Search Results (192)

Fetal alcohol spectrum disorders (FASD) encompass a continuum of developmental abnormalities caused by prenatal alcohol exposure, resulting in persistent neurodevelopmental and structural defects. Accumulating evidence indicates that redox dysregulation plays a central role in the pathogenesis of FASD. Ethanol disrupts cellular redox homeostasis by promoting excessive reactive oxygen species production and depleting endogenous antioxidants, thereby perturbing key redox-sensitive molecular networks. Dysregulation of these pathways leads to mitochondrial dysfunction, endoplasmic reticulum stress, lysosome dysfunction, and disrupted cellular processes, including proliferation, differentiation, and migration, while also promoting apoptosis and neuroinflammation, ultimately leading to the developmental abnormalities characteristic of FASD. Recent studies demonstrate that antioxidant supplementation or targeted modulation of redox-sensitive signaling can mitigate these deleterious effects in preclinical models. This review synthesizes current knowledge of the molecular networks underlying redox dysregulation in FASD and discusses emerging antioxidant and dietary interventions with therapeutic potential. Elucidating these mechanisms provides critical insight into the pathogenesis of FASD and may inform the development of effective strategies for the prevention and treatment of FASD. Full article

Neuroplacentology is an emerging field of research supporting that the placenta actively contributes to the fetal brain development through the release of bioactive molecules. Recent angiogenesis-focused data showed that prenatal alcohol exposure (PAE) disrupts inter-organ gene expression between the placenta and fetal cortex. The present study aimed to perform the first comprehensive and untargeted analysis of a murine placenta–cortex transcriptomic database of PAE. Gene lists from a recently NCBI-deposited PAE Placenta–Cortex transcriptomic database were analyzed using g:Profiler for unbiased functional profiling querying Gene Ontology, KEGG, and Reactome databases. Genes intersecting with cell–cell communication terms were submitted to STRING and ShinyGO analyses to identify enriched protein–protein interactions and pathways. Several ligand or receptor candidates were then validated by Western blot. g:Profiler revealed 21 enriched GO functional maps, seven KEGG pathways, and six Reactome pathways, of which 11 were related to cell-to-cell communication. STRING analysis exhibited substantial protein–protein interaction enrichments supporting that proteins belonging to the functional maps and pathways are biologically connected. Notably, 38 ligands or receptors from endocrine families including angiotensinogen, leptin, somatostatin, or PACAP were identified. Western blot analysis of protein candidates showed different validation patterns. In particular, the PACAP receptor family confirmed transcriptomic findings and revealed sex-dependent PAE-impacted expression profiles. The present study indicates that PAE is associated with alterations in the transcriptomic placenta–cortex expression profile, including changes in the expression ratios of several ligands and/or receptors implicated in key physiological pathways such as energy balance, vascular development, and neurogenesis. These transcriptomic associations suggest that altered placenta–fetal brain signaling at the gene expression level may be involved in alcohol-induced neurodevelopmental disorders, highlighting the need for future functional validation studies. Full article

Background/Objectives: The foetal alcohol syndrome spectrum is linked with neurodevelopmental delay and cognitive and educational problems. Direct consequences of prenatal alcohol exposure include impaired processes of neural migration and brain development. Among the important features present in affected children are impaired communicational skills and intelligence. Methods: Here we presented the case–control comparison of 124 children with foetal alcohol syndrome spectrum disorder (FAS: 62 (50%), pFAS: 34 (27.42%) and ARND: 28 (22.58%)) and 53 healthy controls regarding intelligence quotient and a verbal fluency task. The verbal and non-verbal intelligence was measured using the WISC-R scale, and the verbal fluency task encompassed phonemic, semantic and categorial assessment in 15 and 60 s; we used the authors’ parental/caregiver survey to determine risk factors. In statistical analysis both methods of classical parametric/non-parametric tests and machine learning algorithms were used. Results: Foetal alcohol syndrome spectrum patients were clearly distinguished from healthy controls regarding total verbal and non-verbal intelligence, as well as all three categories of verbal fluency (p < 0.01). ML methods distinguished an FAS group with 0.49 precision and 80% recall and for pFAS and ARND diagnoses we obtained: 0.50/0.33 precision and 3%/7% recall. None of the parameters analysed in our study differentiated foetal alcohol syndrome, partial foetal alcohol syndrome and alcohol-related neurodevelopmental disorders. Conclusions: Children with foetal alcohol syndrome spectrum disorder markedly differ from healthy control subjects in intelligence and verbal fluency. The diagnostic sub-types of foetal alcohol spectrum are not clearly defined in obtained neuropsychological and clinical data. Full article

