Pre-conceptional paternal diet impacts on offspring testosterone homoeostasis via epigenetic modulation of cyp19a1/aromatase activity

Paternal eating habits, before and at conception, have a strong impact on offspring future metabolism. By sending specific epigenetic signals through spermatozoa, paternal nutrition influences developing embryos and increases offspring risk of developing dysmetabolism and cardiovascular diseases. Among the intergenerational consequences, paternal epigenetic messages affect embryo DNA methylation altering programmed gene expression. The identification of offspring genetic loci that are epigenetically altered by paternal stimuli is of pivotal interest for timely post-natal treatment of offspring metabolic defects. We here use a murine model to show that, cyp19a1/aromatase, a gene coding for the cytochrome converting testosterone into 17-β estradiol (both potent hormonal mediators of embryo development and metabolism), is an epigenetic transducer of paternal intergenerational inheritance. By affecting cyp19a1 methylation status and alternative splicing, paternal diet coordinates androgens’ metabolism in the progeny affecting it in a sexually dimorphic way and promoting hypoandrogenism, growth retardation and diabetes in male pups.