Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

Catherine E Creeley,Stephen A Johnson,John W Olney,Nuri B Farber,Krikor T Dikranian

doi:10.1186/2051-5960-1-23

Catherine E Creeley, Stephen A Johnson + Show 3 more

Open Access

https://doi.org/10.1186/2051-5960-1-23

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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.

Highlights

In 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
While the original findings pertaining to the apoptogenic action of alcohol and anesthetic drugs on the developing brain were described exclusively in terms of an impact on various neuronal populations, we recently reported that exposure of the neonatal NHP brain to isoflurane [35] or propofol [14] anesthesia triggers a robust apoptotic cell death reaction affecting both neurons and oligodendroglia [OL]
We stained sections adjacent to those we had stained for activated caspase 3 (AC3) or silver, with antibodies to fractin, and found that fractin staining readily detected a similar number of cells in the same WM locations [Figure 1c], and the appearance of these degenerating WM cells when stained with fractin was very similar to their appearance when stained with AC3 or silver [compare Figure 1a,b,c]

Summary

Introduction

In 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. Included among drugs that have apoptogenic potential are several that are sometimes abused by pregnant women During this sensitive period, a single drug exposure, at clinically relevant doses, is sufficient to trigger apoptosis of neurons throughout many regions of the brain [3,4,5,6,7,10,11], and cause long-term neurobehavioral disturbances in both rodents [6,20,21,22] and NHPs [16]. The present study was undertaken to clarify the nature and extent of this toxic reaction to alcohol in WM regions of these alcohol-exposed NHP fetal brains

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