Determining the concentration of fatty acid ethyl esters (FAEEs), ethyl sulfate (EtS), and ethyl glucuronide (EtG) is crucial for establishing the true scale of prenatal alcohol exposure (PAE) and enabling early diagnosis of fetal alcohol spectrum disorders. This study primarily aimed to compare two detection methods: retrospective maternal alcohol consumption surveys and chromatographic analysis of newborn meconium. Among 478 mothers, parallel survey data and meconium samples were collected. Nine FAEEs were measured by gas chromatography–mass spectrometry, and EtG and EtS by liquid chromatography–tandem mass spectrometry. The study also aimed to establish marker cut-offs and evaluate their clinical utility. While only 4% (approximately) of mothers reported alcohol consumption during pregnancy, the biomarker analysis suggested a significant underestimation of the actual PAE scale, highlighting the limitations of self-reported data. Analysis using the cumulative biomarker index for two biomarkers with a threshold of ≥5 indicated that alcohol consumption affected approximately 3% of the studied population, further demonstrating the low reliability of maternal self-reports. Ultimately, this study confirms that the combined EtG and EtS measurements provide the most reliable diagnostic information for PAE and underscores the necessity of objective meconium screening in clinical practice. Full article

Alcohol (ethanol; EtOH) intake affects one in ten pregnancies in the United States and is a leading cause of developmental defects collectively known as fetal alcohol spectrum disorders (FASDs). Cerebral circulation is a critical target of prenatal ethanol exposure (PEE), yet the target(s) involved remain poorly understood. In adult cerebral circulation, mitochondrial function is essential in regulating smooth muscle contractility, suggesting mitochondria as a potential target of alcohol in the developing cerebral arteries. In this study, pregnant C57BL/6J mice were administered ethanol (3, 4.5, 6, or 7 g/kg) during either the second trimester equivalent of human pregnancy (gestational days 9–19), or the third trimester equivalent during postnatal days 1–10. Maternal and progeny blood ethanol concentrations, progeny brain weight, cerebral artery oxygen consumption, and corticosterone levels were measured. At lower ethanol concentrations (3 g and 4.5 g/kg), no significant alterations in fetal cerebral artery mitochondrial function were detected. In contrast, heavy maternal ethanol exposure (6 g/kg) significantly increased mitochondrial respiratory parameters in developing cerebral arteries during the third trimester equivalent of human pregnancy. Sex-specific dimorphism was also observed at this developmental stage. Corticosterone was not elevated in fetuses and pups. In summary, our findings demonstrate developmental stage- and sex-dependent vulnerabilities of cerebrovascular oxygen consumption to ethanol exposure. Full article

Background/Objectives: This article aims to investigate the multifaceted effects of alcohol on neurophysiopathological development from gestational stages through adult life and the consequent dynamic-relational challenges in individuals with Fetal Alcohol Spectrum Disorder (FASD). FASD, resulting from prenatal alcohol exposure (PAE), is characterized by a range of neurological, cognitive, behavioral, and sometimes physical impairments. This article explores how alcohol and its toxic metabolites cross the placenta, inducing direct cellular toxicity and epigenetic alterations that disrupt critical neurodevelopmental processes such as neurogenesis and brain circuit formation. Clinically, individuals with FASD exhibit diverse deficits in executive functioning, learning, memory, social skills, and sensory-motor abilities, leading to significant lifelong disabilities. A central focus is the application of the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) criteria to comprehensively frame these disabilities. The ICF’s biopsychosocial model allows for a multidimensional assessment of impairments in body functions and structures, limitations in activities, and restrictions in participation, while also considering the crucial role of environmental factors. Methods: PubMed and Semantic Scholar databases were searched for relevant papers published in English. Results: This article highlights the utility of the ICF in creating individualized functioning profiles to guide interventions and support services, addressing the limitations of traditional assessment methods. Conclusions: While the ICF framework offers a robust approach for understanding and managing FASD, further research is essential to develop and validate FASD-specific ICF-based assessment tools to enhance support and social participation for affected individuals. Full article

