(266) Epigenetic Effects of Adverse Lifestyle Choices in Males

Laura Chavez^1,2; Prashant Kumar^1,2; Kaitlyn Mason^1,2; Jake Lehle^1,2; Yu-Huey Lin^1,2; Rachelle Bross^1,3; Yanhe Lue^1,3; Harry B. Rossiter^1,4; Ronald Swerdloff^1,5; Christina Wang^1,3; Wei Yan^1,6,7; John R. McCarrey^1,2

¹National Center for Male Reproductive Epigenomics

²Department of Neuroscience, Developmental and Regenerative Biology, University of Texas at San Antonio, San Antonio, TX, USA

³The Clinical and Translational Research Center, The Lundquist Institute and Harbor-UCLA Medical Center, Torrance, CA, USA

⁴Respiratory Research Center, The Lundquist Institute and Harbor-UCLA Medical Center, Torrance, CA, USA

⁵Division of Endocrinology, Department of Medicine, The Lundquist Institute and Harbor-UCLA Medical Center, Torrance, CA, USA

⁶The Lundquist Institute for Biomedical Innovation at Harbor-UCLA, Torrance, CA, USA

⁷School of Molecular Biosciences, Washington State University, Pullman, WA, USA

Abstract Text:

Obesity is an epidemic in the US, with 1 in 3 adults and 1 in 5 children being obese. Additionally, obesity is a major risk factor for metabolic disorders. Hispanic communities in particular display a high prevalence of metabolic disorders and obesity associated with low socioeconomic status and low health literacy. While genomic impacts of offspring health are well-established, there is now increasing evidence that epigenetic determinants, such as genomic patterns of DNA methylation or specific histone modifications, also impact offspring health. Currently, research into paternal origins of health and disease (POHaD) is working to identify the effects of adverse paternal lifestyles on the epigenome of sperm to determine if acquired abnormal epigenomic patterns may affect offspring development and life-long health outcomes. However, the mechanisms by which adverse lifestyle choices may disrupt normal epigenetic programming in a male’s germ line in a manner that can be transmitted to his offspring remain unknown. As part of the NICHD-supported National Centers for Translational Research in Reproduction and Infertility (NCTRI), the National Center for Male Reproductive Epigenomics was established to specifically address the question: how do obesity and lack of exercise impact the sperm epigenome and how might the effects of paternal lifestyle adversely impact offspring health? This study brought together expertise in male reproductive biology and medicine, nutrition, exercise physiology, stem cell biology, and epigenomics and transcriptomics. Hispanic men aged 18 to 40 years were recruited to participate in this study and were grouped as obese/inactive (OI; n=54) or lean/active (LA; n=15) based on initial assessments of BMI, metabolic and lipid panels, daily caloric consumption, and physical activity. Nucleic acids were extracted from samples of swim-up sperm, and genomic DNA was bisulfite converted and processed for detection of DNA methylation at individual CpG sites using the Infinium MethylationEPIC v2.0 BeadChip from Illumina. Overall, genomic patterns of DNA methylation in sperm samples of OI compared to LA individuals were similar with notable inter-individual variability within each group. However over 11,000 individual, differentially methylated cytosines (DMCs; p-value < 0.05) and 10 differentially methylated regions (DMRs) distinguished OI men from LA men. The DMCs were distributed throughout the genome but were highly enriched at transcription factor binding sites and showed an overall trend of hypermethylation. DMRs were significantly enriched at ENCODE cis-regulatory elements (CREs) including promoter-like signatures, proximal and distal enhancers, and repeat elements. Finally, gene ontology (GO) enrichment analysis showed an enrichment of DMCs at genes involved in biological processes including protein binding, DNA binding, and transcription regulator activity. Our data suggests that DNA methylation differences in sperm of OI relative to LA Hispanic men occur at CREs important for transcriptional regulation, suggesting these epimutations may contribute to dysregulation of normal gene expression patterns that may adversely impact health of offspring.