Impact Of Prenatal Alcohol Exposure Research Articles

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner.

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. 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. 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. 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.

The Impact of Prenatal Alcohol Exposure on Longitudinal Growth, Nutritional Status, and Insulin-Like Growth Factor 1 in Early Childhood in Leyte, the Philippines

To assess the impact and potential mechanistic pathways of prenatal alcohol exposure (PAE) on longitudinal growth and nutritional status in early childhood. A cohort of 296 mother-infant dyads (32% with PAE vs 68% unexposed) were recruited in Leyte, the Philippines, and followed from early gestation through 24months of age. PAE was assessed using serum phosphatidylethanol (PEth) captured twice prenatally and in cord blood and supplemented with self-reported alcohol consumption. Linear mixed models were used to examine longitudinal effects of PAE on growth from birth through 2years including key potential mediating factors (placental histopathology, and infant serum leptin and Insulin-like Growth Factor 1 [IGF-1]). After adjusting for potential confounders, we found that PAE was significantly associated with a delayed blunting of linear growth trajectories (height-for-age z-score, body length) and weight (weight-for-age z-score, body weight) that manifested between 4 and 6months and continued through 12-24months. PAE was also associated with a decreased rate of mid-upper-arm circumference growth from birth to 12months, and a lower mean IGF-1 levels at birth and 6months. This study demonstrates a delayed impact of PAE on growth that manifested around 6months of age, underscoring the importance of routine clinical monitoring in early childhood. Furthermore, the findings supported prior animal model findings that suggest a mechanistic role for IGF-1 in PAE-induced growth delay.

Sex-specific Differences in Resting Oscillatory Dynamics in Children with Prenatal Alcohol Exposure

At rest children with prenatal alcohol exposure (PAE) exhibit impaired static and dynamic functional connectivity, along with decreased alpha oscillations. Sex-specific information regarding the impact of PAE on whole-brain resting-state gamma spectral power remains unknown. Eyes-closed and eyes-open MEG resting-state data were examined in 83 children, ages 6–13 years of age. Using a matched design, the sample consisted of 42 typically developing children (TDC) (22 males/20 females) and 41 children with PAE and/or a fetal alcohol spectrum disorders (FASD) diagnosis (21 males/20 females). Whole-brain source resting-state spectral power was examined to determine group and sex specific relationships. Within gamma, we found sex and group specific changes such that female participants with PAE/FASD had increased gamma power when compared to female TDC and male participants with PAE/FASD. These differences were detected in most source regions analyzed during both resting-states, and were observed across the age spectrum examined. Within delta, we found sex and group specific changes such that female participants with PAE/FASD had decreased delta power when compared to female TDC and male participants with PAE/FASD. The reduced delta oscillations in female participants with PAE/FASD were detected in several source regions during eyes-closed rest and were evident at younger ages. These results indicate PAE alters neural oscillations during rest in a sex-specific manner, with females with PAE/FASD showing the largest perturbations. These results further demonstrate PAE has global effects on resting-state spectral power and connectivity, creating long-term consequences by potentially disrupting the excitation/inhibition balance in the brain, interrupting normative neurodevelopment.

Exploring behavioral phenotypes in a mouse model of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders are one of the leading causes of developmental abnormalities worldwide. Maternal consumption of alcohol during pregnancy leads to a diverse range of cognitive and neurobehavioral deficits. Although moderate-to-heavy levels of prenatal alcohol exposure (PAE) have been associated with adverse offspring outcomes, there is limited data on the consequences of chronic low-level PAE. Here, we use a model of maternal voluntary alcohol consumption throughout gestation in a mouse model to investigate the effects of PAE on behavioral phenotypes during late adolescence and early adulthood in male and female offspring. Body composition was measured by dual-energy X-ray absorptiometry. Baseline behaviors, including feeding, drinking, and movement, were examined by performing home cage monitoring studies. The impact of PAE on motor function, motor skill learning, hyperactivity, acoustic reactivity, and sensorimotor gating was investigated by performing a battery of behavioral tests. PAE was found to be associated with altered body composition. No differences in overall movement, food, or water consumption were observed between control and PAE mice. Although PAE offspring of both sexes exhibited deficits in motor skill learning, no differences were observed in basic motor skills such as grip strength and motor coordination. PAE females exhibited a hyperactive phenotype in a novel environment. PAE mice exhibited increased reactivity to acoustic stimuli, and PAE females showed disrupted short-term habituation. Sensorimotor gating was not altered in PAE mice. Collectively, our data show that chronic low-level exposure to alcohol in utero results in behavioral impairments.

