Search

Background: Prenatal alcohol exposure poses significant risks to offspring mental health. However, the interplay between genetic predispositions to mental health disorders and prenatal alcohol exposure remains incompletely understood, limiting our ability to develop effective interventions for these conditions. Methods: Data from the Adolescent Brain and Cognitive Development (ABCD) Study were analyzed to explore associations between polygenic risk scores (PRS) for mental disorders and maternal alcohol consumption during pregnancy. Logistic regression and structural equation modeling were utilized to assess these relationships. Results: Maternal alcohol consumption after pregnancy awareness was significantly associated with an increased genetic risk for specific mental health disorders, particularly bipolar disorder in offspring. The relationship between maternal alcohol consumption and mental health outcomes was influenced by polygenic risk scores, with both externalizing and internalizing problems being affected. Conclusions: Our findings highlight the specific interaction between increased genetic risk for bipolar disorder and prenatal alcohol exposure in shaping offspring mental health outcomes. The significant associations we observed underscore the importance of considering both polygenic risk scores and prenatal alcohol exposure when assessing mental health risks in children. These insights emphasize the need for targeted interventions that address both genetic predispositions and environmental exposures to better understand and mitigate the impact on offspring mental health. [ABSTRACT FROM AUTHOR]

Background: The Developmental Origins of Health and Disease Hypothesis (DOHaD) suggests prenatal alcohol exposure (PAE) should have implications for adult physical and mental health. Since the health profile of older adults with PAE and diagnoses of fetal alcohol spectrum disorder (FASD) is unknown, the current study evaluates self‐reported health problems of midlife adults with and without a history of PAE to describe these outcomes. Methods: Participants (N = 357) recruited from longitudinal cohorts in Atlanta, GA and Seattle, WA completed a health survey assessing a range of physical conditions. Initial analysis compared the frequency of conditions between alcohol‐exposed and nonexposed groups. To identify patterns within groups, 10 problem areas were subjected to latent class analysis (LCA). Finally, the direct effect of PAE on health outcomes was evaluated using multilevel modeling, controlling for effects of other factors. Results: Compared with unexposed controls, individuals with PAE reported significantly higher frequencies of problems with hearing, dentition, heart, cancer, gastritis, kidney stones, bladder, diabetes, thyroid, skin, and seizures. LCA found that controls yielded two classes, with 45% reporting sleep and vision problems and 55% reporting sleep, vision, cardiovascular, endocrine, immune, and dental problems. The PAE group yielded three classes, with 13% endorsing few health problems, 43% reporting sleep, vision, immune, and dental problems, and 43% reporting sleep, vision, cardiovascular, urinary, endocrine, skin, immune, dental, and gastrointestinal problems. With multivariate analysis, controlling for other influences, PAE was associated directly with hearing, urinary, dental, and gastrointestinal problems. A similar pattern was found for alcohol‐exposed individuals who did and did not meet criteria for fetal alcohol syndrome (FAS). Discussion: Patients affected by alcohol may report greater frequency and range of health adversity. That PAE was only uniquely associated with a limited set of problems suggests that many health outcomes in midlife result from an initial vulnerability potentiated by postnatal stress resulting from other associated factors. [ABSTRACT FROM AUTHOR]

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were assessed by quantitative western blot. Novel SERT isoforms were sequenced and analyzed. Opioid-exposed but not EtOH-exposed maternal placentas showed SERT cleavage and formation of new SERT fragments (isoforms). Alcohol-exposed cases showed reduced SERT levels. Antibodies to the N-terminal SERT region did not recognize either of the two cleavage products, while antibodies to the central and C-terminal regions recognized both bands. The secondary band seen in the opioid group may represent a hypophosphorylated SERT fragment. These changes in SERT modifications and expression may result in altered fetal brain serotonergic neurotransmission, which could have neurodevelopmental implications. [ABSTRACT FROM AUTHOR]

Prenatal ethanol exposure can cause a broad range of abnormalities in newborns known as Fetal Alcohol Spectrum Disorder (FASD). Despite significant progress in understanding the disease mechanisms of FASD, there remains a strong global need for effective therapies. To evaluate the therapeutic potential of sulforaphane (SFN), an active compound extracted from cruciferous vegetables, in preventing FASD, ethanol-exposed zebrafish embryos were pretreated, co-treated, or post-treated with various concentrations of SFN. The FASD-like morphological features, survival rate, hatching rate, and vascular development were then assessed in the zebrafish embryos. It was found that pretreatment with 2 μM SFN during 3–24 hpf had no noticeable protective effects against teratogenicity induced by subsequent 1.5% ethanol exposure during 24–48 hpf. In contrast, co-treatment with 2 μM SFN and 1.5% ethanol during 3–24 hpf significantly alleviated a range of ethanol-induced malformations, including reduced body length, small eyes, reduced brain size, small otic vesicle, small jaw, and pericardial edema. Post-treatment with 3 μM SFN for 4 days following 1.5% ethanol exposure during 3–24 hpf also significantly reduced the characteristic features of FASD, decreasing the mortality rate and restoring body length, eye size, brain size, and otic vesicle circumference. Moreover, we found that ethanol, even at a low dose (0.5%), causes vascular development deficit in the zebrafish embryos, which were also largely rescued by SFN treatment. These data indicated that SFN has great potential to be used in the prevention and treatment of FASD. [ABSTRACT FROM AUTHOR]

Background: Individuals with fetal alcohol spectrum disorder (FASD) experience complex needs that often necessitate support from multiple systems. There is growing evidence that people with FASD may benefit from integrated service delivery (ISD), but little is known about ISD elements and processes for this population. Method: Using a multi‐method approach involving a literature review, analysis of programme data, and staff interviews, we examined how ISD is enacted at a rural Canadian FASD centre, and identified facilitators, barriers, and potential impacts of ISD at the centre. Results: We describe key elements of integrated FASD programming and identify important contextual factors and themes related to ISD barriers, facilitators, and impacts: (1) connection, (2) freedom and autonomy, (3) client‐centred care, (4) learning and growth, (5) and reframing expectations. Conclusions: This study may help to inform a roadmap for enhancing FASD service delivery and guiding FASD research and policy in Canada and beyond. [ABSTRACT FROM AUTHOR]

Background: A growing body of literature links prenatal mood and substance use to children's cognitive and behavioral development. The relative contribution of these risk factors on children's executive function (EF) in the context of socioeconomic adversities needs further evaluation. To address this gap, we investigated the role of prenatal maternal anxiety and depression on childhood EF, specifically inhibitory control and working memory, within the context of socioeconomic adversities and prenatal substance use. We hypothesized that higher maternal mood symptoms, higher persistent prenatal drinking and smoking, and lower socioeconomic status would be associated with lower EF skills during early childhood. Methods: We used data from 334 mother–child dyads followed prospectively through pregnancy and the offspring's childhood. Prenatal maternal depression and anxiety were assessed via standardized questionnaires. Prenatal alcohol and tobacco consumption were assessed via a timeline follow-back interview. The EF touch battery assessed child inhibitory control and working memory at 3–5 years of age (4.76 ± 0.58 years, 171 females). Separate linear regression models were used to estimate the association of prenatal tobacco, alcohol, anxiety, and depression exposure with our two components of child EF, inhibitory control and working memory, while adjusting for gestational age, sex, and age at assessment. The following variables were also included as covariates: maternal educational achievement, employment status, parity, and household crowding index. Results: Children of mothers with high trait anxiety scores had reduced inhibitory control compared to children of mothers without trait anxiety or depression (β = -0.12, 95% CI:-0.22,-0.01). Children of mothers in the moderate to high continuous smoking group showed lower inhibitory control (β = − 0.19, 95% CI:-0.38,-0.01) compared to children of mothers in the none smoking group. Additionally, lower maternal education and higher household crowding were each associated with reduced inhibitory control. We found no significant association between prenatal maternal depression, anxiety, or socioeconomic factors with working memory. Conclusions: These results underscore the need for comprehensive context-specific intervention packages, including mental health support for women to promote healthy inhibitory control development in children. [ABSTRACT FROM AUTHOR]

