Search Results (50)

Prenatal alcohol exposure (PAE) can cause fetal alcohol spectrum disorder (FASD). The FASD continuum encompasses facial dysmorphism, growth failure, and central nervous system (CNS) abnormalities/dysfunctions. Because some of these features may not be apparent in newborns, detecting PAE in the neonatal period is challenging, while early diagnosis may improve neurodevelopmental outcomes. Maternal self-reported alcohol consumption is limited by recall bias and denial, leading to misdiagnosis. Currently, there is a lack of universally implemented and standardized tools for identifying PAE/FASD in children across clinical settings. We aimed to review the existing literature on PAE assessment methods. Analysis of alcohol metabolites in neonatal meconium is the most widely studied and appears to be feasible for routine use, but it has some limitations. Recent advances in understanding the effects of alcohol on neurotransmitters, growth factors, and gene activity have contributed to the development of novel diagnostic strategies and have brought us closer to effective PAE detection. Some laboratory assays appear to be feasible for implementation in routine clinical practice, i.e., testing for pro- and anti-inflammatory cytokines, including interleukins (IL): IL-6, IL-1β, IL-10, and tumor necrosis factor-alpha (TNF-α) and Insulin-like Growth Factor 1(IGF1). These molecular approaches hold promise but require replication and validation before becoming the standard in clinical practice. Further research on biomarkers and other screening tools should continue to determine their feasibility and availability. Full article

Background: Prenatal alcohol exposure (PAE) is a major preventable cause of neurodevelopmental impairment. Little is known about its impact on real-life child/adolescent academic outcomes, which are key functional indicators of long-term social participation. Methods: PAE was assessed in a sample of 156 participants via (1) meconium ethyl glucuronide (EtG) concentration (≥10 ng/g; EtG-positive, n = 36) and (2) third-trimester maternal self-report (SR-positive, n = 40). At primary school (6–10 years, t1) and secondary school ages (12–14 years, t2), exposed and non-exposed children were compared regarding primary school grades (t1) and secondary track placement (t2). Results: At t1, EtG-positive children exhibited lower school report grades by trend (n = 15, p = 0.068–0.085) with a moderate effect size (r = 0.36–0.39). SR-positive children demonstrated significantly lower school report grades (n = 15, p = 0.016) with strong effect (r = 0.56). At t2, both exposure groups had increased trend-significant odds of attending lower educational tracks (EtG-positive/-negative: n = 153, OR = 1.84, p = 0.059; SR-positive/-negative: n = 153, OR = 1.78, p = 0.066). Conclusions: PAE is associated with reduced real-life academic outcomes across development. School performance represents a sensitive functional outcome of neurodevelopmental vulnerability following PAE. Meconium EtG may contribute to postnatal identification of affected children. Full article

Background/Objectives: Fetal alcohol spectrum disorders (FASDs) occur in nearly 5% of children in the United States and have been associated with alterations in neurological functions, neuroanatomical changes, and behavioral deficits encompassing an individual’s lifetime. Alterations in myelination have been reported in both rodent models and humans. The cerebellum is a heavily myelinated brain region, and oligodendrocyte and myelination transcripts have been reported to be altered in the cerebellum following early-life ethanol (EtOH) exposure in a mouse model. In this study, we investigated cerebellar-recruited behaviors in adult female mice that were exposed to EtOH from postnatal day (P) 4 to P9. We investigated whether changes in oligodendrocyte lineage markers were present in adulthood. Methods: C57BL/6J offspring received a total of 5.0 g/kg/day of either ethanol (EtOH) or saline in two separate doses delivered subcutaneously two hours apart from P4 to P9. On P21, offspring were weaned and housed with same-sex littermates throughout the duration of the study. From P60 to P90, females underwent behavioral testing including an open field test (OFT), rotarod, and balance beam. Behavior naïve littermates were euthanized on P105, and cerebella were collected for qPCR to assess oligodendrocyte lineage transcripts. Results: We reported that, following EtOH exposure from P4 to P9, adult female mice had increased ambulatory behaviors in the OFT and subtle changes in behavior in the rotarod and balance beam compared to saline-exposed controls. Despite the behavioral changes observed in adulthood, we found that alterations in oligodendrocyte lineage transcripts present on P10 did not persist into adulthood. Conclusions: Subcutaneous injection of EtOH from P4 to P9 resulted in long-term consequences in locomotor and cerebellar-recruited behaviors in female mice. 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

