Epigenetic Alterations Reversible Before Transmission to Offspring

There is no association between common genetic variants and prostate cancer survival.
There is no association between common genetic variants and prostate cancer survival.
Preventing Transgenerational Effects of Paternal Trauma

It is well-known that traumatic experiences in early life can increase the risk of psychological disorders and stress vulnerability later in life. Thanks to the ever-expanding study of epigenetics, it is now clear that those adverse experiences can alter the genetic expression of one’s offspring and subsequent generations, resulting in behavioral responses to stress that are similar to those of the affected parent. 

“In some cases, however, negative experiences can have some benefits and lead to better adapted physiological and behavioral responses,” wrote the authors of a new study reported in Neuropsychopharmacology. “Resilience is a form of adaptive response manifested by active or passive coping in adverse conditions,” following trauma exposure, they explained in their paper.

The new findings indicate that this acquired resilience can also be passed on and that the epigenetic alterations can be reversed through exposure to an enriched environment, thereby preventing transmission of the effects of trauma to the offspring.

Researchers at the University of Zurich and ETH Zurich exposed mice to a model of unpredictable maternal separation combined with unpredictable maternal stress (MSUS) to test its effects on male offspring and their progeny. Pregnant mice were kept alone until delivery, after which they were separated from the newborn mice (the F1 generation) for 3 hours per day at unpredictable times. During those times, the mothers were exposed to randomly-applied additional stress consisting of either restraint or a forced-swim test.

Once they reached adulthood, the F1 males–used instead of females to avoid potential confounding effects of the estrous cycle– were bred to generate offspring (F2). The F1 and F2 males were then exposed to tests of coping responses in progressively aversive conditions, including the light-dark box test, the active avoidance task, and the fixed ratio paradigm. From the time of weaning until they reached adulthood, some mice were placed in enriched cages with social groups, ample space, food and water, and recreation, while other mice were placed in standard housing.

The responses of both F1 and F2 mice to aversive conditions compared with controls indicated “reduced escape response suggestive of a form of resistance to aversive conditions in both generations,” and suggest intergenerational transmission of the altered coping responses, according to the paper. These effects were associated with increased hippocampal expression of the glucocorticoid receptor (GR) and with reduced DNA methylation of GR promoter in germs cells and the hippocampus. The GR receptor plays a major role in shutting down the stress response and in long-term recovery from chronic stress, particularly regarding active avoidance behavior. It is especially responsive to the epigenetic influence of early environmental factors.

The researchers also found that the epigenetic alterations are reversible when the fathers are exposed to environmental enrichment in adulthood. “This is accompanied by a correction of DNA hypomethylation at some CpGs of the GR gene in the sperm of fathers and the hippocampus of the offspring,” said the authors. “These findings highlight the influence of both negative and positive environmental factors on behavior across generations, and the plasticity of the epigenome across life,” they concluded.

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Gapp K, Bohacek J, Grossmann J, et al. Potential of environmental enrichment to prevent transgenerational effects of paternal trauma. Neuropsychopharmacology. 2016. doi: 10.1038/npp.2016.87.