Microbiota and nutrition as risk and resiliency factors following prenatal alcohol exposure.

Alcohol exposure in adulthood can result in inflammation, malnutrition, and altered gastroenteric microbiota, which may disrupt efficient nutrient extraction. Clinical and preclinical studies have documented convincingly that prenatal alcohol exposure (PAE) also results in persistent inflammation and nutrition deficiencies, though research on the impact of PAE on the enteric microbiota is in its infancy. Importantly, other neurodevelopmental disorders, including autism spectrum and attention deficit/hyperactivity disorders, have been linked to gut microbiota dysbiosis. The combined evidence from alcohol exposure in adulthood and from other neurodevelopmental disorders supports the hypothesis that gut microbiota dysbiosis is likely an etiological feature that contributes to negative developmental, including neurodevelopmental, consequences of PAE and results in fetal alcohol spectrum disorders. Here, we highlight published data that support a role for gut microbiota in healthy development and explore the implication of these studies for the role of altered microbiota in the lifelong health consequences of PAE.

Disrupted dynamic functional network connectivity in fetal alcohol spectrum disorders.

Prenatal alcohol exposure (PAE) can result in harmful and long-lasting neurodevelopmental changes. Children with PAE or a fetal alcohol spectrum disorder (FASD) have decreased white matter volume and resting-state spectral power compared to typically developing controls (TDC) and impaired resting-statestaticfunctionalconnectivity. The impact of PAE on resting-state dynamic functional network connectivity (dFNC) is unknown. Using eyes-closed and eyes-open magnetoencephalography (MEG) resting-state data, global dFNC statistics and meta-states were examined in 89 children aged 6-16 years (51 TDC, 38 with FASD). Source analyzed MEG data were used as input to group spatial independent component analysis to derive functional networks from which the dFNC was calculated. During eyes-closed, relative to TDC, participants with FASD spent a significantly longer time in state 2, typified by anticorrelation (i.e., decreased connectivity) within and between default mode network (DMN) and visual network (VN), and state 4, typified by stronger internetwork correlation. The FASD group exhibited greater dynamic fluidity and dynamic range (i.e., entered more states, changed from one meta-state to another more often, and traveled greater distances) than TDC. During eyes-open, TDC spent significantly more time in state 1, typified by positive intra- and interdomain connectivity with modest correlation within the frontal network (FN), while participants with FASD spent a larger fraction of time in state 2, typified by anticorrelation within and between DMN and VN and strong correlation within and between FN, attention network, and sensorimotor network. There are important resting-state dFNC differences between children with FASD and TDC. Participants with FASD exhibited greater dynamic fluidity and dynamic range and spent more time in states typified by anticorrelation within and between DMN and VN, and more time in a state typified by high internetwork connectivity. Taken together, these network aberrations indicate that prenatal alcohol exposure has a global effect on resting-state connectivity.

Impact of Prenatal Alcohol Exposure on the Development and Myocardium of Adult Mice: Morphometric Changes, Transcriptional Modulation of Genes Related to Cardiac Dysfunction, and Antioxidant Cardioprotection.

