71 cytotrophoblast cell lines, real-time intracellular Ca2+ concentration was monitored by fluo-4 epifluorescence microscopy and apoptosis was assessed by flow cytometry of cells fluorescently labeled for DNA fragmentation ( TUNEL) and annexin V binding. Results Intracellular Ca2+ concentrations increased synchronously in all cells within 10 seconds of exposure to 50 mM EtOH, but not at lower EtOH concentrations (10 to 25 mM) incapable of inducing apoptosis. Trophoblast cells treated with inhibitors of Ca2+ signaling ( BAPTA- AM, U73122, xestospongin D, BAPTA, SKF-96365) produced no intracellular Ca2+ transients after exposure to 50 mM EtOH and were protected from cell death induced by EtOH. Conclusions EtOH-induced apoptosis in human cytotrophoblast cells, identified by DNA fragmentation and externalized phosphatidylserine, was dependent upon Ca2+ signaling. Both intracellular Ca2+ mobilization and extracellular Ca2+ influx were required, as well as phosphatidylinositol signaling. Inhibition by SKF-96365 suggests that the capacitative Ca2+ entry mechanism that utilizes TRPC channels was activated by EtOH. Apoptosis occurs downstream of Ca2+ signaling in trophoblasts and may contribute to placental insufficiency and poor fetal growth associated with FASD. [ABSTRACT FROM AUTHOR]

Background Accurate identification of prenatal alcohol exposure ( PAE) in the newborn period offers an opportunity for early identification of children at risk of future neurocognitive problems and the implementation of interventional approaches earlier in life. PAE newborn screening by measuring phosphatidylethanol in dried blood spot ( PEth- DBS) cards is feasible, logistically easier, and more cost-efficient compared with other biomarkers. However, the sensitivity and specificity of this method have yet to be established. Methods This prospective cohort study examined validity of PEth- DBS among 28 infants with PAE and 32 controls relative to maternal self-report and other biomarkers. Pregnant women were recruited from a University of New Mexico clinic and followed to early postpartum period. The composite index, which was based on self-reported measures of alcohol use and allowed to classify subjects into PAE and control groups, was the criterion measure used to estimate sensitivity and specificity of PEth- DBS. Results The study included large proportions of patients representing ethnic minorities (7.4% American Indian, 81.7% Hispanic/ Latina), low education (54.2%

Background Prenatal ethanol ( Et OH) and prenatal stress have both been independently shown to induce learning deficits and anxiety behavior in adult offspring. However, the interactive effects of these 2 developmental teratogens on behavioral outcomes have not been systematically evaluated. Methods We combined an established moderate prenatal Et OH consumption paradigm where Long- Evans rat dams voluntarily consume either a 0 or 5% Et OH solution in 0.066% saccharin water (resulting in a mean peak maternal serum Et OH concentration of 84 mg/dl) with a novel prenatal stress paradigm. Pregnant rats were exposed to 3% 2,3,5-trimethyl-3-thiazoline (TMT) for 20 minutes a day on gestational days 13, 15, 17, and 19. Adult female offspring were evaluated for anxiety-like behavior using an elevated plus-maze and hippocampal-sensitive learning using a 2-trial trace conditioning ( TTTC) task. Results TMT exposure produced a threefold increase in maternal serum corticosterone compared to nonexposed, unhandled controls. Neither prenatal exposure paradigm, either alone or in combination, altered maternal weight gain, Et OH consumption, maternal care of litters, litter size, pup birth weight, or pup weight gain up to weaning. Offspring exposed to prenatal stress displayed significant increases in anxiety-like behavior in the elevated plus maze in terms of open arm entries and time spent on the open arms, with no significant effect of prenatal Et OH exposure and no interaction of the 2 prenatal exposures. Performance in a TTTC task revealed a significant effect of prenatal Et OH exposure on freezing behavior on the testing day, with no significant effect of prenatal stress exposure and no interaction of the 2 prenatal exposures. Conclusions While each prenatal exposure independently produced different behavioral outcomes, the results indicate that there is no significant interaction of prenatal Et OH and prenatal stress exposures on learning or anxiety at the exposure levels employed in this dual exposure paradigm. Subsequent studies will examine whether similar outcomes occur in male offspring and whether other measures of anxiety or learning are differentially impacted by these prenatal exposure paradigms. [ABSTRACT FROM AUTHOR]

