Materiały źródłowe

• #1 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448178/

  Fetal alcohol syndrome is one of a spectrum of disorders under the umbrella term of fetal alcohol spectrum disorder (FASD). There is a total of five disorders that comprise fetal alcohol spectrum disorders. They are fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), a neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), and alcohol-related birth defects (ARBD). All of these fetal alcohol spectrum disorders are used to classify the wide-ranging physical and neurological effects that prenatal alcohol exposure can inflict on a fetus. […] All of the conditions that comprise fetal alcohol spectrum disorders stem from one common cause, which is prenatal exposure to alcohol. Alcohol is extremely teratogenic to a fetus. Its effects are wide-ranging and irreversible. Although higher amounts of prenatal alcohol exposure have been linked to increased incidence and severity of fetal alcohol spectrum disorders, there are no studies that demonstrate a safe amount of alcohol that can be consumed during pregnancy. There is also no safe time during pregnancy in which alcohol can be consumed without risk to the fetus. Alcohol is teratogenic during all three trimesters. In summary, any amount of alcohol consumed at any point during pregnancy has the potential cause of irreversible damage that can lead to a fetal alcohol spectrum disorder.

• #2 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. […] The risk of FASD increases with the amount consumed, the frequency of consumption, and the longer duration of alcohol consumption during pregnancy, particularly binge drinking. […] Diagnosis is based on an assessment of growth, facial features, central nervous system, and alcohol exposure by a multidisciplinary team of professionals. The main criteria for diagnosis of FASD are nervous system damage and alcohol exposure, with FAS including congenital malformations of the lips and growth deficiency. […] Almost all experts recommend that the mother abstain from alcohol use during pregnancy to prevent FASDs. […] After a pregnant woman consumes alcohol, the alcohol crosses through the placenta and umbilical cord to the developing fetus. Alcohol metabolizes slowly in the fetus and remains for a long time when compared to an adult.

• #3 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448178/

  The exact mechanism by which alcohol causes its teratogenic effects is not known. For obvious ethical reasons, formal studies on the effects of alcohol on human brain development are limited. Most of our data come from animal models and associations with alcohol exposure. […] We do know that alcohol is a teratogen that causes irreversible damage to the central nervous system (CNS). From associations with alcohol exposure, we are aware that that damage is widespread, causing not only a decrease in brain volume but also damage to structures within the brain. We also know from associations that high levels of alcohol consumption in the first trimester resulted in an increased likelihood of facial and brain anomalies. High levels of alcohol consumption in the second trimester are associated with increased incidences of spontaneous abortions. Lastly, in the third trimester, high levels of alcohol consumption are associated with decreased height, weight, and brain volume. Associations with alcohol exposure show that the neurobehavioral deficits associated with fetal alcohol spectrum disorders can occur within a wide range of exposure to alcohol and at any point in the pregnancy. […] From animal models, we know that prenatal alcohol exposure affects all stages of brain development through a variety of mechanisms, the most significant of which result in cognitive, motor, and behavioral dysfunction.

• #4 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/974016-overview

  Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.

• #5 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/974016-overview

  Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.

• #6 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  The placenta allows free entry of ethanol and toxic metabolites like acetaldehyde into the fetal compartment. The so-called placental barrier is practically absent concerning ethanol. […] The developing fetal nervous system appears particularly sensitive to ethanol toxicity. The latter interferes with proliferation, differentiation, neuronal migration, axonal outgrowth, integration, and fine-tuning of the synaptic network. In short, all major processes in the developing central nervous system appear compromised. […] Fetal tissues are quite different from adult tissues in function and purpose. For example, the main detoxifying organ in adults is the liver, whereas the fetal liver is incapable of detoxifying ethanol, as the ADH and ALDH enzymes have not yet been brought to expression at this early stage.

• #7 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/974016-overview

  Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.

• #8 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/974016-overview

  Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.

• #9 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-018-0095-4

  Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). […] In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention. […] EtOH and its catabolite acetaldehyde are toxic themselves, but according to the current knowledge oxidative stress is the major damage pathway. […] Increased DNA damage triggers apoptosis pathways leading to neurodegeneration. […] Therefore, the downstream effects of EtOH, oxidative stress towards permanent, and long-term influence in the developing brain needs to be elucidated to understand the etiology thoroughly.

• #10 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  Prenatal alcohol exposure is the leading preventable cause of cognitive deficit in developed countries and can lead to fetal alcohol spectrum disorder (FASD). This term encompasses a wide range of physical, mental, behavioral, and cognitive effects that result from damage caused by exposure to alcohol during intrauterine life. […] Foetal alcohol spectrum disorder (FASD) is an umbrella term that encompasses a broad spectrum of physical, mental, behavioural and cognitive abnormalities that may manifest in individuals with a history of prenatal exposure to alcohol. […] Alcohol toxicity depends directly on ethanol and its metabolites (acetaldehyde and reactive oxygen species [ROS]). The oxidative stress caused by alcohol and ROS is caused by an increased production of nicotinamide adenine dinucleotide (NADH), which results in an increased NAD/NADH ratio that is balanced by the formation of lactate dehydrogenase. Ethanol crosses the placenta, and while its concentration in amniotic fluid is 40% the concentration in maternal blood, its slow clearance results in prolonged foetal exposure. The foetal brain is the main target on account of its greater metabolic requirements and production of ROS combined with the lower concentration of enzymes and antioxidants.

• #11 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-018-0095-4

  Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). […] In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention. […] EtOH and its catabolite acetaldehyde are toxic themselves, but according to the current knowledge oxidative stress is the major damage pathway. […] Increased DNA damage triggers apoptosis pathways leading to neurodegeneration. […] Therefore, the downstream effects of EtOH, oxidative stress towards permanent, and long-term influence in the developing brain needs to be elucidated to understand the etiology thoroughly.