This article presents information on how the child welfare (CW) system informs caregivers about prenatal substance exposure (PSE) and related concerns, and how those caregivers communicate back to CW about PSE issues. Focus group and interview data for this qualitative study were collected in Fall 2019 and Spring 2020 from two states, each including four local (regional/county) CW agency sites. Caregivers were eligible for inclusion if they had cared for a child served by one of the sites, with priority for those who had cared for a child with known PSE or related special needs, resulting in a total of 44 caregivers. Of these, 41 had served as non-relative caregivers, while 10 had served as informal or formal kinship caregivers. Caregivers emphasized the need for more information-sharing from CW professionals related to the histories and needs of the children in their care. Thematic findings underscore that having more information about the general impact of PSE and exposure status of individual children could better prepare caregivers. CW agencies can use these findings to inform training, information sharing, and caregiver support.When caregivers have relevant information about the children in their care, outcomes for development, family preservation, and support can be improved. [ABSTRACT FROM AUTHOR]

Perinatal risk factors are implicated in the development of psychopathology, but their role in bipolar disorder (BD) and hypomania is unclear. Using data from a prospective community cohort, this is the first study to investigate the association between a range of perinatal risk factors, hypomanic symptoms, and 'high-risk' for BD in the general population. Parent report of perinatal events were available for 26,040 eighteen-month-olds from the Twins Early Development Study. Subsequent self-report hypomania was measured at ages 16 (Hypomania Checklist-16; N = 2943) and 26 (Mood Disorders Questionnaire; N = 7748). Participants were categorised as 'high-risk' for BD using established classifications. Linear and logistic regressions were conducted within a generalised estimating equations framework to account for relatedness in the sample. Prenatal alcohol exposure (β = 0.08, SE = 0.04, p =.0002) and number of alcohol units consumed (β = 0.09, SE = 0.02, p <.0001) were associated with hypomanic symptoms at age 16, and number of alcohol units (OR = 1.13, 95 % CI:1.06–1.21, p =.0003) and maternal stress (OR = 1.68, 95 % CI:1.21–2.34, p =.002) were associated with 'high-risk' for BD age 16. Prenatal tobacco exposure (β = 0.10, SE = 0.04, p <.0001) and number of cigarettes smoked (β = 0.10, SE = 0.01, p <.0001) were associated with hypomanic symptoms and 'high-risk' for BD at age 26, although these result were attenuated controlling for parental psychiatric history. Familial confounding could not be fully adjusted for. Rater reports include some biases. These findings show perinatal risk factors to be associated with subclinical hypomania and 'high-risk' for BD. Future work should explore the mechanisms underlying these longitudinal associations, which could shed light on prevention and intervention efforts. • Prenatal alcohol and tobacco exposure were associated with hypomanic symptoms. • Prenatal alcohol exposure was linked to 'high-risk' for bipolar disorder at age 16. • Maternal stress during pregnancy was linked to 'high-risk' at age 16. • Prenatal tobacco exposure was linked to 'high-risk' for bipolar disorder at age 26. • Prenatal tobacco exposure's association with 'high-risk' may be due to confounders. [ABSTRACT FROM AUTHOR]

Background/Objectives: Malnutrition is a significant concern in paediatric populations, particularly among children with neurodevelopmental disorders such as foetal alcohol spectrum disorder (FASD). This study aimed to examine macronutrient and micronutrient imbalances and assess the nutritional status of a group of patients with FASD. Methods: This study involved an analysis of the serum levels of key nutrients in a group of children diagnosed with FASD. Macronutrients and micronutrients were measured to identify any imbalances, including vitamin D, B12, E, A, albumin, and serum protein, among others. Results: The study found a high prevalence of vitamin D deficiency among the patients. Additionally, elevated serum concentrations of micronutrients such as vitamin B12, E, and A were observed in 8%, 7%, and 19% of patients, respectively. Macronutrient imbalances were noted, including high levels of albumin and serum protein, indicating a possible metabolic disturbance. Unexpectedly, high rates of hypercholesterolemia were observed, raising concerns about an increased risk of metabolic syndrome in this population. Conclusions: These findings suggest that the principal issue among patients with FASD is an altered metabolism rather than nutritional deficiencies. Potential causes of these abnormalities could include oxidative stress and changes in body composition. The results underline the need for further research to better understand the unique nutritional challenges in children with FASD and to guide the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

While benchmark dose (BMD) methodology is well‐established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two‐dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose–response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionFetal alcohol spectrum disorder (FASD) is a highly prevalent neurodevelopmental disability caused by prenatal alcohol exposure (PAE). Healthcare professionals (HCP) are key in prevention, diagnosis, and supporting individuals with FASD. This study explored the FASD knowledge, attitudes, and practices among HCP in Aotearoa, New Zealand (NZ).We conducted an online survey of HCP working in NZ. The survey measured knowledge of FASD, beliefs and attitudes about FASD, experiences and practices with FASD and future training.Of the 96 participants, more than 90% self-reported a good or very good understanding of FASD, and around half had a patient with FASD. However, less than half felt prepared to support someone with FASD. Participants identified lack of professional training, services, and funding as barriers to support individuals with FASD.We identified a need to provide training and promote awareness and recognition for HCP to support individuals with FASD. [ABSTRACT FROM AUTHOR]

Changes in maternal gut microbiota due to stress and/or ethanol exposure can have lasting effects on offspring's health, particularly regarding immunity, inflammation response, and susceptibility to psychiatric disorders. The literature search for this review was conducted using PubMed and Scopus, employing keywords and phrases related to maternal stress, ethanol exposure, gut microbiota, microbiome, gut–brain axis, diet, dysbiosis, progesterone, placenta, prenatal development, immunity, inflammation, and depression to identify relevant studies in both preclinical and human research. Only a limited number of reviews were included to support the arguments. The search encompassed studies from the 1990s to the present. This review begins by exploring the role of microbiota in modulating host health and disease. It then examines how disturbances in maternal microbiota can affect the offspring's immune system. The analysis continues by investigating the interplay between stress and dysbiosis, focusing on how prenatal maternal stress influences both maternal and offspring microbiota and its implications for susceptibility to depression. The review also considers the impact of ethanol consumption on gut dysbiosis, with an emphasis on the effects of prenatal ethanol exposure on both maternal and offspring microbiota. Finally, it is suggested that maternal gut microbiota dysbiosis may be significantly exacerbated by the combined effects of stress and ethanol exposure, leading to immune system dysfunction and chronic inflammation, which could increase the risk of depression in the offspring. These interactions underscore the potential for novel mental health interventions that address the gut–brain axis, especially in relation to maternal and offspring health. [ABSTRACT FROM AUTHOR]

Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a 'suggested clinical immobilization test'. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35–15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37–8.64]), and RLS (OR: 7.00, p = 0.01, [1.49–32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82–12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54–22.1]), RLS (OR: 4.05, p = 0.01, [1.33–12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17–6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors. [ABSTRACT FROM AUTHOR]

Introduction: Tobacco and alcohol are the two most common substances used during pregnancy, and both can disrupt neurodevelopment, resulting in cognitive and behavioral deficits including language difficulties. Previous studies show that children with prenatal substance exposure exhibit microstructural alterations in major white matter pathways, though few studies have investigated the impact of prenatal substance exposure on white matter microstructure and language skills during the toddler years. Methods: In this study, 93 children (34 exposed to alcohol and/or tobacco) aged 23 years from the Drakenstein Child Health Study, South Africa, completed Expressive and Receptive Communication assessments from the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and underwent diffusion MRI scans. Diffusion images were preprocessed, and 11 major white matter tracts were isolated. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted for each white matter tract. Linear regression was used to examine differences between the tobacco/alcohol exposed group and unexposed controls for FA, MD, and language scores, as well as relationships between brain metrics and language. There were no significant group differences in language scores or FA. Results: Children with alcohol or tobacco exposure had lower average MD in the splenium of the corpus callosum compared to unexposed controls. Significant interactions between prenatal substance exposure and language scores were seen in 7 tracts but did not survive multiple comparisons correction. Discussion: Our findings show that prenatal alcohol and/or tobacco exposure appear to alter the relationship between white matter microstructure and early language skills in this population of toddlers, potentially laying the basis of language deficits observed later in older children with prenatal substance exposure, which may have implications for learning and interventions. [ABSTRACT FROM AUTHOR]

Alcohol consumption in pregnancy can affect genome regulation in the developing offspring but results have been contradictory. We employed a physiologically relevant murine model of short-term moderate prenatal alcohol exposure (PAE) resembling common patterns of alcohol consumption in pregnancy in humans. Early moderate PAE was sufficient to affect site-specific DNA methylation in newborn pups without altering behavioural outcomes in adult littermates. Whole-genome bisulfite sequencing of neonatal brain and liver revealed stochastic influence on DNA methylation that was mostly tissue-specific, with some perturbations likely originating as early as gastrulation. DNA methylation differences were enriched in non-coding genomic regions with regulatory potential indicative of broad effects of alcohol on genome regulation. Replication studies in human cohorts with fetal alcohol spectrum disorder suggested some effects were metastable at genes linked to disease-relevant traits including facial morphology, intelligence, educational attainment, autism, and schizophrenia. In our murine model, a maternal diet high in folate and choline protected against some of the damaging effects of early moderate PAE on DNA methylation. Our studies demonstrate that early moderate exposure is sufficient to affect fetal genome regulation even in the absence of overt phenotypic changes and highlight a role for preventative maternal dietary interventions. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) refers to the exposure of the developing fetus due to alcohol consumption during pregnancy and can have life-long consequences for learning, behavior, and health. Understanding the impact of PAE on the developing brain manifests challenges due to its complex structural and functional attributes, which can be addressed by leveraging machine learning (ML) and deep learning (DL) approaches. While most ML and DL models have been tailored for adult-centric problems, this work focuses on applying DL to detect PAE in the pediatric population. This study integrates the pre-trained simple fully convolutional network (SFCN) as a transfer learning approach for extracting features and a newly trained classifier to distinguish between unexposed and PAE participants based on Tl-weighted structural brain magnetic resonance (MR) scans of individuals aged 2-8 years. Among several varying dataset sizes and augmentation strategy during training, the classifier secured the highest sensitivity of 88.47% with 85.04% average accuracy on testing data when considering a balanced dataset with augmentation for both classes. Moreover, we also preliminarily performed explainability analysis using the Grad-CAM method, highlighting various brain regions such as corpus callosum, cerebellum, pons, and white matter as the most important features in the model's decision-making process. Despite the challenges of constructing DL models for pediatric populations due to the brain's rapid development, motion artifacts, and insufficient data, this work highlights the potential of transfer learning in situations where data is limited. Furthermore, this study underscores the importance of preserving a balanced dataset for fair classification and clarifying the rationale behind the model's prediction using explainability analysis. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorders (FASD) are a group of conditions that occur due to prenatal alcohol exposure (PAE), which impacts physical, behavioral, and cognitive ability. The literature demonstrates that healthcare professionals lack knowledge and understanding of FASD, resulting in children and young people (CYP) often getting misdiagnosed with neurodevelopmental disorders or the diagnosis of FASD missed, increasing their risk of experiencing secondary mental health difficulties. Child and Adolescent Mental Health Services (CAMHS) are the commissioned service to diagnose neurodevelopmental conditions and support CYP with mental health difficulties, therefore, it is likely that CYP with probable or diagnosed FASD will present in CAMHS. There is currently no research exploring the awareness and understanding of FASD within these services. Methods: Constructivist grounded theory was utilized to explore the barriers and facilitators clinicians experience when assessing and supporting CYP with probable or diagnosed FASD within CAMHS. A sample of 12 CAMHS clinicians from an NHS Mental Health Trust situated in the Northeast of England were interviewed. Interviews were transcribed and analyzed and grounded theory techniques were utilized to generate an end model. Results: The end model was developed on a box analogy with four categories. 'Unable to Open the Box' captures barriers CAMHS clinicians experience when exploring FASD, 'Things that Help Open the Box' captures facilitators CAMHS clinicians experience when exploring FASD, 'Asking Others About the Box' captures systemic influences CAMHS clinicians may experience when exploring FASD, and 'Making the Box Easier to Open in Future' captures how we can support CAMHS clinicians moving forward to explore FASD. Conclusions: This model provides new insights into the barriers and facilitators CAMHS clinicians experience when assessing and supporting CYP with probable or diagnosed FASD, highlighting key clinical implications. Recommendations for future research are outlined to expand the knowledge base for this area. [ABSTRACT FROM AUTHOR]