The impact of prenatal alcohol exposure (PAE) varies considerably between individuals, leading to morphological and genetic changes. However, minor changes usually go undetected in PAE children. We investigated PAE's effects on gene transcription of genes related to cardiac dysfunction signaling in mouse myocardium and morphological changes. C57Bl/6 mice were subjected to a 10% PAE protocol. In postnatal days 2 and 60 (PN2 and PN60), morphometric measurements in the offspring were performed. Ventricular samples of the heart were collected in PN60 from male offspring for quantification of mRNA expression of 47 genes of nine myocardial signal transduction pathways related to cardiovascular dysfunction. Animals from the PAE group presented low birth weight than the Control group, but the differences were abolished in adult mice. In contrast, the mice's size was similar in PN2; however, PAE mice were oversized at PN60 compared with the Control group. Cardiac and ventricular indexes were increased in PAE mice. PAE modulated the mRNA expression of 43 genes, especially increasing the expressions of genes essential for maladaptive tissue remodeling. PAE animals presented increased antioxidant enzyme activities in the myocardium. In summary, PAE animals presented morphometric changes, transcription of cardiac dysfunction-related genes, and increased antioxidant protection in the myocardium.

The Halstead Category Test: Assessing the Impact of Prenatal Alcohol Exposure

The Halstead Category Test: Assessing the Impact of Prenatal Alcohol Exposure

Path analysis of the impact of prenatal alcohol on adult vascular function.

The vascular system may be particularly vulnerable to prenatal alcohol exposure (PAE). Alterations in angiogenesis and epigenetic changes to vascular development have been implicated as a probable mechanism for this vulnerability. We assessed the long-term impact of prenatal alcohol exposure (PAE) on adult vascular health using a prospective cohort first identified while in utero. Participants with no PAE (n=37, mean age=36.7 [SD = 1.6] years) were compared to participants with PAE (n=51, mean age=36.3 [SD = 1.7] years). Their vascular health was assessed by arterial blood pressure (BP) and peripheral arterial tonometry, which yields an index of endothelial function (reactive hyperemia index) and a measure of arterial stiffness (augmentation index). Blood samples were collected to assess cholesterol levels and insulin resistance (glucose, hemoglobin A1C, and insulin). Path analysis was used to examine the direct and indirect effects of PAE on vascular health after adjusting for other known physical outcomes. Participants with a history of PAE weighed less, trended towards being shorter, had smaller body mass, and had more alcohol-related dysmorphic features than those without PAE. Path analysis suggested that the impact of PAE on BP was through its indirect relationships with height, body mass index, and dysmorphic features and resulted in protective effects relative to the Contrast group who were disproportionately overweight. PAE was also found to have a direct negative effect on endothelial function. An index of total alcohol-related dysmorphic features was negatively had both a direct effect on arterial stiffness and an indirect effect on endothelial function. Prenatal alcohol exposures' impact on vascular function is not independent of other common physical and environmental factors but endothelial function and arterial stiffness seemed most compromised after controlling for these other factors. Level of alcohol-related dysmorphic features seems to be predictive of more adverse effects than endothelial function and vascular stiffness.

The impact of prenatal alcohol and/or tobacco exposure on brain structure in a large sample of children from a South African birth cohort.

Neuroimaging studies have emphasized the impact of prenatal alcohol exposure (PAE) on brain development, traditionally in heavily exposed participants. However, less is known about how naturally occurring community patterns of PAE (including light to moderate exposure) affect brain development, particularly in consideration of commonly occurring concurrent impacts of prenatal tobacco exposure (PTE). Three hundred thirty-two children (ages 8 to 12) living in South Africa's Cape Flats townships underwent structural magnetic resonance imaging. During pregnancy, their mothers reported alcohol and tobacco use, which was used to evaluate PAE and PTE effects on their children's brain structure. Analyses involved the main effects of PAE and PTE (and their interaction) and the effects of PAE and PTE quantity on cortical thickness, surface area, and volume. After false-discovery rate (FDR) correction, PAE was associated with thinner left parahippocampal cortices, while PTE was associated with smaller cortical surface area in the bilateral pericalcarine, left lateral orbitofrontal, right posterior cingulate, right rostral anterior cingulate, left caudal middle frontal, and right caudal anterior cingulate gyri. There were no PAE × PTE interactions nor any associations of PAE and PTE exposure on volumetrics that survived FDR correction. PAE was associated with reduction in the structure of the medial temporal lobe, a brain region critical for learning and memory. PTE had stronger and broader associations, including with regions associated with executive function, reward processing, and emotional regulation, potentially reflecting continued postnatal exposure to tobacco (i.e., second-hand smoke exposure). These differential effects are discussed with respect to reduced PAE quantity in our exposed group versus prior studies within this geographical location, the deep poverty in which participants live, and the consequences of apartheid and racially and economically driven payment practices that contributed to heavy drinking in the region. Longer-term follow-up is needed to determine potential environmental and other moderators of the brain findings here and assess the extent to which they endure over time.

