Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

Abstract

BackgroundIn utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains.ResultsOur findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm3) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains.ConclusionsIn utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes.

Isoflurane-induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain

“…3,15 Alcohol, which has both N -methyl-D-aspartate receptor antagonist and γ-aminobutyric acid A agonist properties, causes a particularly severe neuroapoptosis reaction in both the infant rodent 1,4 and fetal NHP brain, 12 and alcohol is well known to have deleterious effects on the fetal human brain and have long-term adverse neurobehavioral consequences. 38 Also relevant is evidence that alcohol, like isoflurane, causes both neuroapoptosis 12 and oligoapoptosis, 39 and that both alcohol 12 and isoflurane exposure (as shown in this study) of NHP fetuses causes severe damage in the NHP basal ganglia, which coincides with evidence that loss of neuronal mass in the basal ganglia is a consistent finding in patients diagnosed with fetal alcohol spectrum disorder. 38 Similarly, recent neuroimaging evidence 40 documents loss of neuronal mass in the basal ganglia of human patients exposed during the third trimester of pregnancy to antiepileptic drugs that have apoptogenic properties resembling those of alcohol and isoflurane.…”

Acute oligodendrocyte loss with persistent white matter injury in a third trimester equivalent mouse model of fetal alcohol spectrum disorder

“…OL lineage cells are particularly vulnerable to acute excitotoxicity in a maturation-dependent manner (Butts et al 2008; Follett et al 2000; Jantzie et al 2015b; Marinelli et al 2016; Matute et al 2006; Talos et al 2006a; Talos et al 2006b). Acute EtOH exposure can lead to apoptosis of oligodendrocyte lineage cells, as shown in recent studies demonstrating the particular susceptibility of early myelinating OLs to EtOH-induced apoptosis following intravenous administration of high doses of EtOH in macaque monkeys during the third trimester (BECs ranging from 300–400 mg/dl) (Creeley et al 2013). …”

The effects of chronic smoking on the pathology of alcohol-related brain damage

“…A potential WM target for alcohol is the oligodendrocyte, as this cell type has been shown to be as vulnerable to alcohol as neurons in an animal model (Creeley, Dikranian, Johnson, Farber, & Olney, 2013). An important aspect of ARBD is the repeated observations of the reversibility of some of the cognitive impairments with abstinence (Mann, Günther, Stetter, & Ackermann, 1999), predominantly in younger individuals (Pfefferbaum, Adalsteinsson & Sullivan, 2006; Pfefferbaum et al, 2014).…”