Aims Fetal alcohol spectrum disorders (FASDs) impact up to 0.8% of the global population. However, cardiovascular health outcomes in adult patients, along with predictive biomarkers for cardiac risk stratification, remain unknown. Our aim was to utilize a longitudinal cohort study in an animal model to evaluate the impact of embryonic alcohol exposure (EAE) on cardiac structure, function, and transcriptional profile across the lifespan. Methods and results Using zebrafish, we characterized the aftereffects of EAE in adults binned by congenital heart defect (CHD) severity. Chamber sizes were quantified on dissected adult hearts to identify structural changes indicative of cardiomyopathy. Using echocardiography, we quantified systolic function based on ejection fraction and longitudinal strain, and diastolic function based on ventricular filling dynamics, ventricular wall movement, and estimated atrial pressures. Finally, we performed RNA-sequencing on EAE ventricles and assessed how differentially expressed genes (DEGs) correlated with cardiac function. Here, we demonstrate that EAE causes cardiomyopathy and diastolic dysfunction through persistent alterations to ventricular wall structure and gene expression. Following abnormal ventricular morphogenesis, >30% of all EAE adults developed increased atrial-to-ventricular size ratios, abnormal ventricular filling dynamics, and reduced myocardial wall relaxation during early diastole despite preserved systolic function. RNA-sequencing of the EAE ventricle revealed novel and heart failure-associated genes (slc25a33, ankrd9, dusp2, dusp4, spry4, eya4, and edn1) whose expression levels were altered across the animal's lifespan or correlated with the degree of diastolic dysfunction detected in adulthood. Conclusion Our study identifies EAE as a risk factor for adult-onset cardiomyopathy and diastolic dysfunction, regardless of CHD status, and suggests novel molecular indicators of adult EAE-induced heart disease. [ABSTRACT FROM AUTHOR]

Intrauterine alcohol exposure delays bone maturation and intensifies osteoporosis and fracture risk. As most studies emphasize the neurological aspects of intrauterine alcohol exposure, there is a lack of research on the implications pertaining to osseous tissue. Previous studies investigated these effects in fetuses, with limited studies on postnatal life. Postnatal studies are crucial since peak bone growth occurs during adolescence. This study aimed at assessing the effects of prenatal alcohol exposure on the humerus proximal and distal growth plate chondrocytes in 3-week-old rats. Sprague Dawley rats (n=9) were assigned to either the ethanol group (n=3), saline (n=3), and untreated (n=3) group and time-mated. Once pregnant, as confirmed by the presence of a copulation plug, the former 2 groups were treated with 0.015 ml/g of 25.2% ethanol and 0.9% saline. The untreated group received no treatment. The left humeri belonging to 6 pups per group were used. Serial sections were cut with a microtome at 5 µm thickness. These sections were stained with haematoxylin and eosin for assessment of normal morphology or immunolabeled with anti-Ki-67 and transforming growth factor β-1 (TGFβ-1) antibody. Prenatal alcohol exposure adversely effected the growth plate sizes and the number of cells in the proliferative zone. Fewer TGFβ-1 immunopositive and proliferative chondrocytes were found using the anti-Ki-67 antibody. This may explain the growth retardation in offspring exposed to gestational alcohol, showing that gestational alcohol exposure inhibits cell proliferation, aiding the diminished stature. [ABSTRACT FROM AUTHOR]

Benchmark dose analysis aims to estimate the level of exposure to a toxin associated with a clinically significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop a novel approach for calculating benchmark dose lower limits based on an approximate pivot for the nonlinear equation solved by the estimated benchmark dose. The favorable properties of this approach compared to the Delta method and a parameteric bootstrap are discussed. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from six NIH-funded longitudinal cohort studies. Software to reproduce the results in this paper is available online and makes use of the novel semibmd  R package, which implements the methods in this paper. [ABSTRACT FROM AUTHOR]

Exposure to alcohol during fetal development can lead to structural and functional abnormalities in the cerebellum, a brain region responsible for motor coordination, balance, and specific cognitive functions. In this systematic review, we comprehensively analyze a vast body of research conducted on vertebrate animals and humans over the past 13 years. We identified studies through PubMed and screened them following PRISMA guidelines. Data extraction and quality analysis were conducted using Covidence systematic review software. A total of 108 studies met our inclusion criteria, with the majority (79 studies) involving vertebrate animal models and 29 studies focusing on human subjects. Animal models included zebrafish, mice, rats, sheep, and non-human primates, investigating the impact of ethanol on cerebellar structure, gene/protein expression, physiology, and cerebellar-dependent behaviors. Additionally, some animal studies explored potential therapeutic interventions against ethanol-induced cerebellar damage. The human studies predominantly adopted cohort designs, exploring the effects of prenatal alcohol exposure on cerebellar structure and function. Certain human studies delved into innovative cerebellar-based diagnostic approaches for fetal alcohol spectrum disorder (FASD). The collective findings from these studies clearly indicate that the cerebellum is involved in various neurophysiological deficits associated with FASD, emphasizing the importance of evaluating both cerebellar structure and function in the diagnostic process for this condition. Moreover, this review sheds light into potential therapeutic strategies that can mitigate prenatal alcohol exposure-induced cerebellar damage. • The cerebellum is an important target of prenatal ethanol exposure. • We systematically analyzed animal and human research in this area. • PRISM guidelines for systematic review were followed. • A total of 79 animal studies and 29 human studies met inclusion criteria. • Cerebellar dysfunction contributes to many prenatal ethanol-induced neurophysiological deficits. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) affects neurodevelopment in over 59 million individuals globally. Prior studies using dichotomous categorization of alcohol use and comorbid substance exposures provide limited knowledge of how prenatal alcohol specifically impacts early human neurodevelopment. In this longitudinal cohort study from Cape Town, South Africa, PAE is measured continuously—characterizing timing, dose, and drinking patterns (i.e., binge drinking). High-density electroencephalography (EEG) during a visual-evoked potential (VEP) task was collected from infants aged 8 to 52 weeks with prenatal exposure exclusively to alcohol and matched on sociodemographic factors to infants with no substance exposure in utero. First trimester alcohol exposure related to altered timing of the P1 VEP component over the first 6 months postnatally, and first trimester binge drinking exposure altered timing of the P1 VEP components such that increased exposure was associated with longer VEP latencies while increasing age was related to shorter VEP latencies (n = 108). These results suggest alcohol exposure in the first trimester may alter visual neurodevelopmental timing in early infancy. Exploratory individual-difference analysis across infants with and without PAE tested the relation between VEP latencies and myelination for a subsample of infants with usable magnetic resonance imaging (MRI) T1w and T2w scans collected at the same time point as EEG (n = 47). Decreased MRI T1w/T2w ratios (an indicator of myelin) in the primary visual cortex (n = 47) were linked to longer P1 VEP latencies. Results from these two sets of analyses suggest that prenatal alcohol and postnatal myelination may both separately impact VEP latency over infancy. Public Significance Statement: For infants prenatally exposed exclusively to alcohol, continuous measures of first trimester exposure and binge drinking exposure were associated with altered timing of visual neurodevelopment over the first 6 months postnatally. Myelination may serve as a partial mechanism for these differences. The World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test is an acceptable tool to detect alcohol risk in pregnant populations. This work can inform efforts to support pregnant people and their infants pre- and postnatally. [ABSTRACT FROM AUTHOR]

Abstract Background Fetal alcohol spectrum disorder (FASD) is a significant public health concern, yet there is no internationally agreed set of diagnostic criteria or summary of underlying evidence to inform diagnostic decision-making. This systematic review assesses associations of prenatal alcohol exposure (PAE) and outcomes of diagnostic assessments, providing an evidence base for the improvement of FASD diagnostic criteria. Methods Six databases were searched (inception–February 2023). Case-controls or cohort studies examining associations between participants with/without PAE or a FASD diagnosis and the domains of physical size, dysmorphology, functional neurodevelopment and/or brain structure/neurology were included. Excluded studies were non-empirical, sample size

