ABSTRACT
BACKGROUND: Based upon experimental animal studies, the neurodevelopmental abnormalities associated with prenatal alcohol exposure (PNAE)/fetal alcohol spectrum disorder (FASD) have been attributed, at least in part, to epigenetic modifications. However, there are no direct analyses of human brain tissue. METHODS: Immunohistochemical detection of global epigenetic markers was performed on temporal lobe samples of autopsied fetuses and infants with documented PNAE. They were compared to age-, sex-, and postmortem delay-matched control cases (18 pairs; 20 to 70.5 weeks postconception). Temporal lobe tissue from a macaque monkey model of PNAE was also studied (5.7 to 6 months of age). We used antibodies targeting 4 DNA cytosine, 4 histone methylation, and 6 histone acetylation modifications and assigned scores based upon the semiquantitatively graded intensity and proportion of positively labeled nuclei in the ventricular and subventricular zones, ependyma, temporal cortex, temporal white matter, dentate gyrus (DG), and CA1 pyramidal layer. RESULTS: Temporal changes were identified for almost all marks according to the state of maturation in the human brain. In the DG (and 3 other brain regions), a statistically significant increase in H3K9ac was associated with PNAE. Statistically significant decreases were seen among 5mC, H3K4me3, H3K9ac, H3K27ac, H4K12ac, and H4K16ac in select regions. In the macaques, H3K36me3 decreased in the DG, and the ependyma showed decreases in 5fC and H3K36me3. CONCLUSIONS: In human brain, global intranuclear epigenetic modifications are brain region and maturation state-specific. These exploratory results support the general hypothesis that PNAE is associated with a global decrease in DNA methylation, a global decrease in histone methylation, and a global increase in histone acetylation. Although the human and monkey subjects are not directly comparable in terms of brain maturation, considering the rapid temporal changes in global epigenetic modifications during brain development, interspecies comparisons may be extremely difficult.
Subject(s)
Brain/drug effects , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Fetus/drug effects , Maternal Exposure , Animals , Brain/metabolism , Brain/pathology , Cohort Studies , DNA Methylation , Female , Fetus/metabolism , Fetus/pathology , Histone Code , Humans , Infant, Newborn , Macaca nemestrina , Male , Pregnancy , Prenatal Exposure Delayed Effects , Protein Processing, Post-Translational , StillbirthABSTRACT
Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental problem, but neuropathologic descriptions are rare and focused on the extreme abnormalities. We conducted a retrospective survey (1980-2016) of autopsies on 174 individuals with prenatal alcohol exposure or an FASD diagnosis. Epidemiologic details and neuropathologic findings were categorized into 5 age groups. Alcohol exposure was difficult to quantify. When documented, almost all mothers smoked tobacco, many abused other substances, and prenatal care was poor or nonexistent. Placental abnormalities were common (68%) in fetal cases. We identified micrencephaly (brain weight <5th percentile) in 31, neural tube defects in 5, isolated hydrocephalus in 6, corpus callosum defects in 6 (including some with complex anomalies), probable prenatal ischemic lesions in 5 (excluding complications of prematurity), minor subarachnoid heterotopias in 4, holoprosencephaly in 1, lissencephaly in 1, and cardiac anomalies in 26 cases. The brain abnormalities associated with prenatal alcohol exposure are varied; cause-effect relationships cannot be determined. FASD is likely not a monotoxic disorder. The animal experimental literature, which emphasizes controlled exposure to ethanol alone, is therefore inadequate. Prevention must be the main societal goal, however, a clear understanding of the neuropathology is necessary for provision of care to individuals already affected.
