Inherited stress 30.10.2015

Recently, more and more often they say that the way of life of parents, their life experience affects what their descendants will be like. For example, hunger or psychological stress that the previous generation had to endure will affect the psychology and metabolism of the next generation.

Two years ago, researchers at Emory University published a paper in Nature Neuroscience in which they said that frightened mice had babies that were afraid of the same thing that their parents were afraid of. Another well-known example is the increased predisposition to diabetes and obesity in the children and grandchildren of Dutch women who survived the famous famine in the winter of 1944. (Here, as we understand it, the point is not in the specific features of the Dutch famine, but in the fact that biologists and physicians paid attention to this historical situation and tried to investigate it.) Such observations have now accumulated, we repeat, enough already, but there is one problem here : neither hunger, nor psychological stress, nor other similar influences from the outside create mutations, do not change the genetic code expressed in the sequence of nucleotides in DNA. The question arises how then all this is inherited.

It is believed that such effects owe their existence to epigenetic mechanisms that control the activity of genes. There are several types of them, the main of which are the methylation of the nitrogenous bases of DNA, the modification of histones (DNA packaging proteins) and the action of regulatory RNAs. Both methyl groups, and modified histones, and regulatory RNAs can change the functioning of certain genes for a long time, almost for a lifetime, and such mechanisms are often activated under the influence of external factors. Moreover, according to some data, the nature of epigenetic changes can be inherited. However, how exactly this happens - and whether it happens - is still a heated debate.

To move on to the next generation, modifications must be preserved in germ cells, but for the time being, all experiments indicated that in animals, when germ cells mature, all epigenetic marks are erased. But two years ago, Science published an article stating that in some parts of the DNA of germ cells, such marks are still preserved (in that article, we were talking about DNA methylation). And last year, experts from the University of Zurich reported that some regulatory RNAs can serve as carriers of stressful experiences from parents to offspring: after mice were stressed, regulatory molecules appeared both in the hippocampus and blood serum, and in spermatozoa. And the cubs, which were obtained after fertilization with such spermatozoa, demonstrated in behavior and metabolism the same post-stress features that their parents had.

Everything indicated that at least the epigenetic settings associated with regulatory RNAs could be passed down from generation to generation. It remained only to directly confirm the causal relationship between such RNAs and the transmitted effect. This was done by Tracy Bale and her colleagues at the University of Pennsylvania. To date, they have accumulated evidence that the offspring of males who were subjected to stress (whether it be constant white noise, or the smell of a predator, or regular restriction of mobility) react to such circumstances already weaker, which, in particular, is noticeable in a lower level stress hormone corticosterone. On the other hand, it was found that several types of regulatory RNAs accumulate in the spermatozoa of stressed paternal mice (more precisely, they are called microregulatory, microRNA, because of their small size compared to other classes of RNA).

In their new experiments, described in an article in PNAS, the researchers took miRNAs and injected them into fertilized eggs of normal mice, after which they were implanted in females and waited for the mice to appear. Subsequently, they showed the same diminished response to stress as those born directly from frightened males. It was obvious that it was all about foreign microRNAs, because all the genetic material came from ordinary parents, who were not frightened by anything.

Usually microRNAs suppress the activity of genes. As expected, some genes in the eggs did not work after the introduction of regulatory RNAs. The authors of the work also tried to analyze the state of the hypothalamus, a brain gland that controls a huge number of physiological and behavioral reactions (from sleep and food to reproduction). The level of corticosterone, among other things, depends on the hypothalamus. Indeed, in mice grown from miRNA-treated fertilized eggs, some genes in it worked differently; curiously, they were related to collagen and extracellular matrix proteins. How this relates to the stress response is not entirely clear. It is possible that changes in the synthesis of connective tissue collagen and matrix proteins affect the permeability of the blood-brain barrier that stands between the blood and the brain - which, in turn, affects the sensitivity of the hypothalamus to stress signals.

In general, it remains to be seen how changes in genetic activity during the earliest stages of development lead to changes in response to stress. Microregulatory RNAs apparently act indirectly here: their level is not renewed every time after cell division, and in the brain of adult mice their number becomes quite normal. On the other hand, it would be interesting to find out through what molecular mechanisms stress can affect miRNAs in spermatozoa, and what happens in this case with spermatozoa of the next generations. Finally, the stress response is quite complex in structure, and different aspects of it may well be associated with different RNAs.

The data obtained are quite consistent with the results of the Zurich group, which we spoke about above: they also talked about the effect of stress, microRNA and male reproductive cells. By the way, not only stress, but also obesity can be transmitted through the male line, and it seems to be transmitted only to sons - researchers from Ohio University reported this several years ago (although those experiments were again done on mice). Note, however, that it is still quite far from any medical and clinical conclusions: we still do not know under what conditions epigenetic heredity works, and how to separate "genetics" from "epigenetics" under normal, non-laboratory conditions.