Ethanol-mediated alterations in oligodendrocyte differentiation in the developing brain

Darbinian, Nune; Darbinyan, Armine; Merabova, Nana; Bajwa, Ahsun; Tatevosian, Gabriel; Martirosyan, Diana; Zhao, Huaqing; Selzer, Michael E.; Goetzl, Laura

doi:10.1016/j.nbd.2020.105181

Cited by 27 publications

(106 citation statements)

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“…Many human and animal studies have focused on late gestation effects of EtOH, including degeneration and death of neurons, synaptic loss, and activation of microglia and astrocytes (Gatford et al, 2007;Guizzetti et al, 2014;Saito et al, 2016). However, first trimester EtOH exposure is more common and thus, more likely to directly affect OPC differentiation and function (Darbinian et al, 2021). In addition, while the role of EtOH-induced neuroinflammation in FASD has been studied in mid to late gestation animal models (Kane et al, 2012(Kane et al, , 2014Kane and Drew, 2016;Newville et al, 2017), less is known regarding effects in humans, particularly in early gestation, including on OL development.…”

Section: Fetal Alcohol Syndrome and Oligodendrocyte Injurymentioning

confidence: 99%

“…Thus, investigation of the expression of cytokines and chemokines that regulate key signaling pathways in the human developing brain, including those that remain expressed in early postnatal life, is important. Male fetuses are more vulnerable than females to EtOH exposure (May et al, 2017;Darbinian et al, 2021), but human data regarding the mechanism of these sex differences, including on OL pathology, have been limited.…”

Section: Fetal Alcohol Syndrome and Oligodendrocyte Injurymentioning

confidence: 99%

“…A wide range of abnormalities of glial cells, including astrocytes, has been described in FASD (Guizzetti et al, 2014). Recent findings indicated that EtOH reduce late markers of OL maturation, and delay differentiation of OLs (Darbinian et al, 2021). 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.…”

Section: Effect Of Ethanol Exposure On Markers Of Oligodendrocyte Precursor Cell/ Oligodendrocyte Mrna and Protein Expressionmentioning

confidence: 99%

“…Apoptotic signaling was increased in both OPC and OL. 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 (Darbinian et al, 2021).…”

Section: Effect Of Ethanol Exposure On Markers Of Oligodendrocyte Precursor Cell/ Oligodendrocyte Mrna and Protein Expressionmentioning

confidence: 99%

“…including CXC ligands CXCL1/GRO, IL-8, GCP2/CXCL16, ENA-78 and MCP1, in developing brain. Recent findings of EtOHinduced suppression of OL maturation associated with altered expression of chemokines and fatty acids (Sowell et al, 2020) suggest that EtOH-induced delay in differentiation of OPCs can contribute to the failure of remyelination and repair in FAS (Darbinian et al, 2021). It is possible that secretion of these chemokines also may have pathological effects on other cells.…”

Section: Reviewmentioning

confidence: 99%

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Oligodendrocyte pathology in fetal alcohol spectrum disorders

Darbinian

Selzer

2022

Neural Regen Res

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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. Several studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system, including multiple sclerosis and fetal alcohol syndrome. Acute ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues, while ethanol increased the expression of tumor necrosis factor α in mouse and human neurons. White matter lesions have been induced in the developing sheep brain by alcohol exposure in early gestation. Rat fetal alcohol syndrome models have shown reduced axon diameters, with thinner myelin sheaths, as well as reduced numbers of oligodendrocytes, which were also morphologically aberrant oligodendrocytes. Expressions of markers for mature myelination, including myelin basic protein, also were reduced. 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. Future studies using fetal oligodendrocyte- and oligodendrocyte precursor cell-derived exosomes isolated from the mother’s blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in adulthood. By combining various imaging modalities with molecular studies, it may be possible to determine which fetuses are at risk and to intervene therapeutically early in the pregnancy.

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