Background Fetal binge alcohol exposure has been associated with neurobehavioral and cognitive symptoms. This study explored whether binge drinking mainly before recognition of pregnancy predicted high symptom scores on the Strengths and Difficulties Questionnaire ( SDQ) in 5.5-year-old children. Methods In a population-based, longitudinal study representative of pregnant women in Oslo, Norway, questionnaires were answered at 17 and 30 weeks of pregnancy, 6 months after term, and at child age 5.5 years ( n = 1,116, constituting 66% of the original cohort). Logistic regression analyses identified factors predicting high SDQ scores, and multiple regression analyses identified direct effects on the SDQ Total. Results Binge exposure (≥5 standard units per occasion [ SUpo]) during pregnancy week 0 to 6, that is, 0 to 4 weeks after conception, predicted scores in the Abnormal and Borderline range on the SDQ in 5.5-year-olds, after adjusting for other confounding variables. Very early binge exposure less often than once a week predicted high symptom scores on the SDQ Total ( p = 0.05) and Hyperactivity/Inattention (significant), while exposure at least once a week demonstrated a 3- to 5-fold significant increase in high symptom scores on Total, Emotional, and Conduct problems. Reporting ≥8 SUpo had stronger predictive power than reporting 5 to 7 SUpo. The results were not explained by participants reporting major lifetime depression. Other predictive factors, although weaker, were maternal symptoms of depression and anxiety during the child's infancy. High education (mother and father), high income (maternal partner), higher child birth weight, and child female sex reduced the likelihood of high SDQ symptom scores. Path analysis demonstrated early binge exposure to have a direct effect on the SDQ Total score. Conclusions Binge drinking up to 4 weeks after conception had a strong and direct predictive effect on SDQ symptom scores in 5.5-year-olds. These results strongly support the advice to avoid binge drinking when planning pregnancy. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure can contribute to a wide range of neurodevelopmental impairments in children and adults including behavioral and neuropsychiatric disorders. In rhesus monkeys, we examined whether moderate-level prenatal alcohol exposure would alter acoustic startle responses and prepulse inhibition ( PPI) of the acoustic startle. PPI is a highly quantifiable measure of inhibitory neural processes or sensorimotor gating associated with neuropsychiatric disorders. Methods Acoustic startle and PPI of the acoustic startle were tested in 37 adult rhesus monkeys ( Macaca mulatta) from 4 experimental conditions: (i) moderate-level prenatal alcohol-exposed, (ii) prenatally stressed, (iii) moderate-level prenatal alcohol-exposed + prenatally stressed, and (iv) sucrose controls. Results Prenatal alcohol-exposed monkeys showed a higher magnitude of acoustic startle response and disrupted PPI compared with monkeys not exposed to alcohol prenatally. Monkeys in all conditions showed higher hypothalamic-pituitary-adrenocortical ( HPA) axis responses after undergoing the startle procedure, but HPA responses were unrelated to startle response magnitude, latency, or PPI. Conclusions Finding altered PPI in monkeys prenatally exposed to a moderate dose of alcohol suggests that reduced sensorimotor gating is 1 effect of prenatal alcohol exposure. Because reduced sensorimotor gating is observed in many neuropsychiatric disorders, sensorimotor gating deficits could be an aspect of the comorbidity between fetal alcohol spectrum disorder and mental health conditions. [ABSTRACT FROM AUTHOR]