The gut microbiota plays a central role in host energy metabolism and the development of metabolic disorders, partly through its influence on mitochondrial function. Probiotic supplementation, particularly with Lactobacillus rhamnosus GG, has been proposed as a strategy to modulate the microbiota and improve host metabolic health. Adolescent binge-like alcohol consumption is a critical public health issue known to induce neuroinflammation, oxidative stress, mitochondrial dysfunction, and intestinal dysbiosis, contributing to disorders such as alcoholic liver disease (ALD). This study aimed to evaluate the effects of L. rhamnosus GG supplementation on mitochondrial physiology in Sprague Dawley rats exposed to binge-like ethanol (BEP group) or saline (SP group) during adolescence (postnatal days 30–43). Starting on postnatal day 44, L. rhamnosus GG was administered orally for 28 days. Fecal colonization was confirmed by qPCR, and mitochondrial function was assessed in the liver, heart, and bone marrow through quantification of NADH, ATP, ADP/ATP ratio, total antioxidant capacity, and the expression of mitochondrial genes Higd2a, MnSOD1, and AMPKα1. L. rhamnosus GG supplementation induced tissue-specific mitochondrial adaptations. In the liver, it increased Higd2a expression and restored antioxidant and energy balance in ethanol-exposed rats. In the bone marrow, it reversed ethanol-induced metabolic stress and enhanced AMPKα1 expression. In contrast, in the heart, L. rhamnosus GG had minimal impact on mitochondrial energy markers but increased antioxidant capacity, indicating a more limited, redox-focused effect. These findings suggest that L. rhamnosus GG exerts context-dependent, tissue-specific benefits on mitochondrial physiology, primarily through the modulation of antioxidant defenses, activation of AMPKα1, and remodeling of respiratory complexes. This probiotic may represent a promising therapeutic strategy to mitigate mitochondrial dysfunction associated with early-life alcohol exposure. 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) is associated with long-term neurodevelopmental deficits resulting in impaired executive functioning and motor control. Intriguingly, PAE has been linked with an increased risk of transient systemic hypoxia–ischemia (TSHI), which alone results in suboptimal fetal growth and neurodevelopmental consequences. Here, using two translationally relevant preclinical models, we investigated the short-term and lasting effects of PAE and TSHI on the morphology of the medial prefrontal cortex (mPFC), a region important in executive function, and tested whether PAE interacts with TSHI to produce a distinct pattern of injury relative to either condition alone. The four experimental groups included sham (saccharin water, no TSHI), PAE (5% alcohol, no TSHI), TSHI (saccharin water, TSHI), and PAE+TSHI (5% alcohol, TSHI). Brains were extracted for Golgi–Cox staining at Postnatal Day 35 (P35) or P100 and processed for 3D Sholl analysis. The analysis of the mPFC at P35 showed no significant differences in the number of branches or dendritic length overall, although the impact of TSHI compared to alcohol was significant for both. There were no significant differences in the number of Sholl intersections overall at P35, although a sex difference was noted in PAE offspring. At P100, analysis of filament dendritic length and branching number was also significantly impacted by TSHI compared to alcohol. Interestingly, sex was also a significant factor when assessing the impact of alcohol. PAE and TSHI both had an insignificantly increased number of Sholl intersections at P100 compared to the control. The observed changes to dendritic complexity at P100 demonstrate altered neuronal morphology in the mPFC that endure into adulthood. Given the importance of the mPFC in executive functioning, these pilot data provide insight into morphological changes that may contribute to the neurobehavioral deficits observed following exposure to PAE and TSHI and highlight the need for additional investigations into this area. Full article

Many children suffer from neurodevelopmental aberrations that have long-term effects. To understand the consequences of pathological processes during particular periods in neurodevelopment, one has to understand the differences in the developmental timelines of brain regions. The cerebellum is one of the first brain structures to differentiate during development but one of the last to achieve maturity. This relatively long period of development underscores its vulnerability to detrimental environmental exposures throughout gestation. Moreover, as postnatal functionality of the cerebellum is multifaceted, enveloping sensorimotor, cognitive, and emotional domains, prenatal disruptions in cerebellar development can result in a large variety of neurological and mental health disorders. Here, we review major intrauterine insults that affect cerebellar development in both humans and rodents, ranging from abuse of toxic chemical agents, such as alcohol, nicotine, cannabis, and opioids, to stress, malnutrition, and infections. Understanding these pathological mechanisms in the context of the different stages of cerebellar development in humans and rodents can help us to identify critical and vulnerable periods and thereby prevent the risk of associated prenatal and early postnatal damage that can lead to lifelong neurological and cognitive disabilities. The aim of the review is to raise awareness and to provide information for obstetricians and other healthcare professionals to eventually design strategies for preventing or rescuing related neurodevelopmental disorders. Full article