Fetal alcohol spectrum disorder (FASD/FAS) is a chronic inflammatory process of the fetal brain induced by alcohol and mediated by pro-inflammatory (PILM) and pro-resolving (PRLM) lipid mediators of inflammation. DHA (docosahexaenoic acid) is an essential precursor of PRLM. A study examining the response of lipid mediators of inflammation to alcohol insult and DHA supplementation can provide vital information on the pathogenesis of FASD/FAS and the potential ameliorative role of DHA. Four groups of timed pregnant rats were studied: control, low-dose (1.6 g/kg/day) and high-dose (2.4 g/kg/day) alcohol, and high-dose alcohol (2.4 g/kg/day) + DHA (1250 mg/kg/day). The pups were delivered on day 20, and their whole brain was examined for lipid mediators by liquid chromatography mass spectroscopy. The following biomarkers of brain lipid mediators were studied, namely, PILM (LTB4, PGE2, PGF2α, TXB2) and PRLM (LXA5, 4-HDoHE, 17-HDoHE, and MaR1n-3, DPA). The brain PILM and PRLM concentrations decreased significantly (p < 0.001) with high-dose alcohol. However, high-dose alcohol + DHA resulted in a significant (p < 0.001) increase in PRLM levels, viz., LXA5, MaR1n-3 DPA, 17-HDoHE, and a threefold increase in 4-HDoHE. We conclude that DHA supplementation in alcohol-exposed pregnant rats significantly increased levels of brain pro-resolving lipid mediators in the offspring, suggesting a potential role in modulating the inflammatory response. Full article

Prenatal alcohol exposure (PAE) causes neurobehavioral deficits and metabolic syndrome in later life. Prenatal choline supplementation (PCS) improves those behavioral deficits. Here we test whether PCS also ameliorates the attendant metabolic syndrome, using an established mouse model that mirrors aspects of alcohol-related neurodevelopmental disorders. Pregnant dams were exposed to alcohol (3 g/kg) from gestational days 8.5–17.5; some dams received additional choline (175% of requirement) by a daily injection. Offspring were followed through to the age of 86 wks with respect to their body composition and glucose tolerance. We found that PAE affected these outcomes in a sex-dependent manner. Male PAE offspring exhibited an increased fat mass, liver enlargement, elevated fasting glucose, and glucose intolerance. Female PAE offspring exhibited an increased fat mass, but the glucose tolerance and fasting values were unaffected. Regardless of sex, PCS attenuated all these metabolic measures. PCS was shown previously to elevate methyl-related choline metabolites and improve fetal growth, suggesting that it acts by attenuating the in utero stressors that otherwise program the fetus for metabolic syndrome in later life. Importantly, PCS also improved the adiposity, fasting glucose, and glucose tolerance in control offspring consuming the fixed-nutrient AIN-93G diet, suggesting that its choline content (1 g/kg) may be inadequate for optimal rodent health. Full article