• #12 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  Prenatal alcohol exposure is the leading preventable cause of cognitive deficit in developed countries and can lead to fetal alcohol spectrum disorder (FASD). This term encompasses a wide range of physical, mental, behavioral, and cognitive effects that result from damage caused by exposure to alcohol during intrauterine life. […] Foetal alcohol spectrum disorder (FASD) is an umbrella term that encompasses a broad spectrum of physical, mental, behavioural and cognitive abnormalities that may manifest in individuals with a history of prenatal exposure to alcohol. […] Alcohol toxicity depends directly on ethanol and its metabolites (acetaldehyde and reactive oxygen species [ROS]). The oxidative stress caused by alcohol and ROS is caused by an increased production of nicotinamide adenine dinucleotide (NADH), which results in an increased NAD/NADH ratio that is balanced by the formation of lactate dehydrogenase. Ethanol crosses the placenta, and while its concentration in amniotic fluid is 40% the concentration in maternal blood, its slow clearance results in prolonged foetal exposure. The foetal brain is the main target on account of its greater metabolic requirements and production of ROS combined with the lower concentration of enzymes and antioxidants.

• #13 Fetal Alcohol Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/974016-overview

  Alcohol crosses the placenta and rapidly reaches the fetus. Extensive studies have demonstrated equivalent fetal and maternal alcohol concentrations, suggesting an unimpeded bidirectional movement of alcohol between the two compartments. The fetus appears to depend on maternal hepatic detoxification because the activity of alcohol dehydrogenase (ADH) in the fetal liver is less than 10% of that observed in the adult liver. Furthermore, the amniotic fluid acts as a reservoir for alcohol, prolonging fetal exposure. […] The mechanism for the spectrum of adverse effects on virtually all organ systems of the developing fetus is unknown. Ethanol and its metabolite acetaldehyde can alter fetal development by disrupting cellular differentiation and growth, disrupting DNA and protein synthesis and inhibiting cell migration. Both ethanol and acetaldehyde modify the intermediary metabolism of carbohydrates, proteins, and fats. Both also decrease the transfer of amino acids, glucose, folic acid, zinc, and other nutrients across the placental barrier, indirectly affecting fetal growth due to intrauterine nutrient deprivation. Elevated levels of erythropoietin in the cord blood of newborns exposed to alcohol are reported and suggest a state of chronic fetal hypoxia. […] Studies have shown that prenatal alcohol exposure affects the hypothalamic-pituitary-adrenal (HPA) axis as well as alters basal and poststress cortisol levels.

• #14 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  Although alcohol is known to be a teratogen (causing birth defects), the exact biological mechanisms for the development of FAS or FASD are unknown. However, clinical and animal studies have identified a broad spectrum of pathways through which maternal alcohol can negatively affect the outcome of a pregnancy. […] Genetic examinations have revealed a continuum of long-lasting molecular effects that are not only timing specific but are also dosage specific; with even moderate amounts being able to cause alterations. […] Additionally, ethanol may alter fetal development by interfering with retinoic acid signaling as acetaldehyde can compete with retinaldehyde and prevents its oxidation to retinoic acid.

• #15 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  The placenta allows free entry of ethanol and toxic metabolites like acetaldehyde into the fetal compartment. The so-called placental barrier is practically absent concerning ethanol. […] The developing fetal nervous system appears particularly sensitive to ethanol toxicity. The latter interferes with proliferation, differentiation, neuronal migration, axonal outgrowth, integration, and fine-tuning of the synaptic network. In short, all major processes in the developing central nervous system appear compromised. […] Fetal tissues are quite different from adult tissues in function and purpose. For example, the main detoxifying organ in adults is the liver, whereas the fetal liver is incapable of detoxifying ethanol, as the ADH and ALDH enzymes have not yet been brought to expression at this early stage.

• #16 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas

  The human CNS is vulnerable to the teratogenic effects of alcohol from when the neural plate begins to form in the third week through the rest of gestation. […] Certain areas of the developing CNS are particularly susceptible to alcohol-induced birth defects, including the ocular system, corpus callosum, basal ganglia, and cerebellum. […] Alcohol’s impact on developing neurons include an increase in programmed cell death (apoptosis), as well as oxidative stress and damage to radial glia which are the cellular populations that later in the process of development become neurons. […] All of those mechanisms impair the proliferation and migration of cells, and damage to cell populations has been proposed as a process for how alcohol causes birth defects and CNS damage. […] The exact mechanism of alcohol’s teratogenicity in the destruction of certain cell populations is debated, and the above mechanisms may work separately or together.

• #17 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas

  The human CNS is vulnerable to the teratogenic effects of alcohol from when the neural plate begins to form in the third week through the rest of gestation. […] Certain areas of the developing CNS are particularly susceptible to alcohol-induced birth defects, including the ocular system, corpus callosum, basal ganglia, and cerebellum. […] Alcohol’s impact on developing neurons include an increase in programmed cell death (apoptosis), as well as oxidative stress and damage to radial glia which are the cellular populations that later in the process of development become neurons. […] All of those mechanisms impair the proliferation and migration of cells, and damage to cell populations has been proposed as a process for how alcohol causes birth defects and CNS damage. […] The exact mechanism of alcohol’s teratogenicity in the destruction of certain cell populations is debated, and the above mechanisms may work separately or together.

• #18 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas

  Scientists have debated whether or not the alcohol-induced apoptosis prematurely eliminates specific cell populations during development, such as cranial neural crest cells, retinal cells, cerebellum cells and other vulnerable populations. […] Numerous studies confirm that the biomechanical mechanism occurring during this cell death as being a capsase-3 enzyme activation cascade, which is a component of programmed cell death by apoptosis. […] Scientists have also hypothesized that this programmed cell death may be triggered by the metabolic breakdown of alcohol into acetaldehyde, which can inhibit the formation of retinoic acid. […] In addition to those proposed apoptotic mechanisms, alcohol damages the neural stem cell progenitor pools, like radial glia, that give rise to neurons and the supporting glial cells in the CNS. […] Damage to these cell populations can decrease their volumes and it can cause structural abnormalities, which can impact the CNS from its initial development through to the development of neural networks.

