The epigenetic effects of prenatal alcohol exposure in human autopsy brain tissue
Jarmasz, Jessica S
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Fetal alcohol spectrum disorder (FASD) is 100% preventable, yet is the leading cause of developmental disability. Many in vivo studies in animals have established the effects of prenatal alcohol exposure (PNAE) on epigenetic processes in the developing brain. However, no studies directly assess epigenetic processes such as DNA and histone modifications in human brains. Therefore, I hypothesized that PNAE is associated with changes to epigenetic modifications in human brain cells. To test the hypothesis, I first identified a cohort of PNAE / FASD individuals that had undergone autopsy. Descriptive epidemiology and neuropathological findings were summarized for 174 cases. The brain abnormalities included: micrencephaly in 31, neural tube defects in 5, hydrocephalus in 6, corpus callosum defects in 6, prenatal ischemic lesions in 5, and minor subarachnoid heterotopias in 4. I then evaluated the effects of post-mortem delay (PMD) on the stability of epigenetic marks in mouse, pig, and human brain using Western blots and immunohistochemistry. I found all DNA cytosine modifications and most histone methylation marks were stable ≥72 hours. Histone acetylation marks varied, but the majority were stable ≥48 hours. A subset of the PNAE autopsy cases including fetuses and infants (21 weeks gestation to 7 months postnatal; N=18) were selected along with age-, sex- and PMD-matched controls to assess epigenetic modifications in brain previously shown in the experimental literature to be affected by PNAE. I also studied brain samples from a monkey model of PNAE. In human temporal lobe (7 specific regions), I found statistically significant increases in 5mC, 5fC, H3K27me3, H3K36me3, H3K9ac, H3K14ac and H3K27ac, decreases in 5mC, 5caC, H3K4me3, H3K27me3, H3K36me3, H3K9ac, H3K14ac, H3K27ac, H4K5ac, H4K12ac, and H4K16ac, and no change in 5hmC. Overall, H3K4me3 (active transcriptional mark) demonstrated a consistent decrease in 5 of the 7 brain regions studied. Among the macaques, the ependyma showed statistically significant decreases among epigenetic marks 5fC, 5caC, H3K9ac, H3K9me2 / K9me3, and H3K36me3. Comparison of the human infant and macaque brain findings shows overlap in H3K9ac (ependyma- decreased in PNAE) and H3K36me3 (white matter – decreased in PNAE). In conclusion, I demonstrate that changes to specific epigenetic modifications on DNA and on histones occur in association with PNAE in the developing human brain. Human autopsy brain tissue is worth exploring in the context of epigenetics to understand the pathogenesis of FASD.
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