Background Effective treatments for the behavioral and cognitive deficits in children with fetal alcohol spectrum disorders ( FASD) are lacking, and translational approaches using animal models can help develop rational interventions. One such model, binge-like alcohol exposure in neonatal rats during the period of brain development comparable with that of the human third trimester, causes structural and functional damage to the cerebellum and disrupts cerebellar-dependent eyeblink classical conditioning. The eyeblink conditioning deficits first demonstrated in this rat model predicted the similar deficits subsequently demonstrated in children with FASD. Methods The current study extends this translational approach by testing the hypothesis that rehabilitation training involving 20 days of training on traversal of an obstacle course (complex motor learning) would ameliorate the deficits on classical conditioning of eyeblink responses produced by the neonatal alcohol exposure. We have previously shown that this training stimulates cerebellar synaptic plasticity and improves alcohol-induced deficits on motor coordination tasks. Results The current studies found that rehabilitation training significantly attenuated alcohol-induced deficits in acquisition of eyeblink conditioning in females but not in males. These results are consistent with normalization of cerebellar-dependent learning, at least in alcohol-exposed females. Conclusions These findings extend previous studies in this model suggesting that rehabilitation of adolescents with FASD using training with complex motor learning tasks could be effective in ameliorating functional impairments associated with cerebellar damage. Eyeblink classical conditioning deficits are now well documented in children with FASD and could serve as an evaluation measure to continue to develop therapeutic interventions such as complex motor learning. [ABSTRACT FROM AUTHOR]

Early identification of and intervention for fetal alcohol spectrum disorder ( FASD) has been shown to optimize outcomes for affected individuals. Detecting biomarkers of prenatal alcohol exposure ( PAE) in neonates may assist in the identification of children at risk of FASD enabling targeted early interventions. Despite these potential benefits, complicated ethical issues arise in screening for biomarkers of PAE and these must be addressed prior to the implementation of screening programs. Here, we identify and comment, based on a North American perspective, on concerns raised in the current ethical, social, and legal literature related to meconium screening for PAE. Major ethical concerns revolve around the targeting of populations for PAE screening, consent and respect for persons, stigma and participation rates, the cost-benefit analysis of a screening program, consequences of false-positive and false-negative test results, confidentiality and appropriate follow-up to positive screen results, and the use of screen results for criminal prosecution. We identify gaps in the literature on screening for PAE, most notably related to a lack of stakeholder perspectives (e.g., parents, healthcare providers) about screening and the ethical challenges it presents. [ABSTRACT FROM AUTHOR]

Background Eye movement tasks provide a simple method for inferring structural or functional brain deficits in neurodevelopmental disorders. Oculomotor control is impaired in children with fetal alcohol spectrum disorder ( FASD), yet the neuroanatomical substrates underlying this are not known. Regions of white matter have been shown by diffusion tensor imaging ( DTI) to be different in FASD and thus may play a role in the delayed saccadic eye movements. The objective of this study was to correlate oculomotor performance with regional measures of DTI-derived white matter anisotropy in children with FASD. Methods Fourteen children (8 to 13 years) with FASD were recruited for oculomotor assessment and DTI. Eye movement control was evaluated using the pro- and antisaccade tasks, in which subjects look at ( prosaccade) or away from ( antisaccade) a peripheral target. Saccadic reaction time ( SRT; time for subjects to move their eyes after the target appears) and direction errors (saccades made in the incorrect direction relative to the instruction) were measured and correlated to fractional anisotropy ( FA) on a voxel-by-voxel basis across the whole brain white matter. Results A significant positive correlation was observed between antisaccade SRT and FA in a large cluster containing anterior and posterior sections of the corpus callosum just to the right of the midline; prosaccade SRT and FA correlated positively in the genu of the corpus callosum and the right inferior longitudinal fasciculus (ILF), and correlated negatively in the left cerebellum. Conclusions The negative correlation for prosaccade SRT and cerebellum demonstrated that individuals with slower reaction times had lower FA values relative to their faster responding counterparts, a finding that implicates cerebellar dysfunction as a significant contributor to deficits in oculomotor control. The higher FA in the corpus callosum and ILF corresponding to longer reaction times for both pro- and antisaccade was opposite to what was expected, but nonetheless implies that altered brain structure in these regions underlies deficits in oculomotor control. [ABSTRACT FROM AUTHOR]