Prenatal alcohol exposure (PAE) significantly impacts brain structure and function, including cognition and behavior. The cingulum bundle and frontal lobe mediate social-, emotional- and cognitive-related functioning that are affected by PAE. However, the neurobehavioural development of the cingulum and intra-frontal tracts has not been examined in people with PAE. We recruited 29 children and adolescents with PAE and 42 age- and gender-matched unexposed controls. Diffusion magnetic resonance imaging (MRI) data were acquired on a 3 T scanner. The rostral, dorsal and parahippocampal cingulum as well as medio-orbitofrontal, lateral-orbitofrontal, dorsolateral-prefrontal and medial-prefrontal tracts, were delineated and their fractional anisotropy and mean (MD), radial (RD), and axial (AD) diffusivities were calculated using constrained spherical deconvolution and deterministic tractography. We measured behavioural and emotional difficulties using the Behavior Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with diffusion metrics that differed between groups. We found lower MD, RD, and AD in the right parahippocampal cingulum and multiple intra-frontal tracts in youth with PAE compared to controls; however, these differences did not withstand correction for multiple comparisons. While, youth with PAE showed significantly more emotional and behavioural difficulties compared to unexposed controls, these challenges were not associated with differences in diffusion metrics between groups. PAE may be weakly associated with restricted diffusion in the right parahippocampal cingulum and multiple intra-frontal tracts. However, diffusivity changes related to PAE might not be the primary contributor to emotional and behavioural challenges in children and adolescents with PAE. • Prenatal alcohol exposure (PAE) can have lasting effects on the brain • We studied 29 youth with PAE and 42 matched controls using diffusion imaging • Youth with PAE had lower diffusivity in the right cingulum and several intra-frontal tracts • Youth with PAE had more behavioural challenges, but these were not associated with diffusion metrics [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) can lead to a wide range of adverse effects in humans, including impaired self‐control and increased impulsive behavior. Deficits in self‐control can interfere with academic performance and have lasting impacts. In the present study, a rodent model of PAE was used to assess impulsivity through operant conditioning. Pregnant rats were assigned to one of three groups: ad‐lib control (CON), pair‐fed (PF), and alcohol‐exposed (ALC). ALC rats were given a liquid diet containing 6% alcohol, PF rats were yoked to an ALC rat and given a CON liquid diet, and CON rats received ad libitum food. Operant conditioning was used to evaluate extinction in adolescents (Experiment 1) and differential reinforcement of low rates (DRL) in adolescents and adults (Experiment 2). PAE resulted in an increase in responses and resets during DRL testing, indicative of impaired self‐control, an effect that was only observed in adolescent males. Females, regardless of age, did not show increased impulsivity following PAE. This indicates that children with PAE may exhibit attentional deficits similar to those with attention deficit hyperactivity disorder, with males at a higher risk. [ABSTRACT FROM AUTHOR]

Abstract It is estimated that up to 1 in 20 people in the United States may have a fetal alcohol spectrum disorder (FASD), or the array of physical, cognitive, emotional, and social disorders caused by exposure to alcohol during prenatal development (May et al., JAMA 319:474–82, 2018). While this condition is present in a broad range of individuals and families, it has not previously been examined in the military community, where cultural factors including an increased prevalence of alcohol misuse may pose a unique set of challenges (Health.mil, Alcohol misuse, 2024). The Uniformed Services University of the Health Sciences (USUHS), in conjunction with FASD United, hosted the second annual Workshop on Fetal Alcohol Spectrum Disorders Prevention and Clinical Guidelines Research on 20 September 2023 in Washington, DC. Organized as part of a four-year, federally-funded health services research initiative on FASD in the U.S. Department of Defense (DoD) Military Health System (MHS), the workshop provided a forum for exploring the initiative’s focus and progress; examining current knowledge and practice in the research and clinical spheres; and identifying potential strategies to further improve prevention, screening, diagnosis, interventions, and family support. Building off of the 2022 workshop that covered the state of the science surrounding prenatal alcohol exposure and FASD, the 2023 focused primarily on FASD and efforts aimed at identification and management (Koehlmoos et al., BMC Proc 17 Suppl 12:19, 2023). One hundred and thirty attendees from academia, healthcare, federal agencies, and patient advocacy organizations gathered to share research findings; learn from lived experiences; and discuss initiatives to advance research, screening, and services for at-risk pregnant women as well as families and caregivers supporting individuals with FASD.

Abstract Background Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention. Results Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not. Conclusion PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD.

This article explores the role of potassium channels in animal models of post-traumatic stress disorder (PTSD) and their potential therapeutic implications. Potassium channels are important in regulating brain function and have been associated with various neuropsychiatric disorders. Animal models have shown that different types of potassium channels play a role in fear-related behaviors and memory. Genome-wide association studies have identified genes involved in fear and stress responses that may contribute to vulnerability to PTSD. Specific potassium channel subtypes have been implicated in the development of certain PTSD symptoms and may be potential targets for treatment. Activation or inhibition of these channels can affect fear responses and consolidation of fear memories. The article acknowledges the need for further research in humans and the limitations of the available evidence. [Extracted from the article]

It is estimated that up to 1 in 20 people in the United States may have a fetal alcohol spectrum disorder (FASD), or the array of physical, cognitive, emotional, and social disorders caused by exposure to alcohol during prenatal development (May et al., JAMA 319:474–82, 2018). While this condition is present in a broad range of individuals and families, it has not previously been examined in the military community, where cultural factors including an increased prevalence of alcohol misuse may pose a unique set of challenges (Health.mil, Alcohol misuse, 2024). The Uniformed Services University of the Health Sciences (USUHS), in conjunction with FASD United, hosted the second annual Workshop on Fetal Alcohol Spectrum Disorders Prevention and Clinical Guidelines Research on 20 September 2023 in Washington, DC. Organized as part of a four-year, federally-funded health services research initiative on FASD in the U.S. Department of Defense (DoD) Military Health System (MHS), the workshop provided a forum for exploring the initiative's focus and progress; examining current knowledge and practice in the research and clinical spheres; and identifying potential strategies to further improve prevention, screening, diagnosis, interventions, and family support. Building off of the 2022 workshop that covered the state of the science surrounding prenatal alcohol exposure and FASD, the 2023 focused primarily on FASD and efforts aimed at identification and management (Koehlmoos et al., BMC Proc 17 Suppl 12:19, 2023). One hundred and thirty attendees from academia, healthcare, federal agencies, and patient advocacy organizations gathered to share research findings; learn from lived experiences; and discuss initiatives to advance research, screening, and services for at-risk pregnant women as well as families and caregivers supporting individuals with FASD. [ABSTRACT FROM AUTHOR]

