Extending the Developmental Origins of Health and Disease theory: does paternal diet contribute to breast cancer risk in daughters?

The Developmental Origins of Health and Disease (DOHaD) theory focuses on the consequences of periconceptional and in utero exposures. A wide range of environmental conditions during early development are now being investigated as a driving force for epigenetic disruptions that enhance disease risk in later life, including cardiovascular, metabolic, endocrine, and mental disorders and even breast cancer. Most studies involve mother-child dyads, with less focus on environmental influences through the father. Over the last few years, however, new insights have been introduced on paternal effects and the plasticity of the epigenome of developing sperm cells have been proposed to underlie inheritable changes from ancestral exposures. The field is evolving rapidly and study results from animal models are promising. Although caution should be taken in translating animal data to humans, epidemiological findings also suggest a prominent role of the father. Therefore, we here propose an extension to the DOHaD theory to include also paternally inheritable influences.

Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study.

BACKGROUND: Epigenetic reprogramming in mammalian gametes resets methylation marks that regulate monoallelic expression of imprinted genes. In males, this involves erasure of the maternal methylation marks and establishment of paternal-specific methylation to appropriately guide normal development. The degree to which exogenous factors influence the fidelity of methylation reprogramming is unknown. We previously found an association between paternal obesity and altered DNA methylation in umbilical cord blood, suggesting that the father's endocrine, nutritional, or lifestyle status could potentiate intergenerational heritable epigenetic abnormalities. In these analyses, we examine the relationship between male overweight/obesity and DNA methylation status of imprinted gene regulatory regions in the gametes. METHODS: Linear regression models were used to compare sperm DNA methylation percentages, quantified by bisulfite pyrosequencing, at 12 differentially methylated regions (DMRs) from 23 overweight/obese and 44 normal weight men. Our study population included 69 volunteers from The Influence of the Environment on Gametic Epigenetic Reprogramming (TIEGER) study, based in NC, USA. RESULTS: After adjusting for age and fertility patient status, semen from overweight or obese men had significantly lower methylation percentages at the MEG3 (ß = -1.99; SE = 0.84; p = 0.02), NDN (ß = -1.10; SE = 0.47; p = 0.02), SNRPN (ß = -0.65; SE = 0.27; p = 0.02), and SGCE/PEG10 (ß = -2.5; SE = 1.01; p = 0.01) DMRs. Our data further suggest a slight increase in DNA methylation at the MEG3-IG DMR (ß = +1.22; SE = 0.59; p = 0.04) and H19 DMR (ß = +1.37; SE = 0.62; p = 0.03) in sperm of overweight/obese men. CONCLUSIONS: Our data support that male overweight/obesity status is traceable in the sperm epigenome. Further research is needed to understand the effect of such changes and the point of origin of DNA methylation differences between lean and overweight/obese men. Together with our earlier reports on paternal obesity and epigenetic shifts in the offspring, our studies set the groundwork for future studies investigating male gametic methylation aberrations due to paternal lifestyle factors such as obesity.