## How far does epigenetics go in humans?

As already indicated by the example of mice and their Agouti gene, an epigenetic change can be hereditary and passed onto offspring. It is therefore appropriate to distinguish between two types of inheritance of epigenetic modifications: intergenerational and transgenerational types (Figure 6.9). In the case of intergenerational inheritance, this is a manifestation of epigenetic change and its inheritance only to the extent of individuals who were directly exposed to the factor that changed the epigenome. In this case, the factor acts on a person whose epigenetic state changes and other genes begin to be expressed (P0 generation), or on the fetus that is currently developing in the womb (F1 generation) or on the germ cells of the parent or this foetus (the basis of the F2 generation). This can be illustrated using cigarette smoke as an example. If a man smokes during puberty, when his sperm are starting to form, the effect of the chemicals from the smoke will not only affect his health, but will also be written into the sex germ cells and manifest in his sons, who may have a higher tendency to obesity. This type of inheritance is observed in humans and is described in more detail and illustrated with many examples in Chapter 6 – From epigenetics to human diseases.

However, there is also longer-term transgenerational transmission. It has not yet been described in humans, but it can be observed in some model organisms (especially rodents). During transgenerational transmission, changes in gene expression caused by epigenetic modifications are inherited and manifested even in individuals that have never been exposed to the given factor (the F3 generation and onwards), not even at the level of the germ cells from which they originated. An example is a study on the nematode worm Caenorhabditis elegans (see chapter 20 - the small but mighty nematode) in which imprinting was analysed representing an early experience during a critical period that can permanently change an individual's behaviour. The stimulus for imprinting was olfactory sensation, specifically the volatile substance benzaldehyde, to which the offspring were exposed during the first 24 hours after hatching. In adults, chemotaxis was then observed, which is the movement of the individual in the direction from which the given smell comes, as it was familiar to the nematode since childhood. Olfactory imprinting was dependent on the expression of the SRA-11 gene, which encodes one of the chemoreceptors. If benzaldehyde acted on only one generation at an early age (P0 generation), chemotaxis was still evident in the F1 generation, but not in the F2 generation. However, if four consecutive generations were exposed to the presence of benzaldehyde, chemotaxis became heritable and stable for at least 40 consecutive generations. This suggests that somewhere between the first and fourth generations exposed to benzaldehyde, there was a change from a temporary effect to a stable transgenerational transmission. However, similar studies in humans are still lacking. The problem is the need for a large statistical sample and the monitoring of several successive generations, which is logistically challenging, time-consuming as well as ethically and financially demanding.