Individuals with prenatal alcohol exposure (PAE) commonly experience co-occurring diagnoses, which are often overlooked and misdiagnosed and have detrimental impacts on accessing appropriate services. The prevalence of these co-occurring diagnoses varies widely in the existing literature and has not been examined in PAE without an FASD diagnosis. A search was conducted in five databases and the reference sections of three review papers, finding a total of 2180 studies. 57 studies were included in the final analysis with a cumulative sample size of 29,644. Bayesian modeling was used to determine aggregate prevalence rates of co-occurring disorders and analyze potential moderators. 82 % of people with PAE had a co-occurring diagnosis. All disorders had a higher prevalence in individuals with PAE than the general population with attention deficit hyperactivity disorder, learning disorder, and intellectual disability (ID) being the most prevalent. Age, diagnostic status, and sex moderated the prevalence of multiple disorders. While prevalence of disorders is crucial information, it does not provide a direct representation of daily functioning and available supports. Results should be interpreted in collaboration with more individualized research to provide the most comprehensive representation of the experience of individuals with PAE. Co-occurring diagnoses are extremely prevalent in people with PAE, with older individuals, females, and those diagnosed with FASD being most at risk for having a co-occurring disorder. These findings provide a more rigorous examination of the challenges faced by individuals with PAE than has existed in the literature, providing clinicians with information to ensure early identification and effective treatment of concerns to prevent lifelong challenges. • No study has examined mental health prevalence rates in individuals with PAE but not FASD. • 57 articles including 29,644 individuals with alcohol exposure were found and analyzed. • 82 % of individuals with alcohol exposure have at least one co-occurring disorder • Older individuals, females, and those with an FASD diagnosis had higher prevalences of multiple disorders.. • These findings help inform both the diagnosis and support of individuals with alcohol exposure [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE. • The H3R inverse agonist SAR-152954 reversed LTP deficits in the dentate gyrus following prenatal alcohol exposure (PAE). • These outcomes align with results obtained previously with the H3R inverse agonist ABT-239. • Time-frequency analyses provide a sensitive measure of PAE effects on baseline evoked responses and LTP. • SAR-152954 was associated with numerical, non-significant, decreases in input/output responses for PAE and control offspring. [ABSTRACT FROM AUTHOR]

Background: Data from birth registries can be studied to assess the prevalence of prenatal alcohol use and associated maternal and neonatal outcomes. Methods: Linked maternal and neonatal data (2015–2018) for alcohol-exposed pregnancies were obtained from the Better Outcomes Registry and Network (BORN) Ontario. Descriptive statistics were generated for maternal demographics, prenatal substance use, mental health/substance use history, and neonatal outcomes. Logistic regression models were performed to assess the odds of prenatal heavy (binge or weekly) alcohol and other substance use based on mental health/substance use history and other maternal demographics, and the impacts of heavy alcohol use and other prenatal substance exposures on neonatal outcomes. Results: A total of 10,172 (2.4%) women reported alcohol use during pregnancy. One-third had pre-existing or current mental health and/or substance use problems, which was associated with significantly higher odds of heavy alcohol use during pregnancy. Prenatal exposure to heavy alcohol use was associated with increased odds of neonatal abstinence syndrome (2.5 times); respiratory distress syndrome (2.3 times); neonatal intensive care unit (NICU) admission (58%); and hyperbilirubinemia (57%). Prenatal exposure to one or more substances in addition to alcohol was associated with significantly higher odds of fetal/maternal/placental pregnancy complications; preterm birth; NICU admission; low APGAR scores; one or more confirmed congenital anomalies at birth; respiratory distress syndrome; and intrauterine growth restriction. Conclusions: It is crucial to routinely screen childbearing-age and pregnant women for alcohol and other substance use as well as mental health problems in order to prevent adverse maternal and neonatal outcomes. [ABSTRACT FROM AUTHOR]

This article explores the neuropsychological profile of autism and fetal alcohol spectrum disorder. These distinct conditions can have a similar presentation, and there is increasing interest in distinguishing between the neurobehavioural presentations as part of assessment and diagnosis. Although there are similarities in the neurodevelopmental profile of autism and fetal alcohol spectrum disorder, there are discreet differences in social cognition that may be useful to consider during assessment. This article argues that neuropsychological assessment of social cognition, as well as executive functions including inhibitory control, will be useful when considering a diagnosis, as these factors may underpin differences caused by prenatal alcohol exposure, or autism. Research in this area is in its infancy, and more investigation is needed. [ABSTRACT FROM AUTHOR]

This study compared the Behavior Assessment System for Children-Third Edition (BASC-3) to the Child Behavior Checklist (CBCL) and the Vineland Adaptive Behavior Scales-Third Edition (VABS-3) in children with and without histories of prenatal alcohol exposure. Data were collected from Collaborative Initiative on Fetal Alcohol Spectrum Disorders Phase 4 sites. Caregivers rated their child's behavior using three questionnaires: BASC-3, CBCL, and VABS-3. BASC-3 Adaptive Skills, Externalizing Problems, and Internalizing Problems scores were correlated with comparable scores from the CBCL (Externalizing and Internalizing Problems) and VABS-3 (Adaptive Skills) both within and across groups. Sensitivity, specificity, and positive and negative predictive values were calculated for the BASC-3. BASC-3 sensitivity rates were 78.1%, 80.5%, and 47.0% and specificity rates were 79.4%, 80.4%, and 81.5% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Positive predictive values were 87.1%, 88.0%, and 81.9% and negative predictive values were 67.0%, 69.8%, and 46.3% for Adaptive Skills, Externalizing Problems, and Internalizing Problems, respectively. Results replicated previous reports of behavioral and adaptive difficulties in children with prenatal alcohol exposure. These findings provide support for using the BASC-3 in this population. [ABSTRACT FROM AUTHOR]

Introduction: Fetal Alcohol Spectrum Disorders (FASD) are characterized by a variety of multiple cognitive and behavioral impairments, with intellectual, attentional, and executive impairments being the most commonly reported. In populations with multiple neurodevelopmental disorders, the Full Scale Intelligence Quotient (FSIQ) may not be a proper measure of intellectual abilities, rarely interpreted in FASD clinical practice because the heterogeneity of the cognitive profile is deemed too strong. We propose a quantitative characterization of this heterogeneity, of the strengths and weaknesses profile, and a differential analysis between global cognitive (FSIQ) and elementary reasoning abilities in a large retrospective monocentric FASD sample. Methods: Using clinical and cognitive data (Wechsler Intelligence Scale for Children) from 107 children with FASD, we characterized subject heterogeneity (variance and scatter of scaled/composite scores), searched for strengths and weaknesses, and specified intellectual functioning in terms of FSIQ and elementary reasoning (General Abilities Index, Highest Reasoning Scaled Score), in comparison with standardization norms and a Monte-Carlo-simulated sample from normalization data. Results: Performance of children with FASD was lower on all subtests, with a significant weakness in working memory and processing speed. We found no increase in the variance and scatter of the scores, but a discordance between the assessment of global cognitive functioning (28% borderline, 23% deficient) and that of global and elementary reasoning abilities (23–9% borderline, 15–14% deficient). Conclusion: Our results question the notion of WISC profile heterogeneity in FASD and point to working memory and processing speed over-impairment, with global repercussions but most often preserved elementary reasoning abilities. [ABSTRACT FROM AUTHOR]

According to the Developmental Origins of Health and Disease hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight--indicators of a suboptimal intrauterine environment. In different animal models, the main suboptimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signaling pathways controlling endocrine, excretion, and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation. NEW & NOTEWORTHY Human data and experimental animal data show that suboptimal environments during fetal development increase the risk of renal and vascular diseases in adult-life. This is related to permanent changes in kidney structure, function, and expression of genes and signaling pathways controlling filtration, excretion, and endocrine function. Uncovering the mechanisms by which offspring renal development and function is impacted is important for identifying ways to mitigate the development of diseases that strain health care services worldwide. [ABSTRACT FROM AUTHOR]

