Environmentally-induced sperm RNAs shape placentation and fetal growth.

Sperm RNAs are environment-sensitive and mediate paternally-induced epigenetic inheritance of traits. The sperm RNA cargo is delivered to the oocyte during fertilization but precise mechanisms by which the 'epigenetic memory' it carries alters embryonic development to shape the progeny phenotypes remains poorly understood. Here, we used two mouse paradigms of male pre-conception experiences to study whether environmentally-induced sperm RNAs regulate placenta development. Using zygotic injections, we show that the sperm RNA load from DDT-treated and obese males impacts placenta function and fetal growth in opposite ways. Mechanistically, these environmentally-driven sperm RNAs disrupt early embryonic development and cell lineage specification. They also dictate the mature placenta cellular composition, nutrient stores, vascularization and imprinted genes landscape. Our findings provide direct evidence that sperm RNAs shape placentation, offering a mechanism by which fathers influence their progeny beyond their shared genome. These data also highlight the role of paternal non-genetic factors in pregnancy outcomes.