• #19 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas

  Scientists have debated whether or not the alcohol-induced apoptosis prematurely eliminates specific cell populations during development, such as cranial neural crest cells, retinal cells, cerebellum cells and other vulnerable populations. […] Numerous studies confirm that the biomechanical mechanism occurring during this cell death as being a capsase-3 enzyme activation cascade, which is a component of programmed cell death by apoptosis. […] Scientists have also hypothesized that this programmed cell death may be triggered by the metabolic breakdown of alcohol into acetaldehyde, which can inhibit the formation of retinoic acid. […] In addition to those proposed apoptotic mechanisms, alcohol damages the neural stem cell progenitor pools, like radial glia, that give rise to neurons and the supporting glial cells in the CNS. […] Damage to these cell populations can decrease their volumes and it can cause structural abnormalities, which can impact the CNS from its initial development through to the development of neural networks.

• #20 Fetal Alcohol Syndrome (FAS) | Embryo Project Encyclopedia

  https://embryo.asu.edu/pages/fetal-alcohol-syndrome-fas

  Scientists have debated whether or not the alcohol-induced apoptosis prematurely eliminates specific cell populations during development, such as cranial neural crest cells, retinal cells, cerebellum cells and other vulnerable populations. […] Numerous studies confirm that the biomechanical mechanism occurring during this cell death as being a capsase-3 enzyme activation cascade, which is a component of programmed cell death by apoptosis. […] Scientists have also hypothesized that this programmed cell death may be triggered by the metabolic breakdown of alcohol into acetaldehyde, which can inhibit the formation of retinoic acid. […] In addition to those proposed apoptotic mechanisms, alcohol damages the neural stem cell progenitor pools, like radial glia, that give rise to neurons and the supporting glial cells in the CNS. […] Damage to these cell populations can decrease their volumes and it can cause structural abnormalities, which can impact the CNS from its initial development through to the development of neural networks.

• #21

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  In a concluding section on Future Directions, we pose the possibility that epigenetic changes in early development that can affect OPC and OL function in adulthood. […] The mechanisms underlying the white matter damage are not well understood, but because CNS myelin is formed by oligodendrocytes (OLs), a greater focus on these cells is warranted. […] However, effects on glial cells have been reported. […] The EtOH-induced decreases in OL and OPC numbers were transient, although myelination deficits persisted into adulthood. […] It was suggested that EtOH exposure interferes with the expression of OL lineage-specific markers in human neural progenitor cells undergoing OL lineage progression, blocks the differentiation of OL lineage stem cells, and causes a downregulation of the late OPC marker, MBP.

• #22

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain dysmyelination. […] Recent studies have shed light on the molecular mechanisms underlying these white matter abnormalities. Rodent models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor cells. Ethanol exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological specimens. […] The accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal development.

• #23

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  Thus, two mechanisms were proposed to account for the effects of EtOH exposure in causing dysmyelination – a delay in maturation of OPC to OL, as well as a loss of mature OL, and apoptotic signaling may contribute to both of these. […] Knowledge regarding the molecular mechanisms causing the abnormalities is limited. […] Recent findings of EtOH-induced suppression of OL maturation associated with altered expression of chemokines and fatty acids suggest that EtOH-induced delay in differentiation of OPCs can contribute to the failure of remyelination and repair in FAS. […] Thus, part of the neurotoxic effect of EtOH may be mediated by release of TNF- from EtOH-activated microglia. […] Recent data on the effect of EtOH on OL development demonstrated that expression of the neuroprotective IGF-1 was reduced, while the neurotoxic TNF- was increased.

• #24

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  Thus, two mechanisms were proposed to account for the effects of EtOH exposure in causing dysmyelination – a delay in maturation of OPC to OL, as well as a loss of mature OL, and apoptotic signaling may contribute to both of these. […] Knowledge regarding the molecular mechanisms causing the abnormalities is limited. […] Recent findings of EtOH-induced suppression of OL maturation associated with altered expression of chemokines and fatty acids suggest that EtOH-induced delay in differentiation of OPCs can contribute to the failure of remyelination and repair in FAS. […] Thus, part of the neurotoxic effect of EtOH may be mediated by release of TNF- from EtOH-activated microglia. […] Recent data on the effect of EtOH on OL development demonstrated that expression of the neuroprotective IGF-1 was reduced, while the neurotoxic TNF- was increased.

• #25

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  Thus, two mechanisms were proposed to account for the effects of EtOH exposure in causing dysmyelination – a delay in maturation of OPC to OL, as well as a loss of mature OL, and apoptotic signaling may contribute to both of these. […] Knowledge regarding the molecular mechanisms causing the abnormalities is limited. […] Recent findings of EtOH-induced suppression of OL maturation associated with altered expression of chemokines and fatty acids suggest that EtOH-induced delay in differentiation of OPCs can contribute to the failure of remyelination and repair in FAS. […] Thus, part of the neurotoxic effect of EtOH may be mediated by release of TNF- from EtOH-activated microglia. […] Recent data on the effect of EtOH on OL development demonstrated that expression of the neuroprotective IGF-1 was reduced, while the neurotoxic TNF- was increased.

• #26 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  Fetal alcohol spectrum disorders (FASD) are a set of abnormalities caused by prenatal exposure to ethanol and are characterized by developmental defects in the brain that lead to various overt and non-overt physiological abnormalities. […] However, the molecular mechanisms of neuron–glia interactions that lead to the development of FASD are not clearly understood. […] It has been reported that alcohol exposure during pregnancy affects the morphology of glial cells (including all radial glia and other transient glial structures), which induces a phenotypic shift and activates inflammatory signaling in the fetal brain. The neuroinflammatory shifts in glial cell function are detrimental to neuron survival and ultimately responsible for neuronal cell death. […] Therefore, to better understand FASD pathogenesis, we will emphasize neuron–glial–immune interactions in more detail.

