Search Results (161)

Fetal alcohol spectrum disorder (FASD) is a significant public health issue that affects children. It results from ethanol exposure during pregnancy, leading to considerable physical, neurodevelopmental, behavioral, and cognitive deficits. The exact mechanism is not well understood. Recently, considerable attention has been focused on the influence of gut microbiome on brain development through the gut–brain axis. Changes in the gut microbiome resulting from ethanol exposure may contribute to the pathology of FASD, potentially involving neuroinflammation. This literature review summarizes the existing research and primary animal studies on the impact of early ethanol exposure on the gut microbiome, neuroinflammation, brain development, and behavioral consequences. The evidence suggests that early ethanol exposure alters the gut microbiome, which may induce neuroinflammation, brain damage, and cognitive impairment. However, a clear causal relationship among these factors remains to be fully elucidated. Full article

Background: Prenatal alcohol exposure (PAE) can reduce fetal growth and cause neurodevelopmental disability. Prenatal choline supplements attenuate PAE-induced behavioral and growth deficits; however, the underlying mechanisms are unknown. Alcohol alters nutrient metabolism and potentially increases nutrient needs. Here, we investigate how alcohol affects choline metabolism in the maternal–fetal dyad and the role of supplemental choline. Methods: Pregnant C57BL/6J mice were assigned to one of four groups: alcohol-exposed (3 g/kg alcohol/day) or control +/− 100 mg/kg choline daily from embryonic day (E)8.5–17.5. We performed an exploratory hypothesis-generating analysis of targeted metabolomics on choline-related metabolites in the maternal liver, plasma, placenta, and fetal brain at E17.5 and Spearman correlation analyses to determine their association with gestational and fetal growth outcomes. Results: Although choline levels were largely unaffected by alcohol or choline, alcohol increased many lipid products in the CDP–choline pathway; this was not normalized by choline. Alcohol increased placental CDP–ethanolamine and reduced the maternal hepatic SAM/SAH ratio as well as dimethylglycine and the serine/glycine ratio across the dyad, suggesting a functional insufficiency in methyl donor pools. These outcomes were rescued by supplemental choline. Correlation analyses among choline metabolites and fetal growth outcomes suggest that maternal plasma methionine, serine, and the serine/glycine ratio may be predictive of maternal–fetal choline status. Conclusions: The increased hepatic lipid synthesis that characterizes chronic alcohol exposure may draw choline into phospholipid biosynthesis at the expense of its use as a methyl donor. We propose that PAE increases choline needs, and that its supplementation is necessary to fulfill these competing demands for lipid and methyl use. Full article

We investigated the molecular and clinical profile of five boys carrying the fragile X messenger ribonucleoprotein 1 (FMR1) mutation and who suffered from the effects of prenatal alcohol exposure. Fragile X syndrome (FXS) testing was performed using PCR and Southern Blot analysis, and fragile X messenger ribonucleoprotein protein (FMRP) expression levels were measured by Western blot analysis. Clinical evaluation included cognitive functions, adaptive skills, autism phenotype, and severity of behavior measures. Fetal Alcohol Spectrum Disorder (FASD) was also assessed. Five adopted male siblings were investigated, four of which (cases 1, 2, 3, and 4) were diagnosed with FXS, FASD, and ASD, and one, the fraternal triplet (case 5), was diagnosed with FASD and ASD and no FXS. The molecular profile of case 1 and 2 showed the presence of a hypermethylated full mutation (FM) and the resulting absence of FMRP. Cases 3 and 4 (identical twins) were FM-size mosaics (for the presence of an FM and a deleted allele), resulting in 16% and 50% FMRP expression levels, respectively. FMRP expression level was normal in case 5 (fraternal twin). Severe behavioral problems were observed in all cases, including aggression, tantrum, self-harming, anxiety, and defiant behavior, due to different mutations of the FMR1 gene, in addition to biological exposure, home environmental factors, and potentially to additional background gene effects. Full article

