Lifetime stress experience: transgenerational epigenetics and germ cell programming

Abstract

The transgenerational epigenetic programming involved in the passage of environmental exposures to stressful periods from one generation to the next has been examined in human populations, and mechanistically in animal models. Epidemiological studies suggest that gestational exposures to environmental factors including stress are strongly associated with an increased risk of neurodevelopmental disorders, including attention deficit-hyperactivity disorder, schizophrenia, and autism spectrum disorders. Both maternal and paternal life experiences with stress can be passed on to offspring directly during pregnancy or through epigenetic marks in the germ cell. Animal models of parental stress have examined relevant offspring phenotypes and transgenerational outcomes, and provided unique insight into the germ cell epigenetic changes associated with disruptions in neurodevelopment. Understanding germline susceptibility to exogenous signals during stress exposure and the identification of the types of epigenetic marks is critical for defining mechanisms underlying disease risk.

Keywords: development; fetal; germline; histone; maternal; methylation; microRNA; paternal; sperm.

Figure 1.. Tipping the balance toward neurodevelopmental disease presentation likely depends on multiple interacting factors, ultimately combining a genetic predisposition with environmental insults experienced at key developmental/susceptible periods in life. For example, when mapped onto a given genetic variation that promotes susceptibility, an environmental exposure to prenatal stress may act as a second hit in a two- or three-hit model, where the next stress insult experienced during later points in life tips the scale in the direction of disease onset. In such a model, the prenatal exposure to stress is acting as a point of epigenetic programming due to an increased genetic vulnerability that when added together leads to sensitivity to later life perturbations.

Figure 2.. Animal models of paternal germ cell programming have demonstrated clear transgenerational epigenetic outcomes following exposure to various perturbations in which the male was exposed prior to breeding. Recent studies have included models of social defeat, chronic stress, cocaine exposure, dietary manipulations, endocrine disrupters, and conditioned fear.^-

Figure 3.. Points in spermatogenesis where environmental insults are most able to reprogram epigenetic marks. Prior to DNA compaction for the mature sperm, active transcription and storage of RNA is ongoing through the spermatogonium, spermatocyte, and spermatid stages. Once compaction of paternal DNA involving protamine swamping for most all histones has occurred, there is no clear means by which epigenetic marks can be altered in the mature sperm.