Paternal Nongenetic Intergenerational Transmission of Metabolic Disease Risk

Paternal metabolic disease before conception and during spermatogenesis can adversely impact the metabolic health of offspring in later life. Here, we review the current understanding of sperm epigenetic markers as contributors to intergenerational transmission of disease risk in both human and animal studies, and review potential intervention strategies.

Epidemiological studies suggest an increased risk of adverse outcomes in the offspring of fathers with obesity, diabetes, advanced age, smoking, and ancestral exposures. Potential molecular mechanisms contributing to intergenerational disease risk include genetics (DNA sequence) as well as epigenetic factors in the sperm, such as DNA methylation, chromatin and histone modification, and coding and noncoding RNAs. Potential strategies to interrupt intergenerational transmission of disease risk include increased physical activity, weight loss, bariatric surgery, cold exposure, and improved glycemic control prior to conception. Many studies suggest environmental factors experienced by fathers can program disease risk in the next generation via sperm cell-mediated transmission. Better understanding the mechanisms through which paternal metabolism influences sperm cells will help to design better intervention strategies. Future research will focus on the molecular signals that mediate the impact of paternal factors on sperm epigenetic signals and also how these affect offspring embryonic development and disease risk during adult life.