• #27 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  Importantly, microglia represent almost 80% of all brain-resident immune cells. […] These activated microglia have shown to increase the release of pro-inflammatory molecules including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), nitrite, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) through the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. […] The Toll-like receptor (TLR)4 is the most studied member of the TLR family that responds to inflammatory stimuli via mediating inflammatory signal transduction. […] These results imply that TLR4 and downstream signaling pathways are crucial for ethanol-induced activation of microglia. […] Together, these studies show that alcohol exposure activates microglia, which then release toxic factors that promote neuronal apoptosis.

• #28 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  Importantly, microglia represent almost 80% of all brain-resident immune cells. […] These activated microglia have shown to increase the release of pro-inflammatory molecules including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), nitrite, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) through the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. […] The Toll-like receptor (TLR)4 is the most studied member of the TLR family that responds to inflammatory stimuli via mediating inflammatory signal transduction. […] These results imply that TLR4 and downstream signaling pathways are crucial for ethanol-induced activation of microglia. […] Together, these studies show that alcohol exposure activates microglia, which then release toxic factors that promote neuronal apoptosis.

• #29 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  The interaction between glial cells (including astrocytes) and vasculature is critical for the maintenance of BBB and the proper functions of the nervous system. […] Thus, it is important to understand how astrocyte functions are altered during alcohol exposure to determine the exact neuron–glia–immune relationship. […] Ethanol exposures trigger pro-inflammatory signaling pathways in astrocytes and that the bidirectional communications between astrocytes and microglia further modulate CNS inflammation through the release of multiple cytokines and inflammatory mediators. […] The activation of NLRP3 in astrocytes by ethanol has been found to cause inflammation and neuronal death. […] Together, these results indicate that ethanol exposures trigger pro-inflammatory signaling pathways in astrocytes and that the bidirectional communications between astrocytes and microglia further modulate CNS inflammation through the release of multiple cytokines and inflammatory mediators.

• #30 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  The interaction between glial cells (including astrocytes) and vasculature is critical for the maintenance of BBB and the proper functions of the nervous system. […] Thus, it is important to understand how astrocyte functions are altered during alcohol exposure to determine the exact neuron–glia–immune relationship. […] Ethanol exposures trigger pro-inflammatory signaling pathways in astrocytes and that the bidirectional communications between astrocytes and microglia further modulate CNS inflammation through the release of multiple cytokines and inflammatory mediators. […] The activation of NLRP3 in astrocytes by ethanol has been found to cause inflammation and neuronal death. […] Together, these results indicate that ethanol exposures trigger pro-inflammatory signaling pathways in astrocytes and that the bidirectional communications between astrocytes and microglia further modulate CNS inflammation through the release of multiple cytokines and inflammatory mediators.

• #31 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-018-0095-4

  The aim of this paper is to provide a current status and a gap analysis of FASD knowledge with a focus on molecular pathways. […] Long-term effects include changes in the levels of growth factors, cytoskeleton, cell adhesion molecules, and in the neurotransmitter system. […] Especially neuronal crest formation is affected probably due to destabilization of -catenin. […] Furthermore, EtOH itself and oxidative stress-induced downstream pathways cause changes in DNA methylation, leading to changes in epigenetic imprinting. […] There are several omics data driven approaches to investigate the downstream effects of EtOH-induced damage, which lead to the distinct phenotype of FASD. […] The genetic background of FASD susceptibility is not yet fully understood but there are hints that different polymorphisms of ADH, CYP and taste receptors play a role. […] As oxidative stress is likely a major pathway of EtOH toxicity in FASD, antioxidants would be the logic treatment of choice. […] Another possibility would be to look at the downstream pathways for drug targets/interventions.

• #32 Epigenetics of Trauma Transmission and Fetal Alcohol Spectrum Disorder: What Does the Evidence Support?

  https://www.mdpi.com/1660-4601/20/17/6706

  Fetal alcohol spectrum disorder (FASD) results from the teratogenic impact of alcohol consumption during pregnancy. […] It has been hypothesized that children born with FASD are more susceptible to trauma-related cognitive and developmental deficits, and one theory is that prenatal alcohol exposure could alter the epigenome in a way that alters the stress response. […] The molecular mechanisms underpinning the teratogenic effects of alcohol exposure are complex and poorly understood; however, evidence continues to help elucidate the role of epigenetic mechanisms. […] It is generally accepted that prenatal alcohol exposure in utero can cause epigenetic modifications in the developing fetus. […] Changes to epigenetic modifications are the likely mechanism mediating these changes to the transcriptome.

• #33 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  In summary, developmental exposures to ethanol are associated with delayed maturation of oligodendrocytes that may cause a long-lasting effect on myelination in children and adolescents with FASD. […] Epigenetics has been recognized to play an important role in the emergence of a specific phenotype (M1 or M2) of microglia following an environmental challenge. […] It is evident from the data of these studies that alcohol-induced epigenetic abnormalities can alter microglial activity to make them more neurotoxic. […] Further research may be necessary to understand how other glial cells are epigenetically primed and interact with neurons during the pathogenesis of FASD, allowing for the development of novel therapies to combat stress-related problems associated with FASD. […] These data suggest that exosomes play an important role in microglia–neuron interaction.

• #34 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  In summary, developmental exposures to ethanol are associated with delayed maturation of oligodendrocytes that may cause a long-lasting effect on myelination in children and adolescents with FASD. […] Epigenetics has been recognized to play an important role in the emergence of a specific phenotype (M1 or M2) of microglia following an environmental challenge. […] It is evident from the data of these studies that alcohol-induced epigenetic abnormalities can alter microglial activity to make them more neurotoxic. […] Further research may be necessary to understand how other glial cells are epigenetically primed and interact with neurons during the pathogenesis of FASD, allowing for the development of novel therapies to combat stress-related problems associated with FASD. […] These data suggest that exosomes play an important role in microglia–neuron interaction.

• #35 Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

  https://www.mdpi.com/2073-4409/12/18/2323

  These studies signify the in utero exosomal transfer of ethanol effect on stem cell maintenance and differentiation, including miRNA profile. […] It would be interesting to study if correcting the altered level of exosome-derived miRNAs in amniotic fluid using miRNA mimics or inhibitors can mitigate the detrimental effect of alcohol on development.