Sex-Related Differences in Voluntary Alcohol Intake and mRNA Coding for Synucleins in the Brain of Adult Rats Prenatally Exposed to Alcohol.

Maternal alcohol consumption is one of the strong predictive factors of alcohol use and consequent abuse; however, investigations of sex differences in response to prenatal alcohol exposure (PAE) are limited. Here we compared the effects of PAE throughout gestation on alcohol preference, state anxiety and mRNA expression of presynaptic proteins α-, β- and γ-synucleins in the brain of adult (PND60) male and female Wistar rats. Total RNA was isolated from the hippocampus, midbrain and hypothalamus and mRNA levels were assessed with quantitative RT-PCR. Compared with naïve males, naïve female rats consumed more alcohol in “free choice” paradigm (10% ethanol vs. water). At the same time, PAE produced significant increase in alcohol consumption and preference in males but not in females compared to male and female naïve groups, correspondingly. We found significantly lower α-synuclein mRNA levels in the hippocampus and midbrain of females compared to males and significant decrease in α-synuclein mRNA in these brain areas in PAE males, but not in females compared to the same sex controls. These findings indicate that the impact of PAE on transcriptional regulation of synucleins may be sex-dependent, and in males’ disruption in α-synuclein mRNA expression may contribute to increased vulnerability to alcohol-associated behavior.

The impact of prenatal alcohol exposure on gray matter volume and cortical surface area of 2 to 3-year-old children in a South African birth cohort.

BackgroundThere is a growing literature that demonstrates the effects of prenatal alcohol exposure (PAE) on brain development in school‐aged children. Less is known, however, on how PAE impacts the brain early in life. We investigated the effects of PAE and child sex on subcortical gray matter volume, cortical surface area (CSA), cortical volume (CV), and cortical thickness (CT) in children aged 2 to 3 years.MethodsThe sample was recruited as a nested cross‐sectional substudy of the Drakenstein Child Health Study. Images from T1‐weighted magnetic resonance imaging were acquired on 47 alcohol‐exposed and 124 control children (i.e., with no or minimal alcohol exposure), aged 2 to 3 years, some of whom were scanned as neonates. Brain images were processed through automated processing pipelines using FreeSurfer version 6.0. Subcortical and a priori selected cortical regions of interest were compared.ResultsSubcortical volume analyses revealed a PAE by child sex interaction for bilateral putamen volumes (Left: p = 0.02; Right: p = 0.01). There was no PAE by child sex interaction effect on CSA, CV, and CT. Analyses revealed an impact of PAE on CSA (p = 0.04) and CV (p = 0.04), but not CT in this age group. Of note, the inferior parietal gyrus CSA was significantly smaller in children with PAE compared to control children.ConclusionsFindings from this subgroup scanned at age 2 to 3 years build on previously described subcortical volume differences in neonates from this cohort. Findings suggest that PAE persistently affects gray matter development through the critical early years of life. The detectable influence of PAE on brain structure at this early age further highlights the importance of brain imaging studies on the impact of PAE on the young developing brain.

