Stress-induced epigenetic changes last up to four generations in mice

One of the most intriguing aspects of epigenetics is its ability to confer transgenerational changes. General belief used to be that inheritance pertained exclusively to DNA, and that what did not affect DNA could not be inherited. Epigenetics encompasses all molecular "processes that regulate genome activity independent of DNA sequence [1]." It has revolutionized the way we view heritability: epigenetic changes do not alter the DNA sequence, only the way genes are expressed. And yet environmental exposures and chronic stress, two factors that can indeed change gene expression patterns, have been shown to induce epigenetic transgenerational inheritance. In other words, you could have inherited some epigenetic switch from your parents, even though the epigenetic switch was caused by some exposure your parents experienced, not you!

In order for this to happen, the epigenetic modification has to be incorporated into the germ line.

In a recent PNAS paper [1], Crews et al. showed the

"epigenetic transgenerational inheritance of a behavioral phenotype induced by an environmental toxicant (a fungicide) and transmitted through the germ line, involving a permanent alteration in the sperm epigenome (i.e., DNA methylation)."

Crews et al. looked at the effects of chronic restraint stress in young male mice. Because social status also influences the way individuals react to stress, with dominant individuals usually being able to cope better than subordinate ones, they housed the experimental mice together with different mixes of social structures. The "stress" was the exposure of a gestational female to a fungicide (vinclozolin), which disrupts endocrine activity. The effects were changes in the brain and behavior and, eventually, the early onset of disease. These were still observed over four generations later.

"We find that this ancestral exposure promotes weight gain and, as such, provides pivotal empirical evidence that exposure to an endocrine disruptor in generations past results in substantial weight gain in the descendants."

In the study, the authors refer the exposure of the mother as "ancestral exposure" to indicate that it wasn't a direct exposure on the individuals under study.

In particular, the researchers observed that the changes in body weight were correlated with lower secretions of corticosterone and higher testosterone circulating levels. The researchers performed other tests in order to measure the sociability of the fungicide exposed animals versus the non-(ancestrally)-exposed ones under stressful circumstances. In both stressful and non-stressful circumstances, the animals ancestrally exposed to the fungicide showed higher levels of anxiety.

Finally, Crews et al. performed gene networks analyses in order to evaluate changes in gene expression between the two mice groups. They looked in several brain regions, including subregions of the hippocampus and the primary and secondary motor cortex. Interestingly, the most altered pathway was the olfactory one.

"An olfactory receptor promoter has been shown to have an epigenetic transgenerational alteration in sperm. [...] Why should genes involved in olfaction be expressed in areas of the brain not involved with olfaction and taste? Olfactory and vomeronasal receptors as a group are among the most rapidly evolving of all genes and have been linked to higher processing centers in the brain as well as to behavior."

[1] David Crewsa, Ross Gillettea, Samuel V. Scarpinoa, Mohan Manikkamb, Marina I. Savenkovab, and Michael K. Skinner (2012). Epigenetic transgenerational inheritance of altered stress responses PNAS DOI: 10.1073/pnas.1118514109