• #36 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. […] The risk of FASD increases with the amount consumed, the frequency of consumption, and the longer duration of alcohol consumption during pregnancy, particularly binge drinking. […] Diagnosis is based on an assessment of growth, facial features, central nervous system, and alcohol exposure by a multidisciplinary team of professionals. The main criteria for diagnosis of FASD are nervous system damage and alcohol exposure, with FAS including congenital malformations of the lips and growth deficiency. […] Almost all experts recommend that the mother abstain from alcohol use during pregnancy to prevent FASDs. […] After a pregnant woman consumes alcohol, the alcohol crosses through the placenta and umbilical cord to the developing fetus. Alcohol metabolizes slowly in the fetus and remains for a long time when compared to an adult.

• #37 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448178/

  Fetal alcohol syndrome is one of a spectrum of disorders under the umbrella term of fetal alcohol spectrum disorder (FASD). There is a total of five disorders that comprise fetal alcohol spectrum disorders. They are fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), a neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE), and alcohol-related birth defects (ARBD). All of these fetal alcohol spectrum disorders are used to classify the wide-ranging physical and neurological effects that prenatal alcohol exposure can inflict on a fetus. […] All of the conditions that comprise fetal alcohol spectrum disorders stem from one common cause, which is prenatal exposure to alcohol. Alcohol is extremely teratogenic to a fetus. Its effects are wide-ranging and irreversible. Although higher amounts of prenatal alcohol exposure have been linked to increased incidence and severity of fetal alcohol spectrum disorders, there are no studies that demonstrate a safe amount of alcohol that can be consumed during pregnancy. There is also no safe time during pregnancy in which alcohol can be consumed without risk to the fetus. Alcohol is teratogenic during all three trimesters. In summary, any amount of alcohol consumed at any point during pregnancy has the potential cause of irreversible damage that can lead to a fetal alcohol spectrum disorder.

• #38 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-018-0095-4

  The aim of this paper is to provide a current status and a gap analysis of FASD knowledge with a focus on molecular pathways. […] Long-term effects include changes in the levels of growth factors, cytoskeleton, cell adhesion molecules, and in the neurotransmitter system. […] Especially neuronal crest formation is affected probably due to destabilization of -catenin. […] Furthermore, EtOH itself and oxidative stress-induced downstream pathways cause changes in DNA methylation, leading to changes in epigenetic imprinting. […] There are several omics data driven approaches to investigate the downstream effects of EtOH-induced damage, which lead to the distinct phenotype of FASD. […] The genetic background of FASD susceptibility is not yet fully understood but there are hints that different polymorphisms of ADH, CYP and taste receptors play a role. […] As oxidative stress is likely a major pathway of EtOH toxicity in FASD, antioxidants would be the logic treatment of choice. […] Another possibility would be to look at the downstream pathways for drug targets/interventions.

• #39 Fetal alcohol spectrum disorder – Wikipedia

  https://en.wikipedia.org/wiki/Fetal_alcohol_spectrum_disorder

  Although alcohol is known to be a teratogen (causing birth defects), the exact biological mechanisms for the development of FAS or FASD are unknown. However, clinical and animal studies have identified a broad spectrum of pathways through which maternal alcohol can negatively affect the outcome of a pregnancy. […] Genetic examinations have revealed a continuum of long-lasting molecular effects that are not only timing specific but are also dosage specific; with even moderate amounts being able to cause alterations. […] Additionally, ethanol may alter fetal development by interfering with retinoic acid signaling as acetaldehyde can compete with retinaldehyde and prevents its oxidation to retinoic acid.

• #40 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448178/

  The exact mechanism by which alcohol causes its teratogenic effects is not known. For obvious ethical reasons, formal studies on the effects of alcohol on human brain development are limited. Most of our data come from animal models and associations with alcohol exposure. […] We do know that alcohol is a teratogen that causes irreversible damage to the central nervous system (CNS). From associations with alcohol exposure, we are aware that that damage is widespread, causing not only a decrease in brain volume but also damage to structures within the brain. We also know from associations that high levels of alcohol consumption in the first trimester resulted in an increased likelihood of facial and brain anomalies. High levels of alcohol consumption in the second trimester are associated with increased incidences of spontaneous abortions. Lastly, in the third trimester, high levels of alcohol consumption are associated with decreased height, weight, and brain volume. Associations with alcohol exposure show that the neurobehavioral deficits associated with fetal alcohol spectrum disorders can occur within a wide range of exposure to alcohol and at any point in the pregnancy. […] From animal models, we know that prenatal alcohol exposure affects all stages of brain development through a variety of mechanisms, the most significant of which result in cognitive, motor, and behavioral dysfunction.

• #41 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  Although prenatal exposure is a necessary condition, the genetic aetiology and pathogenesis of the neurodevelopmental disorders observed in cases of FASD is unknown. The discovery of genetic and epigenetic markers of FASD would contribute greatly to its diagnosis. […] No amount of alcohol is safe to consume during pregnancy, although its negative effects depend mainly on the dose, duration and pattern of consumption and individual genetic susceptibility. […] The current evidence suggests that low-to-moderate prenatal exposure can result in persistent changes in multiple neurotransmitters and neuromodulators and cause neurocognitive impairment. […] Significant exposure to alcohol in the first trimester is mainly associated with facial anomalies and major structural anomalies, in the second trimester, with increased risk of spontaneous miscarriage, and in the third trimester, with impaired weight gain, linear growth and brain growth.

