Like father, like son

Our realisation that epigenetics offers our offspring an opportunity to adapt on a timescale far faster than a genome message can change, has give us new insights into the basis of number of diseases. Take diabetes and hypertension, for instance, which are more common in the offspring of parents with metabolic syndromes themselves. But are the epigenetic changes that underpin these altered disease risks a highly focused response to one component of an adverse environment, or a more generalised genetic alarm signal whereby the body alters its resilience against a range of potential threats. Speaking to Chris Smith, Oliver Rando thinks it’s the latter...

Oliver - Over the last decade or so, it’s become increasingly clear that the environment experienced by a father can affect the health and the behaviour of his children. Many of the environments chosen include dietary regimens or stressors that affect many aspects of a father’s health. In this study, we wish to understand whether or not fathers tell their children much more specific information about the world they saw. To do this, we chose to use nicotine, both because nicotine is a commonly used drug in human populations and so, this will be relevant to human biology. Also because nicotine has a very specific molecular function which is that it binds to a receptor. And so, we could ask whether or not children are specifically more or less responsive to nicotine and only nicotine, or whether or not children become generally drug resistant or generally anxious, or something of this nature.

Chris - In other words, is there a very specific in type programming for a certain stimulus and a certain outcome or is there more like a molecular tripwire here where a range of things can sound the alarm and it then puts in play a whole range of responses and it wouldn’t matter what tripped the tripwire. You'd see the same range of responses.

Oliver - That's an excellent way to put it. We do this in inbred mice. One of the reasons to use inbred mice is, so that all the mice have the same genomes. We treat pairs of male mice. Half of them are exposed to nicotine. They're drinking water actually. The other half consume a control solution. We then take those mice and we allow them to mate with females then we take the male mice away so that they don’t directly interact with the children. And then we analyse a variety of behaviours and phenotypes in their children.

Chris - What trends emerge?

Oliver - So, quite a few things don’t change in the children. They don’t become grossly more or less sensitive to nicotine. However, the children of nicotine-exposed fathers become more resistant to toxic doses of nicotine.

Chris - This is like a sort of defence priming. If your parent has been exposed to X then you are now primed to encounter things like X and defend yourself against them.

Oliver - That's correct. that’s certainly how it seemed at first. The next part of the study was to ask whether or not the children are primed for X or whether or not the children are primed for a broader range of things. to do this, we also exposed the children to cocaine and much to our surprise, even the children of fathers exposed to nicotine, those children became more resistant to cocaine as well. So that now tells us that even though fathers were exposed to one drug, the children become more broadly resistant to toxic levels of drugs.

Chris - We’re using this term “children” and that could mean male and female. Was there a difference between the male and female offspring? Do they both respond in this way or is it just one of the two?

Oliver - We only see the sons exhibiting changes in their resistance.

Chris - Interesting. So how do you think that’s being passed on then?

Oliver - Well, we have no idea. We haven't done any molecular work on the sperm which is of course the likeliest place for this information to be. In other types of paternal effect system, so in other experiments where we treat males with different environments and look at the children, we are very keen on the idea that small RNAs are the carriers of the information about the environment. But in this particular study, we did not look in the sperm at all.

Chris - Let’s explore why do you think this effect exists at all?

Oliver - It certainly can be construed as being adaptive. By “adaptive”, I mean useful for the kids. If fathers are exposed to nicotine, their children become more resistant to this toxin. So that’s certainly something that you can imagine being evolutionarily advantageous. Why their children become more resistant to multiple toxins, I'm less confident in speculating about, but at least in the case of when the fathers are in an environment where there's lots of nicotine about, the children will be better suited for that environment.

Chris - Obviously, these are rodent studies and we’ve got to be cautious about translating them to humans. What would be the implication then if you have a child growing up or developing in an environment where the father is being exposed to various chemicals? What might be the implications for that child’s own use of nicotine or exposure to nicotine subsequently?

Oliver - In the mouse model, we did look at self-administration which is a model for addictive behaviour. We saw no difference in the self-administration of nicotine in this offspring. But it cannot extrapolated to humans particularly well because mice are notoriously bad model for nicotine addiction because the half-life of nicotine is much shorter in mice. So while we have no evidence that it would affect predisposition towards smoking, studies in humans will need to be done to really make sure that that’s true.