This study establishes a fetal cannabinoid syndrome model to evaluate the effects of high doses of dronabinol (synthetic THC) during pregnancy and lactation on behavioral and brain changes in male and female progeny and their susceptibility to alcohol consumption. Female C57BL/6J mice received dronabinol (10 mg/kg/12 h, p.o.) from gestational day 5 to postnatal day 21. On the weaning day, the offspring were separated by sex, and on postnatal day 60, behavioral and neurobiological changes were analyzed. Mice exposed to dronabinol exhibited increased anxiogenic and depressive-like behaviors and cognitive impairment. These behaviors were associated with neurodevelopment-related gene and protein expression changes, establishing, for the first time, an association among behavioral changes, cognitive impairment, and neurobiological alterations. Exposure to dronabinol during pregnancy and lactation disrupted the reward system, leading to increased motivation to consume alcohol in the offspring. All these modifications exhibited sex-dependent patterns. These findings reveal the pronounced adverse effects on fetal neurodevelopment resulting from cannabis use during pregnancy and lactation and strongly suggest the need to prevent mothers who use cannabis in this period from the severe and permanent side effects on behavior and brain development that may occur in their children. Full article

Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25–57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration. Full article

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber–DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice. Full article

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. Full article

The long-term effects of environmental pollution have been of concern as several pollutants are carcinogenic, potentially inducing a variety of cancers, including childhood cancer, which is a leading cause of death around the world and, thus, is a public health issue. The present scoping review aimed to update and summarize the available literature to detect specific environmental pollutants and their association with certain types of childhood cancer. Studies published from 2013 to 2023 regarding environmental pollution and childhood cancer were retrieved from the PubMed database. A total of 174 studies were eligible for this review and were analyzed. Our search strategy brought up most of the articles that evaluated air pollution (29%) and pesticides (28%). Indoor exposure to chemicals (11%), alcohol and tobacco use during pregnancy (16%), electromagnetic fields (12%), and radon (4%) were the subjects of less research. We found a particularly high percentage of positive associations between prenatal and postnatal exposure to indoor (84%) and outdoor (79%) air pollution, as well as to pesticides (82%), and childhood cancer. Positive associations were found between leukemia and pesticides and air pollution (33% and 27%); CNS tumors and neuroblastoma and pesticides (53% and 43%); and Wilms tumor and other rare cancers were found in association with air pollution (50%). Indoor air pollution was mostly reported in studies assessing several types of cancer (26%). Further studies are needed to investigate the mechanisms underlying the potential associations between indoor/outdoor air pollution and pesticide exposure with childhood cancer risk as more preventable measures could be taken. Full article

Fetal alcohol spectrum disorders (FASD) caused by developmental ethanol exposure lead to cerebellar impairments, including motor problems, decreased cerebellar weight, and cell death. Alterations in the sole output of the cerebellar cortex, Purkinje cells, and central nervous system immune cells, microglia, have been reported in animal models of FASD. To determine how developmental ethanol exposure affects adult cerebellar microglia and Purkinje cells, we used a human third-trimester binge exposure model in which mice received ethanol or saline from postnatal (P) days 4–9. In adolescence, cerebellar cranial windows were implanted and mice were aged to young adulthood for examination of microglia and Purkinje cells in vivo with two-photon imaging or in fixed tissue. Ethanol had no effect on microglia density, morphology, dynamics, or injury response. However, Purkinje cell linear frequency was reduced by ethanol. Microglia–Purkinje cell interactions in the Purkinje Cell Layer were altered in females compared to males. Overall, developmental ethanol exposure had few effects on cerebellar microglia in young adulthood and Purkinje cells appeared to be more susceptible to its effects. Full article

Maternal exposures during pregnancy can impact the establishment of the ovarian reserve in offspring, the lifetime supply of germ cells that determine a woman’s reproductive lifespan. However, despite alcohol consumption being common in women of reproductive age, the impact of prenatal alcohol on ovarian development is rarely investigated. This study used an established rat model of periconceptional ethanol exposure (PCEtOH; 12.5% v/v ethanol) for 4 days prior to 4 days post-conception. Ovaries were collected from neonates (day 3 and day 10), and genes with protein products involved in regulating the ovarian reserve analyzed by qPCR. Adult offspring had estrous cycles monitored and breeding performance assessed. PCEtOH resulted in subtle changes in expression of genes regulating apoptosis at postnatal day (PN) 3, whilst those involved in regulating growth and recruitment of primordial follicles were dysregulated at PN10 in neonatal ovaries. Despite these gene expression changes, there were no significant impacts on breeding performance in adulthood, nor on F2-generation growth or survival. This contributes additional evidence to suggest that a moderate level of alcohol consumption exclusively around conception, when a woman is often unaware of her pregnancy, does not substantially impact the fertility of her female offspring. Full article