Background Heavy alcohol consumption during pregnancy negatively impacts the physical growth of the fetus. Although the deleterious effects of alcohol exposure during late gestation on fetal brain development are well documented, little is known about the effect on fetal bone mechanical properties or the underlying mechanisms. The purpose of this study was to investigate the effects of late gestational chronic binge alcohol consumption and alcohol-induced acidemia, a critical regulator of bone health, on functional properties of the fetal skeletal system. Methods Suffolk ewes were mated and received intravenous infusions of saline or alcohol (1.75 g/kg) over 1 hour on 3 consecutive days per week followed by 4 days without treatment beginning on gestational day ( GD) 109 and concluding on GD 132 (term = 147 days). The acidemia group was exposed to increased inspired fractional concentrations of CO2 to closely mimic the alcohol-induced decreases in maternal arterial p H seen in the alcohol group. Results Fetal femurs and tibias from the alcohol and acidemia groups were ~3 to 7% shorter in length compared with the control groups ( p < 0.05). Three-point bending procedure demonstrated that fetal femoral ultimate strength ( MPa) for the alcohol group was decreased ( p < 0.05) by ~24 and 29%, while the acidemia group exhibited a similar decrease ( p < 0.05) of ~32 and 37% compared with the normal control and saline control groups, respectively. Bone extrinsic and intrinsic mechanical properties including maximum breaking force ( N) and normalized breaking force ( N/kg) of fetal bones from the alcohol and acidemia groups were significantly decreased ( p < 0.05) compared with both control groups. Conclusions We conclude that late gestational chronic binge alcohol exposure reduces growth and impairs functional properties of the fetal skeletal system and that the repeated episodes of alcohol-induced maternal acidemia may be at least partially responsible for these effects. [ABSTRACT FROM AUTHOR]

Background During late prenatal and early postnatal life, the reproductive system in males undergoes an extensive series of physiological and morphological changes. Prenatal ethanol ( EtOH) exposure has marked effects on the development of the reproductive system, with long-term effects on function in adulthood. The present study tested the hypothesis that prenatal EtOH exposure will delay the onset of spermatogenesis. Methods Development of the seminiferous tubules and the onset of spermatogenesis were examined utilizing a rat model of fetal alcohol spectrum disorder ( FASD). Male offspring from ad libitum-fed control (C), pair-fed ( PF), and EtOH-fed (prenatal alcohol exposure [PAE]) dams were terminated on postnatal ( PN) days 5, 15, 18, 20, 25, 35, 45, and 55, to investigate morphological changes through morphometric analysis of the testes from early neonatal life through young adulthood. Results PAE males had lower relative (adjusted for body weight) testis weights compared with PF and/or C males from PN15 through puberty ( PN45). In addition, fewer gonocytes (primordial germ cells) were located on the basal lamina on PN5, while more of those touching the basal lamina were dividing in PAE compared with PF and C males, suggesting delayed cell division and migration processes. As well, the percentage of tubules with open lumena was lower in PAE compared with PF and C males on PN18 and 20, and PAE males had fewer primary spermatocytes per tubule on PN18 and round spermatids per tubule on PN25 compared with C males. Finally, the percentage of tubules at stages VII and VIII, when mature spermatids move to the apex of the epithelium and are released, was lower in PAE compared with PF and/or C males in young adulthood ( PN55). Conclusions Maternal EtOH consumption appears to delay both reproductive development and the onset of spermatogenesis in male offspring, with effects persisting at least until young adulthood. [ABSTRACT FROM AUTHOR]