Sexually dimorphic organization of open field behavior following moderate prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can produce deficits in a wide range of cognitive functions but is especially detrimental to behaviors requiring accurate spatial information processing. In open field environments, spatial behavior is organized such that animals establish "home bases" marked by long stops focused around one location. Progressions away from the home base are circuitous and slow, while progressions directed toward the home base are non-circuitous and fast. The impact of PAE on the organization of open field behavior has not been experimentally investigated. In the present study, adult female and male rats with moderate PAE or saccharin exposure locomoted a circular high walled open field for 30minutes under lighted conditions. The findings indicate that PAE and sex influence the organization of open field behavior. Consistent with previous literature, PAE rats exhibited greater locomotion in the open field. Novel findings from the current study indicate that PAE and sex also impact open field measures specific to spatial orientation. While all rats established a home base on the periphery of the open field, PAE rats, particularly males, exhibited significantly less clustered home base stopping with smaller changes in heading between stops. PAE also impaired progression measures specific to distance estimation, while sex alone impacted progression measures specific to direction estimation. These findings support the conclusion that adult male rats have an increased susceptibility to the effects of PAE on the organization of open field behavior.

The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine.

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) on attentional regulation skills was explored in a randomized clinical trial conducted in Ukraine. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to one of three groups [No study-provided supplements, Multivitamin/Mineral Supplement (MVM), or MVM plus Choline]. Their offspring were seen in the preschool period and a reaction time task was administered. Participants were asked to press a response button as quickly as possible as 30 stimuli from the same category (animals) were presented consecutively and then followed by six stimuli from a novel category (vehicles). Number correct, mean latency of the response over trials, and variability in the latency were analyzed separately by sex. During the initial animal trials, boys whose mothers received MVM during pregnancy had more correct responses and reduced response latency compared to boys whose mothers had no MVM treatment. During vehicle trials, maternal choline supplementation was associated with increased response speed in males without a PAE history. Females receiving supplements did not show the same benefits from micronutrient supplementation and were more adversely impacted by prenatal alcohol exposure. Relationships between maternal levels of choline, betaine, and dimethylglycine (DMG) and task performance were also assessed. Although no effects were found for choline after adjusting for multiple comparisons, lower baseline DMG level was associated with greater accuracy and shorter latency of responses in the initial animal trials and shorter latency in the vehicle trials in female preschoolers. Level of betaine in Trimester 3 was associated with reduced variability in the latency of male responses during the animal trials. Maternal micronutrient supplementation in pregnancy appears to improve preschool reaction time performance, but the effects varied as a function of sex and PAE exposure status.

Modulatory role of prenatal alcohol exposure and adolescent stress on the response to arthritis challenge in adult female rats.

SummaryBackgroundThere are known environmental risk factors associated with rheumatoid arthritis; however, less is known regarding how the prenatal environment impacts later-life risk for rheumatoid arthritis. Based on preliminary clinical data suggesting that individuals with fetal alcohol spectrum disorder (FASD) are at higher risk for autoimmune disorders, this study investigated the modulatory impact of prenatal alcohol exposure (PAE) on the inflammatory disease profile in an adjuvant-induced arthritis rat model.MethodsPregnant rats received liquid ethanol or control diet throughout gestation. To model the increased exposure to stressors often experienced by individuals with FASD, adolescent offspring were exposed to chronic mild stress (CMS) or remained undisturbed. In adulthood, experimental arthritis was initiated and rats terminated either at the peak or following resolution from inflammation to assess endocrine, immune, and histopathological outcomes.FindingsPAE rats had an increased incidence and severity of, and impaired recovery from, arthritis. Increased joint damage was observed in PAE animals, even in the face of apparent recovery from the clinical signs of arthritis, while it appeared that oestradiol may have a protective role. Moreover, with the combination of PAE and adolescent stress, increased macrophage density was detected in the synovium of PAE but not control rats.InterpretationThese findings demonstrate that PAE alters the severity and course of arthritis, highlighting the potential immunomodulatory impact of adverse prenatal exposures. In particular, these data have implications for understanding preliminary data that suggest a heightened propensity for autoimmune disorders in individuals with FASD.

