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

Abstract

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.

Keywords: epigenetic; immunity; intergenerational; molecular genetics; sncRNA.

Fig. 1

Model for parentally induced inflammatory memory. In the parental generation, a primary infection enhances responses to subsequent challenges through epigenetic reprogramming of cells with immune‐ or barrier function. Paternal signals such as sperm‐borne RNA can induce inflammatory pathways during early embryogenesis, which thereafter are maintained via epigenetic mechanisms. The resulting resilience against infection provides an evolutionary advantage in conditions with persisting infection pressure, whereas it may predispose for inflammation‐driven disease.

Fig. 2

Hypothetical pedigree diagram of epigenetic traits linked to inflammatory memory reflecting the heterogeneity expected in studies of parentally induced phenotypes. Offspring with heterogeneous immune profiles may have survival advantages against certain pathogens (i.e., bacteria vs. viruses).

Fig. 3

During sensitive time‐windows, male gamete development is susceptible to environmental stressors. Diverse stressors such as diet, toxins, and infections change the load of sperm‐borne small noncoding RNA (sncRNA) and other potent signaling molecules. At fertilization, the egg responds to inflammatory signals in sperm by activation of immune‐regulatory genes. Establishment of stable epigenetic states may occur during early cell divisions and placental development to create a unified epigenetic profile in offspring traits, including immune cell activity.