Introduction: Secure infant/child–caregiver attachment is crucial for the development of social and emotional functioning and can affect long-term outcomes, such as adult relationships, but it may also be influenced by prenatal and early childhood risk factors. Children with a history of prenatal alcohol exposure (PAE) have a complex spectrum of strengths and difficulties and often have the additional risk of early life adversity. There is some evidence that children with PAE are at increased risk of insecure attachment, but it is unclear whether this is consistent or why it is the case. No published review has focused on the relationship between PAE and attachment. Methods: A systematic search of seven academic databases using the PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines was undertaken by two reviewers to identify primary studies that have focused on the relationship between PAE and attachment. Quality assessments were undertaken using the Quality of Observational Cohort and Cross-Sectional Studies tool, and the report was written following the PRISMA-ScR checklist. Results: A total of 4199 records were returned from the database searches. A total of 11 studies (eight peer-reviewed papers and three dissertations), published between 1987 and 2021, met the criteria. Five studies showed that PAE was related to insecure or disorganised attachment, two of which showed that infant irritability and caregiver–infant interaction mediated this relationship. The other six studies found no significant relationship between PAE and attachment. Conclusions: This scoping review demonstrates that there is a dearth of published research on this topic, and none that takes advantage of more recent understanding of the relationship between adverse childhood experiences and neurodevelopmental disorders. There is some evidence that PAE may impact the attachment relationship via caregiver–infant interaction and infant irritability, but further studies, including those that assess the additional impact of early life adversity, are needed. Full article

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies. Full article

There are a range of factors that influence alcohol use in pregnancy and create risk of fetal harm. However, limited research has articulated the multilevel nature of these influences and their entanglement. The purpose of this narrative review is to analyze the types of factors that influence alcohol use and consider what factors need to be addressed in future health promotion and intervention efforts. Six databases were searched using EBSCOhost articles published between January and December 2023 on alcohol use in pregnancy and Fetal Alcohol Spectrum Disorder (FASD) prevention. English-language articles were screened for relevance and a subset of articles exploring the prevalence, influences, and risk-factors associated with pregnancy were included for analysis. Thirty-two (n = 32) articles were included in the review and categorized into five key areas of influence on maternal alcohol use: (1) informational factors; (2) stress-related factors; (3) social determinant of health-related (SDoH) influences; (4) preconception- and prenatal-health-related factors; and (5) structural factors. Future efforts to reduce alcohol use in pregnancy should address these five categories of factors through non-judgmental, health-promoting, trauma-informed, harm-reduction-oriented, and culturally safe education, programming, and policy. Full article

Telomeres are protective DNA sequences located at chromosome ends, essential to maintaining genomic stability. This narrative review examines how maternal lifestyle factors during pregnancy influence fetal telomere length (TL). Positive associations have been identified between offspring’s TL and maternal consumption of nutrients such as vitamins C and D, folate, and magnesium. Additionally, adherence to a Mediterranean diet and regular physical activity during pregnancy are correlated with increased placental TL, supporting fetal genomic integrity. Conversely, maternal dietary patterns high in carbohydrates, fats, or alcohol, as well as exposure to triclosan and sleep-disordered breathing, negatively correlate with offspring’s TL. Maternal infections may also shorten TL through heightened inflammation and oxidative stress. However, evidence regarding the impact of other lifestyle factors—including maternal stress, smoking, caffeine intake, polyunsaturated fatty acid consumption, obesity, and sleep quality—remains inconsistent. Given that shorter telomere length has been associated with cardiovascular, pulmonary, and neurodegenerative diseases, as well as certain types of cancer, these findings highlight the vital importance of maternal health during pregnancy in order to prevent potential adverse effects on the fetus. Further studies are required to elucidate the precise timing, intensity, and interplay of these influences, enabling targeted prenatal interventions to enhance offspring health outcomes. Full article