The impact of ethanol on the fetus is a significant concern as an estimated 2–5% of live births may be affected by prenatal alcohol exposure. This exposure can lead to various functional and structural abnormalities in the cerebral cortex, basal ganglia, diencephalon, and cerebellum, resulting in region-specific symptoms. The deficits relate to the motor and cognitive domains, affecting, in particular, general intelligence, attention, executive functions, language, memory, visual perception, and social skills—collectively called the fetal alcohol spectrum disorder (FASD). Recent studies suggest that damage to the developing cerebellum (in form of alcohol exposure) can impair the cortical targets of the cerebello-thalamo-cortical tract. This malfunction in the cerebello-cerebral loop optimization may be due to disruptions in the formation of the foundational elements of the internal model within the developing cerebellum. Alcohol exposure targets multiple nodes in the reciprocal loops between the cerebellum and cerebral cortex. Here, we examine the possibility that prenatal alcohol exposure damages the developing cerebellum and disrupts the connectivity within the cerebello-cerebral neuronal circuits, exacerbating FASD-related cortical dysfunctions. We propose that malfunctions between cerebellar internal model (critically involved in predictions) and cerebral regions contribute to the deficits observed in FASD. Given the major role of the cerebellum in motor, cognitive, and affective functions, we suggest that therapies should target these malfunctions to mitigate the burden of FASD. We discuss the concept of therapies oriented towards malfunctioning cerebello-cerebral loops (TOMCCLs), emphasizing anti-inflammatory strategies and treatments aimed at modulating cerebellar myelination to restore optimal and predictive cerebello-cerebral functions. [ABSTRACT FROM AUTHOR]

Introduction and methods: In this PRISMA-compliant systematic review, we identify and synthesize the findings of research in which neuroimaging and assessments of achievement have been used to examine the relationships among aspects of developmental programming, neurodevelopment, and achievement in reading and mathematics. Results: Forty-seven studies met inclusion criteria. The majority examined the impact of prematurity (n = 32) and prenatal alcohol exposure (n = 13). Several prematurity studies reported a positive correlation between white-matter integrity of callosal fibers and executive functioning and/or achievement, and white matter properties were consistently associated with cognitive and academic performance in preterm and full-term children. Volumetric studies reported positive associations between academic and cognitive abilities and white and gray matter volume in regions such as the insula, putamen, and prefrontal lobes. Functional MRI studies demonstrated increased righthemispheric language processing among preterm children. Altered activation of the frontoparietal network related to numerical abilities was also reported. Prenatal alcohol exposure studies reported alterations in white matter microstructure linked to deficits in cognitive functioning and academic achievement, including mathematics, reading, and vocabulary skills. Volumetric studies reported reductions in cerebral, cerebellar, and subcortical gray matter volumes associated with decreased scores on measures of executive functioning, attention, working memory, and academic performance. Functional MRI studies demonstrated broad, diffuse activation, reduced activation in canonical regions, and increased activation in non-canonical regions during numeric tasks. Discussion: A preponderance of studies linked prematurity and prenatal alcohol exposure to altered neurodevelopmental processes and suboptimal academic achievement. Limitations and recommendations for future research are discussed. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) causes cognitive impairment and a distinctive craniofacial dysmorphology, due in part to apoptotic losses of the pluripotent cranial neural crest cells (CNCs) that form facial bones and cartilage. We previously reported that PAE rapidly represses expression of >70 ribosomal proteins (padj = 10-E47). Ribosome dysbiogenesis causes nucleolar stress and activates p53-MDM2-mediated apoptosis. Using primary avian CNCs and the murine CNC line O9-1, we tested whether nucleolar stress and p53-MDM2 signaling mediates this apoptosis. We further tested whether haploinsufficiency in genes that govern ribosome biogenesis, using a blocking morpholino approach, synergizes with alcohol to worsen craniofacial outcomes in a zebrafish model. In both avian and murine CNCs, pharmacologically relevant alcohol exposure (20mM, 2hr) causes the dissolution of nucleolar structures and the loss of rRNA synthesis; this nucleolar stress persisted for 18-24hr. This was followed by reduced proliferation, stabilization of nuclear p53, and apoptosis that was prevented by overexpression of MDM2 or dominant-negative p53. In zebrafish embryos, low-dose alcohol or morpholinos directed against ribosomal proteins Rpl5a, Rpl11, and Rps3a, the Tcof homolog Nolc1, or mdm2 separately caused modest craniofacial malformations, whereas these blocking morpholinos synergized with low-dose alcohol to reduce and even eliminate facial elements. Similar results were obtained using a small molecule inhibitor of RNA Polymerase 1, CX5461, whereas p53-blocking morpholinos normalized craniofacial outcomes under high-dose alcohol. Transcriptome analysis affirmed that alcohol suppressed the expression of >150 genes essential for ribosome biogenesis. We conclude that alcohol causes the apoptosis of CNCs, at least in part, by suppressing ribosome biogenesis and invoking a nucleolar stress that initiates their p53-MDM2 mediated apoptosis. We further note that the facial deficits that typify PAE and some ribosomopathies share features including reduced philtrum, upper lip, and epicanthal distance, suggesting the facial deficits of PAE represent, in part, a ribosomopathy. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention. Results: Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not. Conclusion: PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. Methods: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology. Results: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. Conclusions: Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD. Plain English summary: Prenatal alcohol exposure (PAE) can lead to a set of lifelong cognitive, behavioural, and physical disabilities known as foetal alcohol spectrum disorder (FASD). FASD is a significant burden on healthcare, justice and education systems, which is set to worsen with rising alcohol consumption rates. FASD children have an increased risk of long bone fracture and adolescents are smaller in stature. However, sex differences and the long-term effects of PAE on the skeleton have not been investigated and was the aim of this study. Using a mouse model of PAE, we examined the function and gene expression of bone-forming cells (osteoblasts). We then analysed the skeletons of male and female mice at 12-weeks-old (adult) and 4-weeks-old (juvenile). PAE reduced osteoblast bone formation in both sexes, compared to control. Differential gene expression was predominantly observed in PAE males and largely involved genes related to blood vessel formation. High resolution x-ray imaging (micro-CT) revealed PAE had a detrimental effect on the inner trabecular bone component in 12-week-old male mice only. Analysis of the outer cortical bone revealed that whilst both male and female PAE mice were negatively affected, anatomical variations were observed. Mechanical testing also revealed differences in bone strength in PAE mice, compared to control. Interestingly, 4-week-old mice did not possess these sex differences observed in our PAE model at 12 weeks of age. Our data suggest PAE has detrimental and yet sex-dependent effects on the skeleton. Establishing these sex differences will support future policies and clinical management of FASD. Highlights: Primary calvarial osteoblasts isolated from male and female PAE mice displayed reduced mineralised bone nodule formation and differential gene expression compared to control. PAE had a detrimental effect on trabecular bone parameters in 12-week-old male mice only. PAE leads to spatial variation in cortical bone parameters and geometry, with male mice negatively affected along the tibial length and female mice only affected at the distal end. Mechanical testing revealed PAE male mice had significantly reduced bone stiffness compared to controls; PAE in both sexes reduced maximum load and yield. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. [ABSTRACT FROM AUTHOR]