Background: Craniofacial malformations lie at the heart of fetal alcohol spectrum disorders (FASDs). While there is growing evidence for a genetic component in FASDs, little is known of the cellular mechanisms underlying these ethanol-sensitive loci in facial development. The bone morphogenetic protein (Bmp) signaling pathway-dependent endoderm pouch formation is a key mechanism in facial development. We have previously shown that multiple Bmp mutants are sensitized to ethanol-induced facial defects. However, ethanol does not directly impact Bmp signaling. This suggests that downstream effectors, like nkx2.3, may mediate the impact of ethanol on Bmp mutants. Methods: We use an ethanol exposure paradigm with nkx2.3 knockdown approaches to test if nkx2.3 loss sensitizes Bmp mutants to ethanol-induced facial defects. We combine morphometric approaches with immunofluorescence and a hybridization chain reaction to examine the cellular mechanisms underlying Bmp–ethanol interactions. Results: We show that Bmp–ethanol interactions alter the morphology of the endodermal pouches, independent of nkx2.3 gene expression. Knockdown of nkx2.3 does not sensitize wild-type or Bmp mutants to ethanol-induced facial defects. However, we did observe a significant increase in CNCC apoptosis in ethanol-treated Bmp mutants, suggesting an ethanol sensitive, Bmp-dependent signaling pathway driving tissue interactions at the heart of FASDs. Conclusions: Collectively, our work builds on the mechanistic understanding of ethanol-sensitive genes and lays the groundwork for complex multi-tissue signaling events that have yet to be explored. Ultimately, our work provides a mechanistic paradigm of ethanol-induced facial defects and connects ethanol exposure with complex tissue signaling events that drive development. Full article

Background: Prenatal alcohol exposure (PAE) models can cause neurodevelopmental abnormalities like those observed in fetal alcohol spectrum disorder (FASD). Previous studies link experimental PAE effects in the brain to impaired signaling through insulin/IGF and Notch pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Importantly, concurrent administration of peroxisome proliferator-activated receptor agonists or dietary soy prevented many aspects of FASD due to their insulin-sensitizing, anti-inflammatory, and antioxidant properties. Objective: To determine if dietary soy interventions during pregnancy would be sufficient to normalize central nervous system structure and function, we examined the effects of maternal gestation-limited dietary soy on cerebellar postnatal development, motor function, and critical signaling pathways. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source. The ethanol and soy feedings were discontinued upon delivery. The offspring were subjected to rotarod motor function tests, and on postnatal day 35, they were sacrificed to harvest cerebella for histological and molecular studies. Results: Despite the postnatal cessation of alcohol exposure, chronic gestational exposure reduced brain weight, caused cerebellar hypoplasia, and impaired motor performance. Gestational dietary soy prevented the ethanol-associated reduction in brain weight and largely restored the histological integrity of the cerebellum but failed to normalize motor performance. Ethanol withdrawal abolished the impairments in insulin/IGF signaling that were previously associated with ongoing ethanol exposures, but ethanol’s inhibitory effects on Notch and Wnt signaling persisted. Soy significantly increased cerebellar expression of the insulin and IGF-1 receptors and abrogated several ethanol-associated impairments in Notch and Wnt signaling. Conclusions: Although gestation-restricted dietary soy has significant positive effects on neurodevelopment, optimum prevention of FASD’s long-term effects will likely require dietary soy intervention during the critical periods of postnatal development, even after alcohol exposures have ceased. Full article