Abstract WP241: Transcriptome Analysis Of The Liver Reveals Novel Mechanisms By Which Prenatal Alcohol Exposure Contributes To Worse Stoke Outcome

Introduction: Susceptibility to adult-onset disease has been linked to early life adversity. In this study, we assessed the impact of a common early adverse experience, prenatal alcohol exposure (PAE), on neurobehavioral outcomes following cerebrovascular ischemic stroke. We also assessed impact of PAE and stroke on the transcriptome of intermediary organs of the gut-brain axis. Specifically, mesenteric adipose and liver, which are supplied by portal circulation from the gut are hypothesized to mediate inflammatory and neuroprotective adaptations to stroke. Methods: Pregnant Sprague Dawley rats were exposed to either vaporized ethanol or room air from gestation day 8 to 19. At 5 months, progeny were subjected to unilateral endothelin-1 induced occlusion of the middle cerebral artery and outcomes evaluated after 2 days. Stroke induced disabilities were assessed from behavioral assays (adhesive removal, Vibrissae evoked fore-limb placement and circling) and infarct size. The liver transcriptome was assessed by sequencing, from age-matched stroke-exposed and naïve offspring. Results: PAE rats had worse neurological scores 2 days post stroke compared to control (p<0.05). We observed that the liver was substantially more transcriptionally responsive to PAE status than adipose tissue. Moreover, PAE offspring exhibited a 1.6-fold increase in upregulated genes and a 2.4-fold increase in down-regulated liver gene transcripts following stroke, compared to control offspring. Only 448 differentially expressed genes (DEGs) were common between the control and PAE groups. DEGs unique to PAE contribute to triglyceride metabolism, steroid metabolism, and cholesterol biosynthesis pathways. Weighted correlation network analysis identified 24 gene network modules, one of which, a liver proinflammatory network, was strongly correlated with post stroke neurological function (Pearson's r=-0.63, p<0.01). Conclusion: The present study shows that PAE predisposes middle-aged rat offspring for worse outcomes following cerebrovascular ischemic stroke. This effect is associated with persistent reprogramming of the liver transcriptome and an exacerbated proinflammatory response.

Impact of prenatal alcohol exposure on intracortical myelination and deep white matter in children with attention deficit hyperactivity disorder

White matter alterations have been reported in children with prenatal alcohol exposure (PAE) and in children with attention deficit hyperactivity disorder (ADHD); however, as children with PAE often present with ADHD, covert PAE may have contributed to previous ADHD findings. Additionally, data regarding intracortical myelination in ADHD are lacking. Therefore, we evaluated intracortical myelination (assessed as the T1w/T2w ratio at 4 cortical ribbon levels) and myelin-related deep white matter features in children (aged 8–13 years) with ADHD with PAE (ADHD + PAE), children with familial ADHD without PAE (ADHD-PAE), and typically developing (TD) children. In widespread tracts, ADHD + PAE children showed higher mean and radial diffusivity than TD and ADHD-PAE children and lower fractional anisotropy than ADHD-PAE children; ADHD-PAE and TD children did not differ significantly. Compared to TD children, ADHD + PAE children had lower intracortical myelination only at the deepest cortical level (mainly in right insula and cingulate cortices), while ADHD-PAE children had lower intracortical myelination at multiple cortical levels (mainly in right insula, sensorimotor, and cingulate cortices); ADHD + PAE and ADHD-PAE children did not differ significantly in intracortical myelination. Considering the two ADHD groups jointly (via non-parametric combination) revealed common reductions in intracortical myelination, but no common deep white matter abnormalities. These results suggest the importance of considering PAE in ADHD studies of white matter pathology. ADHD + PAE may be associated with deeper, white matter abnormalities, while familial ADHD without PAE may be associated with more superficial, cortical abnormalities. This may be relevant to the different treatment response observed in these two ADHD etiologies.

Intersection of Epigenetic and Immune Alterations: Implications for Fetal Alcohol Spectrum Disorder and Mental Health.