Purpose: To review parental pre-pregnancy and pregnancy exposures in relation to pediatric cancer (diagnosis before age 20). Methods: We conducted literature searches using Ovid Medline and Scopus to find primary research studies, review articles, and meta-analyses published from 2014 to 17 March 2021. Results: Strong evidence links increased risk of childhood cancer with maternal diabetes, age, and alcohol and coffee consumption during pregnancy. Both paternal and maternal cigarette smoking before and during pregnancy are associated with childhood cancers. Diethylstilbestrol (DES) exposure in utero has long been known to be causally associated with increased risk of vaginal/cervical cancers in adolescent girls. More recent evidence implicates in utero DES exposure to testicular cancer in young men and possible intergenerational effects on ovarian cancer in the granddaughters of women exposed to DES during pregnancy. There is strong evidence that childhood cancer risk is also associated with both high and very low birth weight and with gestational age. Evidence is also strong for the protective effects of maternal vitamin consumption and a healthy diet during pregnancy. Unlike early studies, those reviewed here show no association between in utero exposure to medical ionizing radiation, which may be explained by reductions over time in radiation doses, avoidance of radiation during pregnancy, and/or by inadequate statistical power to detect small increases in risk, rather than a lack of causal association. Evidence is mixed or conflicting for an association between childhood cancer and maternal obesity, birth order, cesarean/instrumental delivery, and prenatal exposure to diagnostic medical radiation. Evidence is weak or absent for associations between childhood cancer and multiple gestations or assisted reproductive therapies, as well as prenatal exposure to hormones other than DES, and medications. Full article

Clinical and animal studies suggest that multiple brain systems are involved in mediating reward-motivated and related emotional behavior including the consumption of commonly used drugs and palatable food, and there is evidence that the repeated ingestion of or exposure to these rewarding substances may in turn stimulate these brain systems to produce an overconsumption of these substances along with co-occurring emotional disturbances. To understand this positive feedback loop, this review focuses on a specific population of hypothalamic peptide neurons expressing melanin-concentrating hormone (MCH), which are positively related to dopamine reward and project to forebrain areas that mediate this behavior. It also examines neurons expressing the peptide hypocretin/orexin (HCRT) that are anatomically and functionally linked to MCH neurons and the molecular systems within these peptide neurons that stimulate their development and ultimately affect behavior. This report first describes evidence in animals that exposure in adults and during adolescence to rewarding substances, such as the drugs alcohol, nicotine and cocaine and palatable fat-rich food, stimulates the expression of MCH as well as HCRT and their intracellular molecular systems. It also increases reward-seeking and emotional behavior, leading to excess consumption and abuse of these substances and neurological conditions, completing this positive feedback loop. Next, this review focuses on the model involving embryonic exposure to these rewarding substances. In addition to revealing a similar positive feedback circuit, this model greatly advances our understanding of the diverse changes that occur in these neuropeptide/molecular systems in the embryo and how they relate, perhaps causally, to the disturbances in behavior early in life that predict a later increased risk of developing substance use disorders. Studies using this model demonstrate in animals that embryonic exposure to these rewarding substances, in addition to stimulating the expression of peptide neurons, increases the intracellular molecular systems in neuroprogenitor cells that promote their development. It also alters the morphology, migration, location and neurochemical profile of the peptide neurons and causes them to develop aberrant neuronal projections to forebrain structures. Moreover, it produces disturbances in behavior at a young age, which are sex-dependent and occur in females more than in males, that can be directly linked to the neuropeptide/molecular changes in the embryo and predict the development of behavioral disorders later in life. These results supporting the close relationship between the brain and behavior are consistent with clinical studies, showing females to be more vulnerable than males to developing substance use disorders with co-occurring emotional conditions and female offspring to respond more adversely than male offspring to prenatal exposure to rewarding substances. It is concluded that the continued consumption of or exposure to rewarding substances at any stage of life can, through such peptide brain systems, significantly increase an individual’s vulnerability to developing neurological disorders such as substance use disorders, anxiety, depression, or cognitive impairments. Full article

Fetal alcohol spectrum disorder (FASD) is a preventable cause of developmental disabilities linked to prenatal alcohol exposure (PAE). Congenital heart defects (CHDs) are frequently observed in FASD, with a notable association between PAE and dextro-type transposition of the great arteries (d-TGA). A potential pathogenetic mechanism of d-TGA in FASD, involving retinoic acid (RA) deficiency due to the interference of ethanol with RA biosynthesis, is proposed. Further investigation is required to understand the timing and impact of alcohol exposure on congenital anomalies, particularly in the context of CHDs. Full article