• #42 Fetal Alcohol Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK448178/

  The exact mechanism by which alcohol causes its teratogenic effects is not known. For obvious ethical reasons, formal studies on the effects of alcohol on human brain development are limited. Most of our data come from animal models and associations with alcohol exposure. […] We do know that alcohol is a teratogen that causes irreversible damage to the central nervous system (CNS). From associations with alcohol exposure, we are aware that that damage is widespread, causing not only a decrease in brain volume but also damage to structures within the brain. We also know from associations that high levels of alcohol consumption in the first trimester resulted in an increased likelihood of facial and brain anomalies. High levels of alcohol consumption in the second trimester are associated with increased incidences of spontaneous abortions. Lastly, in the third trimester, high levels of alcohol consumption are associated with decreased height, weight, and brain volume. Associations with alcohol exposure show that the neurobehavioral deficits associated with fetal alcohol spectrum disorders can occur within a wide range of exposure to alcohol and at any point in the pregnancy. […] From animal models, we know that prenatal alcohol exposure affects all stages of brain development through a variety of mechanisms, the most significant of which result in cognitive, motor, and behavioral dysfunction.

• #43 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  Although prenatal exposure is a necessary condition, the genetic aetiology and pathogenesis of the neurodevelopmental disorders observed in cases of FASD is unknown. The discovery of genetic and epigenetic markers of FASD would contribute greatly to its diagnosis. […] No amount of alcohol is safe to consume during pregnancy, although its negative effects depend mainly on the dose, duration and pattern of consumption and individual genetic susceptibility. […] The current evidence suggests that low-to-moderate prenatal exposure can result in persistent changes in multiple neurotransmitters and neuromodulators and cause neurocognitive impairment. […] Significant exposure to alcohol in the first trimester is mainly associated with facial anomalies and major structural anomalies, in the second trimester, with increased risk of spontaneous miscarriage, and in the third trimester, with impaired weight gain, linear growth and brain growth.

• #44 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  Although the clinical picture based on the timing of exposure is well defined, neurocognitive and behavioural sequelae may result from exposure at any time during gestation. […] Most patients only exhibit impairment in areas like attention, executive function, spatial and working memory and adaptive behaviour, but a specific neurocognitive and behavioural profile for FASD has yet to be defined. […] The diagnosis is based on international guidelines, with diagnostic criteria including facial features, delayed growth, structural and/or functional disorders of the central nervous system (CNS) and prenatal exposure to alcohol. […] There is considerable interest in identifying the neurocognitive profile of patients with FASD to guide their identification, as there are no universally accepted criteria and the high prevalence of psychological and psychiatric comorbidities in FASD poses challenges to accurate diagnosis.

• #45 Adjusting key protein could improve brain function in children with fetal alcohol syndrome – Children’s NationalSearchLink to: Pioneering gene therapy as a treatment for sickle cell diseaseLink to: Mission critical: Pentagon awards grant to combine two no

  https://innovationdistrict.childrensnational.org/adjusting-key-protein-could-improve-brain-function-in-children-with-fetal-alcohol-syndrome/

  Researchers at Children’s National are testing whether controlling the level of apolipoprotein E could serve as an effective treatment for the poor neurobehavioral outcomes tied to fetal alcohol spectrum disorders. […] Reduced levels of a protein – called apolipoprotein E – are responsible for the lifelong cognitive and neurological symptoms in fetal alcohol spectrum disorders (FASD), according to a new study published in the journal Molecular Psychiatry. […] “The new data shows that we understand the mechanism by which prenatal alcohol exposure causes a decrease of the APOE level in the brain. […] For the first time, researchers found that plasma levels of APOE were reduced in children with FASD, which strongly supports a potential target for therapy. […] “We found that providing a drug that activates the APOE receptor rescued learning deficits and anxiety in pre-clinical models,” said Masaaki Torii, Ph.D., principal investigator at the Center for Neuroscience Research. “The implications offer an exciting glimpse into possible therapies for some of the neurological harms associated with prenatal alcohol exposure and FASD.”

• #46 Adjusting key protein could improve brain function in children with fetal alcohol syndrome – Children’s NationalSearchLink to: Pioneering gene therapy as a treatment for sickle cell diseaseLink to: Mission critical: Pentagon awards grant to combine two no

  https://innovationdistrict.childrensnational.org/adjusting-key-protein-could-improve-brain-function-in-children-with-fetal-alcohol-syndrome/

  Researchers at Children’s National are testing whether controlling the level of apolipoprotein E could serve as an effective treatment for the poor neurobehavioral outcomes tied to fetal alcohol spectrum disorders. […] Reduced levels of a protein – called apolipoprotein E – are responsible for the lifelong cognitive and neurological symptoms in fetal alcohol spectrum disorders (FASD), according to a new study published in the journal Molecular Psychiatry. […] “The new data shows that we understand the mechanism by which prenatal alcohol exposure causes a decrease of the APOE level in the brain. […] For the first time, researchers found that plasma levels of APOE were reduced in children with FASD, which strongly supports a potential target for therapy. […] “We found that providing a drug that activates the APOE receptor rescued learning deficits and anxiety in pre-clinical models,” said Masaaki Torii, Ph.D., principal investigator at the Center for Neuroscience Research. “The implications offer an exciting glimpse into possible therapies for some of the neurological harms associated with prenatal alcohol exposure and FASD.”

• #47 Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02586-6

  A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

• #48 Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02586-6

  This study reports potential mechanism of treatment for patients with PAE could involve the gene that encodes the protein called apolipoprotein E (APOE). APOE controls synaptic plasticity, which is crucial for brain function. […] In this study, we identified an epigenetic mechanism that drives the reduction in brain APOE in PAE mice. Our data also showed that postnatal administration of an APOE receptor agonist (APOE-RA) rescued both learning deficits and anxiety in PAE mice. […] These results indicate that reduced APOE expression due to PAE critically contributes to neurocognitive deficits, and a functional APOE polymorphism is a genetic risk factor that augments the effects of PAE on cognitive performance. Improvement of learning deficits when APOE was increased via an agonist in PAE mice suggest that APOE replenishment is a potential therapy for FASD patients.