Associations and families demand the need to raise awareness of the implications in the cognitive and behavioral development of children with Fetal Alcohol Spectrum Disorder (FASD) that affect their learning and school participation. This study aims to generate a profile of executive and behavioral functioning in children and adolescents diagnosed with FASD. A probabilistic sampling by clusters (associations for individuals with FASD) is applied. The sample is composed of 66 families from three associations. The BRIEF-2 and SENA tests were administered to assess executive and behavioral functioning domains. Data analysis found that the executive and behavioral functioning profile of individuals with FASD varies with age, with greater impairment in middle and late adolescence. Likewise, the domain of executive functioning most affected in any of the developmental stages is working memory. Finally, cognitive impairment in the executive functioning domains has a direct impact on the social and adaptive functioning of people with FASD. [ABSTRACT FROM AUTHOR]

Background: Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. Methods: During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. Results: The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. Conclusions: PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus–pituitary–adrenal axis overactivity. [ABSTRACT FROM AUTHOR]

Background: Fetal alcohol spectrum disorders (FASD) include a range of neurocognitive and behavioral impairments resulting from prenatal alcohol exposure (PAE). Among the PAE‐related cognitive deficits, number processing is particularly affected. This study examines alterations in number processing networks and whether changes in functional connectivity mediate the adverse effects of PAE on arithmetic performance. Methods: Magnetic resonance imaging (MRI) was acquired in 57 children (mean (SD) age = 11.3 (+0.9) yr), 38 with FASD (19 fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 heavily exposed (HE)) and 19 controls. Whole‐brain correlation analyses were performed from five seeds located in regions involved in number processing. Results: Children with FAS/PFAS showed dose‐dependent reductions in resting state functional connectivity between the seed in the right (R) posterior superior parietal lobule and a cluster in the left (L) inferior frontal gyrus, and between a seed in the R horizontal intraparietal sulcus and clusters in the R precentral gyrus and L cerebellar lobule VI. HE children showed lower resting state functional connectivity in a subset of these regions. Lower functional connectivity in the two fronto‐parietal connections partially mediated the adverse effects of PAE on arithmetic performance. Conclusion: This study demonstrates PAE‐related functional connectivity impairments in functional networks involved in number processing. The weaker connectivity between the R posterior superior parietal lobule and the L inferior frontal gyrus suggests that impaired verbal processing and visuospatial working memory may play a role in number processing deficits, while weaker connectivity between the R intraparietal sulcus and the R precentral gyrus points to poorer finger‐based numerical representation, which has been linked to arithmetic computational skills. [ABSTRACT FROM AUTHOR]

Fetal Alcohol Spectrum Disorders affect up to 5% of the population, with additional children affected by prenatal drug exposures. The majority of these children display symptoms of ADHD and poor emotional dysregulation, a common reason for seeking psychiatric care. However, high prevalence of comorbid look-alike symptoms and limited availability of evidence-based treatments complicates psychiatric decision making in this population. The goal of the current study is to report on the effectiveness of psychotropic medications in a case series of 16 individuals with prenatal alcohol/drug exposure and propose a model for psychiatric care for this population. In addition to traditional subjective reports, an objective continuous performance test (T.O.V.A.®) was used to aid with guiding treatment. We found that T.O.V.A.®-scores improved on average from − 6.5 to − 2.9 with our psychiatric approach (p = 0.03). T.O.V.A.®-measurements were helpful in differentiating ADHD symptoms from comorbid symptoms and to guide decision-making on starting and changing medications. [ABSTRACT FROM AUTHOR]

Children and youths diagnosed with FASD may experience a range of adverse health and social outcomes. This cross-sectional study investigated the characteristics and outcomes of children and youths diagnosed with FASD between 2015 and 2018 at the Sunny Hill Centre in British Columbia, Canada and examined the relationships between prenatal substance exposures, FASD diagnostic categories, and adverse health and social outcomes. Patient chart data were obtained for 1187 children and youths diagnosed with FASD and analyzed. The patients (mean age: 9.7 years; range: 2–19) had up to 6 physical and 11 mental health disorders. Prenatal exposure to other substances (in addition to alcohol) significantly increased the severity of FASD diagnosis (OR: 1.18): the odds of FASD with sentinel facial features (SFF) were 41% higher with prenatal cigarette/nicotine/tobacco exposure; 75% higher with exposure to cocaine/crack; and two times higher with exposure to opioids. Maternal mental health issues and poor nutrition also increase the severity of FASD diagnosis (60% and 6%, respectively). Prenatal exposure to other substances in addition to alcohol significantly predicts involvement in the child welfare system (OR: 1.52) and current substance use when adjusted for age (aOR: 1.51). Diagnosis of FASD with SFF is associated with an increased number of physical (R2 = 0.071, F (3,1183) = 30.51, p = 0.000) and mental health comorbidities (R2 = 0.023, F (3,1185) = 9.51, p = 0.000) as compared to FASD without SFF adjusted for age and the number of prenatal substances. Screening of pregnant women for alcohol and other substance use, mental health status, and nutrition is extremely important. [ABSTRACT FROM AUTHOR]

During pregnancy, exposure to alcohol represents an environmental insult capable of negatively impacting embryonic development. This influence can stem from disruption of molecular profiles, ultimately leading to manifestation of fetal alcohol spectrum disorder. Despite the central role of the placenta in proper embryonic development and successful pregnancy, studies on the placenta in a prenatal alcohol exposure and fetal alcohol spectrum disorder context are markedly lacking. Here, we employed a well-established model for preimplantation alcohol exposure, specifically targeting embryonic day 2.5, corresponding to the 8-cell stage. The exposure was administered to pregnant C57BL/6 female mice through subcutaneous injection, involving two doses of either 2.5 g/kg 50 % ethanol or an equivalent volume of saline at 2-hour intervals. Morphology, DNA methylation and gene expression patterns were assessed in male and female late-gestation (E18.5) placentas. While overall placental morphology was not altered, we found a significant decrease in male ethanol-exposed embryo weights. When looking at molecular profiles, we uncovered numerous differentially methylated regions (DMRs; 991 in males; 1309 in females) and differentially expressed genes (DEGs; 1046 in males; 340 in females) in the placentas. Remarkably, only 21 DMRs and 54 DEGs were common to both sexes, which were enriched for genes involved in growth factor response pathways. Preimplantation alcohol exposure had a greater impact on imprinted genes expression in male placentas (imprinted DEGs: 18 in males; 1 in females). Finally, by using machine learning model (L1 regularization), we were able to precisely discriminate control and ethanol-exposed placentas based on their specific DNA methylation patterns. This is the first study demonstrating that preimplantation alcohol exposure alters the DNA methylation and transcriptomic profiles of late-gestation placentas in a sex-specific manner. Our findings highlight that the DNA methylation profiles of the placenta could serve as a potent predictive molecular signature for early preimplantation alcohol exposure.