Background Fetal alcohol syndrome and related disorders (commonly referred to as fetal alcohol spectrum disorder, or FASD) cause significant hardships to the individuals affected. Previously, histological studies in animals have characterized developmental cerebral cortical abnormalities that result from prenatal ethanol ( EtO H) exposure. Additionally, magnetic resonance imaging ( MRI) studies have identified abnormalities associated with fetal EtO H exposure in the cerebral cortices of human children and adolescents. However, there is still a need to bridge the gap between human MRI studies and animal histological studies. The goal of the research presented here was to perform postmortem MRI experiments on rodents, during time periods relative to late human gestation through adulthood, to characterize anomalies associated with FASD throughout development. Additionally, by determining how histologically identified abnormalities are manifest in MRI measurements specifically during the critical early time points, neuroimaging-based biomarkers of FASD can potentially be identified at much earlier ages in humans, thus reducing the impact of these disorders. Methods Cerebral cortical volume, thickness, and surface area were characterized by ex vivo MRI in Long-Evans rat pups born from dams that were EtO H-treated, maltose/dextrin-treated, or untreated throughout gestation at 6 developmental time points (postnatal day [ P] 0, P3, P6, P11, P19, and P60). Results Brain volume, isocortical volume, isocortical thickness, and isocortical surface area were all demonstrated to be reduced following prenatal exposure to EtO H. Significant differences among the treatment groups were observed throughout the range of time points studied, allowing for a comprehensive view of FASD influenced MRI outcomes throughout development. Isocortical surface area and isocortical thickness results contributed independent information important to interpreting effects of prenatal EtO H exposure on cerebral cortical development. Additionally, regional patterns in cortical thickness differences suggested primary sensory areas were particularly vulnerable to gestational EtO H exposure. Conclusions Structural MRI measurements were in accordance with previous histological studies performed in animal models of FASD. In addition to establishing a summary of MRI outcomes throughout development in FASD, this research suggests that MRI techniques are sufficiently sensitive to detect neuroanatomical effects of fetal EtO H exposure on development of the cerebral cortex during the period of time corresponding to late gestation in humans. Importantly, this research provides a link between animal histological data and human MRI data. [ABSTRACT FROM AUTHOR]

Background Children with heavy prenatal alcohol exposure often meet criteria for attention-deficit/hyperactivity disorder ( ADHD). ADHD research has examined subtype differences in symptomatology, including sluggish cognitive tempo ( SCT). This construct is defined by behavioral symptoms including hypoactivity and daydreaming and has been linked to increased internalizing behaviors. The current study examined whether similar findings are displayed in children with prenatal alcohol exposure. Methods As part of a multisite study, caregivers of 272 children (8 to 16 years) completed the SCT Scale and Child Behavior Checklist ( CBCL). Four groups were included: alcohol-exposed children with ADHD ( ALC+; n = 75), alcohol-exposed children without ADHD ( ALC−; n = 35), nonexposed children with ADHD ( ADHD; n = 60), and nonexposed children without ADHD ( CON; n = 102). SCT and CBCL scores were analyzed using 2 (exposure) × 2 ( ADHD) analyses of variance. Pearson's correlations measured the relationships between SCT, CBCL, and Full Scale IQ ( FSIQ). Discriminant function analysis examined whether SCT items could accurately classify groups. Results Analyses revealed significant main effects of exposure and ADHD on SCT and internalizing and externalizing scores and significant interaction effects on SCT and internalizing scores. SCT significantly correlated with internalizing, externalizing, and attention ratings in all groups and with FSIQ in ALC+. Discriminant function analysis indicated that specific SCT items could distinguish ALC− from CON. Conclusions Alcohol-exposed children exhibited elevated SCT scores. Elevations were related to increased parent ratings of internalizing and externalizing behaviors and attention. These findings are observed in alcohol-exposed children regardless of ADHD symptoms and specific SCT items proved useful in distinguishing exposed children, suggesting clinical utility for this measure in further defining the neurobehavioral profile related to prenatal alcohol exposure. [ABSTRACT FROM AUTHOR]