The epigenetic effects of prenatal alcohol exposure in human autopsy brain tissue

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dc.contributor.authorJarmasz, Jessica S
dc.contributor.examiningcommitteeGhavami, Saeid (Human Anatomy and Cell Science) Hannila, Sari (Human Anatomy and Cell Science) Davie, James (Biochemistry and Medical Genetics) Bérubé, Nathalie (University of Western Ontario)en_US
dc.contributor.supervisorDel Bigio, Marc (Human Anatomy and Cell Science)en_US
dc.date.accessioned2018-09-05T20:04:01Z
dc.date.available2018-09-05T20:04:01Z
dc.date.issued2018-08-30en_US
dc.date.submitted2018-08-30T17:43:25Zen
dc.degree.disciplineHuman Anatomy and Cell Scienceen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractFetal 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.en_US
dc.description.noteOctober 2018en_US
dc.identifier.citationJarmasz JS, et al., Human brain abnormalities associated with prenatal alcohol exposure and fetal alcohol spectrum disorder. JNEN. 2017 September 1; 76(9):813–833en_US
dc.identifier.urihttp://hdl.handle.net/1993/33245
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectneuropathologyen_US
dc.subjectepigeneticsen_US
dc.subjectdeveloping brainen_US
dc.subjectautopsyen_US
dc.subjectPrenatal alcohol exposureen_US
dc.subjectFetal alcohol spectrum disorderen_US
dc.subjectHuman brainen_US
dc.subjectMouse brainen_US
dc.subjectPig brainen_US
dc.subjectMonkey brainen_US
dc.subjectMacaca nemestrinaen_US
dc.subjecthistone post-translational modificationsen_US
dc.subjectDNA methylationen_US
dc.subjectimmunohistochemistryen_US
dc.subjectsemiquantitativeen_US
dc.titleThe epigenetic effects of prenatal alcohol exposure in human autopsy brain tissueen_US
dc.typedoctoral thesisen_US
local.subject.manitobayesen_US
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