Dad's legacy: Epigenetic reprogramming and paternal inflammatory memory in offspring health.

Over the past decade, numerous reports have highlighted intergenerational and even transgenerational epigenetic effects resulting from parental exposure to diets, toxins, and stress. In many cases, these parentally induced phenotypes do not seem to confer an obvious benefit, making it challenging to understand the evolutionary drivers behind them. In this perspective, we discuss recent observations in humans and rodents indicating that a parental infection or vaccination can enhance the offspring's ability to cope with infections. Such parental priming of their offspring's immune system and cellular defense would provide immediate protection to the newborn, offering a clear evolutionary advantage. Here, focusing mainly on paternal effects, we propose that a parentally induced inflammatory memory in the offspring could be the underlying mechanism for many of the reported inter- and transgenerational effects. Sperm-borne RNA could be a triggering signal to initiate inflammatory pathways in early embryogenesis. This gene-regulatory state would then be maintained via epigenetic mechanisms throughout each mitosis and last for the individual's lifetime. The accumulating understanding that diet, stress, toxins, and infections affect offspring health raises important questions about public health policies. There is an urgent need to understand what consequences different exposures during sensitive time windows have on future generations.