Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations

Abstract

Both human and animal studies indicate that environmental exposures experienced during early life can robustly influence risk for adult disease. Moreover, environmental exposures experienced by parents during either intrauterine or postnatal life can also influence the health of their offspring, thus initiating a cycle of disease risk across generations. In this Perspective, we focus on epigenetic mechanisms in germ cells, including DNA methylation, histone modification, and non-coding RNAs, which collectively may provide a non-genetic molecular legacy of prior environmental exposures and influence transcriptional regulation, developmental trajectories, and adult disease risk in offspring.

Figure 1. The vicious cycle of intergenerational paternal disease risk

Adverse intrauterine exposure can impact the development and implantation of the embryo, ultimately increasing disease risk in the offspring. In addition, lifestyle also contributes to epigenetic changes, including alterations in the germ cells, both sperm and oocytes.

Figure 2. Intergenerational vs. transgenerational inheritance

Exposures during pregnancy (left) are termed intergenerational when impacting F1 and F2 generation offspring, but are transgenerational when affecting the F3 generation. By contrast, exposures occurring during adult life in either males or females (right) can yield intergenerational effects on the F1 generation and transgenerational effects in F2 offspring. Blue arrows – intergenerational effects; red arrows – transgenerational effects.