Prenatal alcohol exposure (PAE) affects around 40,000 newborns every year and poses a significant health risk. Although much is already known about the neurotoxic mechanisms of PAE, new findings continue to emerge. Studies with mouse models show that PAE leads to overexpression of proinflammatory cytokines and chemokines in the brain, which disrupts important neurodevelopmental processes such as cell migration, survival and proliferation of neurons. The chemokine CXCL16 is overexpressed in the brain following various impairments, including PAE. This study shows that CXCL16 expression varies by developmental stage and sex, consistent with known sexual dimorphism in immune responses. In females, CXCL16 expression may be influenced by estrogen-related mechanisms, possibly related to the alcohol-mediated rebound effect described here. In contrast, the male hippocampus shows greater resilience to PAE-induced CXCL16 changes. Furthermore, the presence of CXCL16 in neuronal nuclei suggests a role in gene regulation, similar to other chemokines such as CCL5 and CXCL4. These findings shed light on the role of chemokines in hippocampal neuroplasticity and may pave the way for better treatment of fetal alcohol spectrum disorder (FASD). Full article

Background/Objectives: Fetal alcohol spectrum disorders comprise a range of neurodevelopmental disorders caused by prenatal alcohol exposure. Recent investigations have revealed that among patients with neurodevelopmental disorders, serum cobalamin (vitamin B12) levels are substantially higher than those of healthy controls. Patients with fetal alcohol spectrum disorders similarly present with higher levels of cobalamin, yet the significance of cobalamin in the pathogenesis of fetal alcohol spectrum disorders remains to be established. This study aimed to examine cobalamin and other cobalamin status markers in patients with fetal alcohol spectrum disorders in comparison with healthy controls. Methods: In total, 80 patients were enrolled in the study—41 diagnosed with fetal alcohol spectrum disorders and 39 healthy controls. The diet history method was used to assess vitamin B12 intake for three days preceding blood sampling. Total vitamin B12 (cobalamin), holotranscobalamin, methylmalonic acid and soluble transcobalamin receptor (CD320) were measured in serum samples. Results: The daily intake of vitamin B12 was higher in patients with fetal alcohol spectrum disorders compared to controls, both in the simple analysis and after adjusting for age (OR for patients with FASDs: 1.82; 95% CI: 1.16–2.87). An elevated serum cobalamin level was noted in some patients from the group with fetal alcohol spectrum disorders. No statistically significant differences were found between the groups in serum levels of cobalamin, holotranscobalamin, CD320 or methylmalonic acid. However, the correlations between cobalamin and its metabolites differed in fetal alcohol spectrum disorders as compared to those in the control group. Conclusions: Our study did not find any deficits of vitamin B12 and its metabolites in patients with fetal alcohol spectrum disorders. Further studies to investigate the role of vitamin B12 in the pathogenesis of fetal alcohol spectrum disorders should be established given the fact that both high and low levels of vitamin B12 may have negative health impacts. Full article

Background/Objectives: Sleep disturbances are common among children with fetal alcohol spectrum disorders (FASD) and are often accompanied by emotional and behavioral challenges. This study aimed to evaluate the relationship between sleep problems, anxiety, and depressive symptoms in children with FASD. Methods: The study included 90 children aged 7 to 16 years diagnosed with FASD, who were primarily in foster or adoptive care. Participants completed validated psychometric tools, including the Children’s Sleep Habits Questionnaire (CSHQ), State Trait Anxiety Inventory for Children (STAIC) and Children’s Depression Inventory 2 (CDI 2). Results: Sleep disturbances were significant, with 71.1% of participants scoring above the clinical threshold in CSHQ. State anxiety, measured by STAIC C-1, was positively correlated with specific sleep difficulties, such as bedtime resistance (r = 0.30, p = 0.008) and sleep anxiety (r = 0.31, p = 0.005). However, no correlation was found between trait anxiety (STAIC C-2) and sleep problems. Parent-reported depressive symptoms, measured using CDI 2:P, were strongly associated with general sleep disturbances (r = 0.27, p < 0.011), parasomnias (r = 0.33, p = 0.002) and daytime sleepiness (r = 0.34, p < 0.001). Conclusions: These findings suggest that sleep disturbances in children with FASD are closely related to state anxiety and depressive symptoms. The results emphasize the need for targeted interventions addressing sleep and emotional health in this population. Further research is needed to examine these relationships and their implications for clinical practice. Full article

