| dc.description.abstract | This dissertation examines the effect of paternal alcohol consumption on fetal growth and on the sperm epigenetic and noncoding RNA profile. Earlier studies have found links between paternal preconception alcohol consumption and fetal growth, offspring behavior and programming of metabolism in the adult offspring. These studies have historically focused on transmission of alcohol exposure mediated changes in sperm DNA methylation and small noncoding RNAs.
Building on this set of research, we conduct our own analysis using a mouse model of voluntary chronic alcohol consumption. We examine the ability of paternal alcohol exposures to cause late-term fetal growth deficits. By measuring fetal and placental parameters at gestational day 16.5, we identify significant growth restriction accompanied by reduced placental efficiency in a sex-independent manner and significant enlargement of placentae of the male offspring. Using transcriptomic analyses in combination with chromatin immunoprecipitation for the regulatory protein CCCTC-binding factor (CTCF), we show that paternal alcohol influences placental gene regulation by altering patterns of large-scale chromatin architecture. Next, using small RNA sequencing, we show that alcohol significantly alters the abundance of different small noncoding RNA subpopulations in sperm. Using mass spectrometry, western blotting and Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq), we further show that alcohol alters the populations of specific histone modifications globally and this is accompanied by differential enrichment of these histones at genes that are involved in neurodevelopment, cell adhesion and embryo development. Finally, using the same approach we characterize changes in sperm histone profiles during epididymal transit. We find that histones associated with enhancers and a subset of gene promoters are differentially enriched in the caput and cauda epididymides.
Findings from our studies illuminate the complex epigenetic basis of the paternally transmitted effects of environmental exposures. They contribute to the existing literature by studying the impact of alcohol on sperm-retained histones and noncoding RNAs as well as its effects on placental epigenetics. Future studies looking at the early embryo developmental program in response to paternal environmental exposures can use similar methods to assess contributions of the sperm epigenome. | en |
