| dc.description.abstract | Fetal alcohol spectrum disorders (FASD) are a spectrum of pathophysiological consequences that include structural, neurological and behavior disorders that arise following prenatal alcohol exposure (PAE). Work by our group and others have begun to associate alcohol-induced alterations in gene expression with heritable alterations in chromatin structure. These observations now include alterations in fetal physiology and gene expression arising from preconception paternal alcohol exposures. In this study, we hypothesized that male preconception alcohol exposure can heritably alter gene expression in placenta and that these changes in transcription are linked to alterations in the positioning of chromatin boundary elements. In this thesis, we begin to examine this assertion by characterizing patterns of gene expression and localizing chromatin boundaries between clusters of dysregulated genes.
Placentas of both male and female offspring from control and alcohol-exposed fathers displayed alterations in the expression of cohorts of genes that are enriched in genetic pathways controlling aspects of molecular transport, protein synthesis, lipid metabolism, small molecule biochemistry, as well as vitamin and mineral metabolism. Importantly, many of the genes displaying alterations in gene expression localized to coregulated gene clusters, suggesting a higher order of transcriptional control was perturbed. Given the established role of DNA methylation in the control of gene expression within co-regulated clusters, we first assessed the enrichment of the methyl donor S-adenosylmethionine (SAM). These experiments did not identify any significant alterations in the levels of SAM in the paternal liver, testis, and kidney nor were we able to identify differences in the fetal brain or placenta. Further examination of chromatin structure at co-regulated promoters, enhancers and insulators within three of the most prominent gene clusters revealed that binding of the chromatin boundary protein CTCF was decreased significantly in offspring of males exposed to alcohol prior to conception. This reduced CTCF occupancy was not due to a global decrease in CTCF protein levels in placentas. These observations provided new insights in the study of male preconception alcohol abuse and the heritable impact of preconception exposures on chromatin organization. | en |