Prenatal alcohol exposure can impact virtually all body systems, resulting in a host of structural, neurocognitive, and behavioral abnormalities. Among the adverse impacts associated with prenatal alcohol exposure are alterations in immune function, including an increased incidence of infections and alterations in immune/neuroimmune parameters that last throughout the life-course. Epigenetic patterns are also highly sensitive to prenatal alcohol exposure, with widespread alcohol-related alterations to epigenetic profiles, including changes in DNA methylation, histone modifications, and miRNA expression. Importantly, epigenetic programs are crucial for immune system development, impacting key processes such as immune cell fate, differentiation, and activation. In addition to their role in development, epigenetic mechanisms are emerging as attractive candidates for the biological embedding of environmental factors on immune function and as mediators between early-life exposures and long-term health. Here, following an overview of the impact of prenatal alcohol exposure on immune function and epigenetic patterns, we discuss the potential role for epigenetic mechanisms in reprogramming of immune function and the consequences for health and development. We highlight a range of both clinical and animal studies to provide insights into the array of immune genes impacted by alcohol-related epigenetic reprogramming. Finally, we discuss potential consequences of alcohol-related reprogramming of immune/neuroimmune functions and their effects on the increased susceptibility to mental health disorders. Overall, the collective findings from animal models and clinical studies highlight a compelling relationship between the immune system and epigenetic pathways. These findings have important implications for our understanding of the biological mechanisms underlying the long-term and multisystem effects of prenatal alcohol exposure, laying the groundwork for possible novel interventions and therapeutic strategies to treat individuals prenatally exposed to alcohol.

Concomitant genetic defects potentiate the adverse impact of prenatal alcohol exposure on cardiac outflow tract maturation.

Prenatal alcohol exposure (PAE) is associated with an increased incidence of congenital heart defects (CHD), in particular outflow tract (OFT) defects. However, the variability in the incidence of CHD following PAE has not been fully explored. We hypothesize that a concomitant, relevant genetic defect would potentiate the adverse effect of PAE and partially explain the variability of PAE-induced CHD incidence. The OFT is formed by the second heart field (SHF). Our PAE model consisted of two intraperitoneal injections (3 g/kg, separated by 6 hr) of 30% ethanol on E6.5 during SHF specification. The impact of genetic defects was studied by SHF-specific loss of Delta-like ligand 4 (Dll4), fibroblast growth factor 8 (Fgf8) and Islet1. Acute PAE alone significantly increased CHD incidence (4% vs. 26%, p= .015) with a particular increase in OFT alignment defects, viz., double outlet right ventricle (0 vs. 9%, p= .02). In embryos with a SHF genetic defect, acute PAE significantly increased CHD incidence (14 vs. 63%, p< .001), including double outlet right ventricle (6 vs. 50%, p< .001) compared to controls. PAE (p= .01) and heterozygous loss of Dll4 (p= .04) were found to independently contribute to CHD incidence, while neither Islet1 nor Fgf8 defects were found to be significant. Our model recapitulates the increased incidence of OFT alignment defects seen in the clinic due to PAE. The presence of a concomitant SHF genetic mutation increases the incidence of PAE-related OFT defects. An apparent synergistic interaction between PAE and the loss of DLL4-mediated Notch signaling in OFT alignment requires further analysis.

Alcohol's Impact on the Fetus.

Background: Alcohol is a teratogen and prenatal exposure may adversely impact the developing fetus, increasing risk for negative outcomes, including Fetal Alcohol Spectrum Disorder (FASD). Global trends of increasing alcohol use among women of childbearing age due to economic development, changing gender roles, increased availability of alcohol, peer pressure and social acceptability of women’s alcohol use may put an increasing number of pregnancies at risk for prenatal alcohol exposure (PAE). This risk has been exacerbated by the ongoing COVID-19 pandemic in some countries. Method: This literature review presents an overview on the epidemiology of alcohol use among childbearing age and pregnant women and FASD by World Health Organization regions; impact of PAE on fetal health, including FASD; associated comorbidities; and social outcomes. Results/Conclusion: The impact of alcohol on fetal health and social outcomes later in life is enormous, placing a huge economic burden on countries. Prevention of prenatal alcohol exposure and early identification of affected individuals should be a global public health priority.