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. Full article

Fetal alcohol spectrum disorder (FASD) encompasses a range of complex neurodevelopmental challenges that arise because of maternal alcohol use during pregnancy. Contrary to previous beliefs, FASD is a wide-ranging condition that is mostly invisible, affecting cognitive, social, and daily living skills. Furthermore, living with FASD may present other challenges, such as mental health issues, substance abuse, and engagement in criminal behavior. FASD is a long-term disability that requires support across the lifespan. The main objective of this research was to determine what, if anything, has changed since a prior review in 2020 of parents with FASD appearing in child intervention courts in Canada. We found eleven relevant reported cases throughout Canada from 2020 to 2024 where parents had a confirmed diagnosis or a potential FASD to be eligible for our study. Within these cases, only one parent was able to reunite with their children because of the strong and supportive system they had. There were four cases where ongoing contact between parent and child(ren) was permitted, Additionally, we found that professionals lack education regarding the potential skills that people with FASD may demonstrate. A person with FASD is seen through the lens of their diagnosis rather than a strengths-based approach, creating stigma, fear, and power imbalance. Stigma has an impact not just on how professionals see people and make decisions but also on policymakers, funding, and support from governments or other social groups. Individuals or parents with FASD are often reluctant to report their diagnosis for fear of being judged or having their children taken from their care. Thus, parents are unable to obtain access to services, and even when they do have access, they must navigate the system on their own. Parents with FASD who are involved in child intervention may be required to participate in many programs simultaneously, potentially resulting in an overwhelming experience. Full article

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. Full article

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. Full article

Background: Despite several diagnostic guidelines, Fetal Alcohol Spectrum Disorders (FASDs) remain underdiagnosed or misdiagnosed, delaying the care of these patients and support for families. Objective: This study aims to help professionals caring for these children and their families to suspect this diagnosis earlier and to provide the most appropriate follow-up. Methods: A retrospective chart review with monocentric recruitment was performed at the Genetics Unit of the University Hospital of Reunion Island. A total of 147 children and adolescents with FASDs were included. Results: Prenatal alcohol exposure was associated with paternal alcohol consumption in 42.9%, and a high rate of prematurity (33.3%) was observed. Sixty percent of children or adolescents were placed in foster families. Learning difficulties without cognitive deficits were found in 65.8% of cases (50/76). Postural control and fine motor skills disabilities were described, respectively, in 54.7% (35/64) and 72.5% (50/69) of cases. A systematic genetic assessment was carried out, identifying in these FASD patients an associated Copy Number Variation (CNVs) in 22.6% of cases. Conclusion: Children with FASDs combine significant vulnerabilities, associating exposure to alcohol during the preconception and/or the prenatal period, prematurity, complex familial and sociocultural living conditions, and a genetic anomaly in almost a quarter of cases. Full article

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. Full article

The formation of the human gut microbiome initiates in utero, and its maturation is established during the first 2–3 years of life. Numerous factors alter the composition of the gut microbiome and its functions, including mode of delivery, early onset of breastfeeding, exposure to antibiotics and chemicals, and maternal stress, among others. The gut microbiome–brain axis refers to the interconnection of biological networks that allow bidirectional communication between the gut microbiome and the brain, involving the nervous, endocrine, and immune systems. Evidence suggests that the gut microbiome and its metabolic byproducts are actively implicated in the regulation of the early brain development. Any disturbance during this stage may adversely affect brain functions, resulting in a variety of neurodevelopmental disorders (NDDs). In the present study, we reviewed recent evidence regarding the impact of the gut microbiome on early brain development, alongside its correlation with significant NDDs, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, cerebral palsy, fetal alcohol spectrum disorders, and genetic NDDs (Rett, Down, Angelman, and Turner syndromes). Understanding changes in the gut microbiome in NDDs may provide new chances for their treatment in the future. Full article