• #49 Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-024-02586-6

  Our previous study found that PAE caused motor learning deficits in mice. Therefore, a correlation analysis between the expression of the DEGs and the motor learning index in PAE mice was conducted. We found that Apoe expression in cluster 2 demonstrated the highest (positive) correlation with the motor learning index. […] The PBMC RNA sequencing and immunohistochemical analysis of the PAE model supported the possibility that the hypoexpression of APOE by PAE in the brain could be involved in neurobehavioral changes in PAE offspring. […] To examine whether application of APOE mitigates neurobehavioral deficits in PAE mice, we tested APOE-RA (or COG 133), which contains the receptor binding unit of human APOE and binds to LRP1, but does not include the lipid-binding domain. […] Our previous study found that the expression of potassium intermediate/small calcium-activated channel, subfamily N, member 2 (KCNN2) was upregulated in the motor cortex of PAE mice, and knockdown of Kcnn2 expression in the motor cortex or pharmacological inhibition of KCNN2 function improved the motor learning deficits in PAE mice. […] In conclusion, our study identified a mechanism by which PAE causes a decrease in the APOE level in the brain through an epigenetic mechanism, leading to neurobehavioral deficits.

• #50 New research helps explain how fetal alcohol exposure increases risk of developmental disorders | Leslie Dan Faculty of Pharmacy, University of Toronto

  https://www.pharmacy.utoronto.ca/news-announcements/new-research-helps-explain-how-fetal-alcohol-exposure-increases-risk-developmental-disorders

  Nowe badania z U of Ts Leslie Dan Faculty of Pharmacy odkryły mechanizmy, które pomagają wyjaśnić, jak białko podatności na raka piersi 1 (BRCA1), najlepiej znane z roli w supresji raka piersi, pomaga zapobiegać zaburzeniom rozwojowym i jak ekspozycja na alkohol może zwiększać ryzyko tych zaburzeń. […] Ktoś z deficytem BRCA1 z powodu czynników genetycznych lub środowiskowych może być w większym ryzyku wystąpienia zaburzeń spektrum alkoholowego płodu po ekspozycji na alkohol w czasie ciąży, mówi Drake. […] Te wyniki dają lepsze zrozumienie, jak deficyt BRCA1 może zwiększać ryzyko zaburzeń spektrum alkoholowego płodu po pojedynczej ekspozycji na alkohol w okresie rozwoju płodowego.

• #51 Review and gap analysis: molecular pathways leading to fetal alcohol spectrum disorders | Molecular Psychiatry

  https://www.nature.com/articles/s41380-018-0095-4

  The aim of this paper is to provide a current status and a gap analysis of FASD knowledge with a focus on molecular pathways. […] Long-term effects include changes in the levels of growth factors, cytoskeleton, cell adhesion molecules, and in the neurotransmitter system. […] Especially neuronal crest formation is affected probably due to destabilization of -catenin. […] Furthermore, EtOH itself and oxidative stress-induced downstream pathways cause changes in DNA methylation, leading to changes in epigenetic imprinting. […] There are several omics data driven approaches to investigate the downstream effects of EtOH-induced damage, which lead to the distinct phenotype of FASD. […] The genetic background of FASD susceptibility is not yet fully understood but there are hints that different polymorphisms of ADH, CYP and taste receptors play a role. […] As oxidative stress is likely a major pathway of EtOH toxicity in FASD, antioxidants would be the logic treatment of choice. […] Another possibility would be to look at the downstream pathways for drug targets/interventions.

• #52 New avenue to correct memory deficit caused by fetal alcohol spectrum disorders – El·lipse

  https://ellipse.prbb.org/new-avenue-to-correct-memory-deficit-caused-by-fetal-alcohol-spectrum-disorders/

  A groundbreaking experimental study conducted by a research team from the Department of Medicine and Life Sciences (MELIS-UPF) in collaboration with the Hospital del Mar Research Institute has identified and validated a neurobiological mechanism to correct memory deficits caused by fetal alcohol spectrum disorders (FASD) in mice. […] This impairment is linked to changes in the endocannabinoid system, specifically a reduction in the expression of the PPAR- receptor, which plays a critical role in learning and memory processes. […] Moreover, the study proposes a potential treatment using the drug pioglitazone, commonly used to control blood sugar levels, as it stimulates PPAR receptors. This treatment was shown to alleviate cognitive memory deficits in mice with FASD during infancy.

• #53 New avenue to correct memory deficit caused by fetal alcohol spectrum disorders – El·lipse

  https://ellipse.prbb.org/new-avenue-to-correct-memory-deficit-caused-by-fetal-alcohol-spectrum-disorders/

  A groundbreaking experimental study conducted by a research team from the Department of Medicine and Life Sciences (MELIS-UPF) in collaboration with the Hospital del Mar Research Institute has identified and validated a neurobiological mechanism to correct memory deficits caused by fetal alcohol spectrum disorders (FASD) in mice. […] This impairment is linked to changes in the endocannabinoid system, specifically a reduction in the expression of the PPAR- receptor, which plays a critical role in learning and memory processes. […] Moreover, the study proposes a potential treatment using the drug pioglitazone, commonly used to control blood sugar levels, as it stimulates PPAR receptors. This treatment was shown to alleviate cognitive memory deficits in mice with FASD during infancy.

• #54 Exercise reduces physical alterations in a rat model of fetal alcohol spectrum disorders | Biological Research | Full Text

  https://biolres.biomedcentral.com/articles/10.1186/s40659-024-00520-2

  PAE generates alterations at the muscle level and in executive function; however it is unknown whether different protocols of voluntary or programmed exercises may be beneficial in the muscular response to tests of strength, coordination, agility, or balance in adolescents PAE. […] The purpose of this study is to investigate whether physical disabilities persist during adolescence and to evaluate different protocols of exercise as a therapeutic intervention in a rat model of FASD. […] We showed that PAE decreases strength and agility in adolescent Sprague Dawley rats, however, we did not observe differences in coordination and balance in PND21. […] Moreover, this is the first study showing the effectiveness of exercise can mitigate motor impairment in PAE adolescent animals. […] The PAE-induces impairment on strength and agility observed in these results could be explained by for a delay in the maturation process in the nerve-muscle junction, features that have been shown at PND14 and PND21 in PAE rats.

• #55 Exercise reduces physical alterations in a rat model of fetal alcohol spectrum disorders | Biological Research | Full Text

  https://biolres.biomedcentral.com/articles/10.1186/s40659-024-00520-2

  PAE generates alterations at the muscle level and in executive function; however it is unknown whether different protocols of voluntary or programmed exercises may be beneficial in the muscular response to tests of strength, coordination, agility, or balance in adolescents PAE. […] The purpose of this study is to investigate whether physical disabilities persist during adolescence and to evaluate different protocols of exercise as a therapeutic intervention in a rat model of FASD. […] We showed that PAE decreases strength and agility in adolescent Sprague Dawley rats, however, we did not observe differences in coordination and balance in PND21. […] Moreover, this is the first study showing the effectiveness of exercise can mitigate motor impairment in PAE adolescent animals. […] The PAE-induces impairment on strength and agility observed in these results could be explained by for a delay in the maturation process in the nerve-muscle junction, features that have been shown at PND14 and PND21 in PAE rats.

• #56 Exercise reduces physical alterations in a rat model of fetal alcohol spectrum disorders | Biological Research | Full Text

  https://biolres.biomedcentral.com/articles/10.1186/s40659-024-00520-2

  Furthermore, ethanol is a teratogen for the development of myocytes, which can alter the organization of sarcomeres and myofilaments, resulting in embryopathic cytoskeletal dysgenesis, caused by dysplasia in the muscle structure rather than by degeneration, since there is no inflammatory response or fibrotic. […] The observed change in PAE, in contrast to control animals, aligns with the concept of hormesis which refers to a biological phenomenon wherein exposure to low doses of potentially harmful stressors yields beneficial effects. […] Our study provides a basis for resistance and endurance training in PAE subjects, which generates an increase in physical qualities. […] The possible limitations of the present study are the number of individuals per group, even though the size effect was calculated, since perhaps the number limits the observation of more robust significance of the study. […] In conclusion, the most effective protocol for strength gain was resistance training due to the characteristics of the work and its individualization.

• #57 Fetal alcohol spectrum disorder: pathogenesis and mechanisms – PubMed

  https://pubmed.ncbi.nlm.nih.gov/25307590/

  This chapter provides an overview of animal model-based studies that have generated information critical to our understanding of the pathogenesis and mechanisms underlying alcohol-induced birth defects, in particular those involving the brain. […] Components of the cascades of alcohol-induced damage that are considered herein are excessive cell death, changes in the cell cycle and proliferation, cell migration, cell morphogenesis, and gene expression as well as free radical damage and interference with cell signaling. […] The roles played by one or more of these various factors in the genesis of structural and functional birth defects are dependent upon alcohol exposure patterns and dosage, the involved tissue, and the prenatal stage(s) at the time of exposure. […] Technologic advances and rapidly increasing knowledge in the fields of genetics, cell, developmental, and neurobiology are critical to accurately piecing together experimental evidence in refining our understanding of the genesis of alcohol-induced birth defects, to the planning and execution of future studies, and to applying the knowledge gained to diminish the severity or occurrence of fetal alcohol spectrum disorder.

• #58

  https://journals.lww.com/nrronline/fulltext/2022/03000/oligodendrocyte_pathology_in_fetal_alcohol.5.aspx

  Thus, the significant correlations that were observed between alcohol measures and DTI values indicated that the white matter damage found in several regions was dose-dependent. […] In order identify proper targets for therapeutic development, it will be necessary to further determine the complex biological disruptions induced in the fetal brain by alcohol exposure, and to identify the links between glial dysfunction and structural, functional and behavioral abnormalities.

• #59 Neurocognitive and behavioral profile of fetal alcohol spectrum disorder | Anales de Pediatría

  https://analesdepediatria.org/en-neurocognitive-behavioral-profile-fetal-alcohol-articulo-S2341287921001344

  A recent study attempted to identify a neurodevelopmental pattern sensitive and specific for FASD. […] Foetal alcohol spectrum syndrome is usually a diagnosis of exclusion after ruling out genetic and malformative disorders that share some of its clinical features. […] Thus, 3 areas need to be assessed that are interrelated and have to be affected: physical features; neurocognitive impairment (intellectual quotient, memory, executive function, abstract reasoning, receptive and expressive language, visual-motor integration and sensory processing, daily living and adaptive skills and processing speed) and behavioural impairment (emotional dysregulation, executive dysfunction, inattention, hyperactivity, impulsivity, irritability or negative affect, sleep disorders, and impaired social skills, adaptive behaviour and/or social communication). […] The damage caused during intrauterine life by prenatal alcohol exposure is irreversible. Nevertheless, early intervention can prevent the development of secondary disorders and improve neurodevelopmental outcomes.

• #60

  https://grantome.com/grant/NIH/R01-AA026068-03

  These data will help to determine the precise mechanisms by which ethanol alters development. […] Together, these novel experiments will provide fundamental insights into the pathogenic mechanisms underlying the effects of ethanol exposure during development, and propel alcohol research into new primary ciliary-related studies. […] The goal of this work is to increase our understanding of the mechanisms underlying FASD in order to aid in prevention and intervention efforts.

• #61 Advances in Research on Fetal Alcohol Spectrum Disorders – News from the National Institute on Alcohol Abuse and Alcoholism

  https://niaaa.scienceblog.com/334/advances-in-research-on-fetal-alcohol-spectrum-disorders/

  Fetal alcohol spectrum disorders (FASD) are the broad range of neurodevelopmental and physical effects that result from prenatal exposure to alcohol. […] Basic, translational, and clinical research are providing valuable insight into the mechanisms that underlie the learning deficits and health problems associated with FASD, thereby shedding light on potential intervention strategies. […] The researchers demonstrated that increased Kcnn2 expression correlated with deficits in motor skill learning caused by prenatal alcohol exposure. […] Prenatal alcohol exposure contributes to an array of lifelong physical, cognitive, and behavioral problems, says Dr. Koob.

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