Experimental Biology 2014: Transgenerational effects of stimulant drugs

This is a summary of a presentation in Symposium 222. Molecular Basis of Addiction: Neurocognitive Deficits and Memory Mon, Apr 28, 9:55 AM - 12:10 PM at the 2014 Experimental Biology meeting.

Mon, Apr 28, 10:25 - 10:40 AM Amphetamine exposure during development causes epigenetic trans-generational changes in drug sensitivity in Caenorhabditis elegant. Authors: Talus McCowan, Bryan Safratowich, Joyce Ohm, Lucia Carvelli

McCowen* presented a study which showed transgenerational effects of amphetamine in a C. elegans model.

Caenorhabditis elegans is a nematode about 1 mm long which has the dubious virtue of having 302 neurons of which a mere 8 are dopaminergic. This makes for a tractable model, particularly when you think you might want to model the entire nervous system.

The model involved Swimming Induced Paralysis (SWIP) which can be induced in a liquid medium by treating the worm with amphetamine. This is a time and dose dependent phenomenon which has been shown to depend on the dopamine transporter and D2/3-like dopamine receptors. Classic targets of the amphetamines.

The study exposed eggs to 500 uM amphetamine or control media for 15 hours. After maturation of the worms, they were subjected to the SWIP test in which it was found that the egg-exposed animals had an enhanced freezing response. In this case it was an increased percentage of the worms freezing in the context of a moderate dose, selected to give parametric range on either side. The authors then examined the F1 generation of worms, which had received no drug treatment up until the SWIP challenge. here it was found that the F1 offspring of the F0 worms exposed to amphetamine during development also had an enhanced response to amphetamine.

The lab is interested in methylation of histones as an epigenetic mechanism that might possibly convey this effect. They found decreases of histone H3 Lys4 trimethylation (H3K4me3) in the F1 offspring of amphetamine incubated worms compared with the offspring of control worms. This was selective as there was no difference in H3K27me3 expression.

Obviously this is just a start, one would think that the advantage of the worm is that you could go out for generations quite readily, in comparison with rodents (see below). So presumably this story will advance by the time we see it in publication. Nevertheless, this joins a growing appreciation of the transgenerational effects of drug. While there are many caveats in translating this to humans, it certainly puts a bright spotlight on familial abuse patterns and our potential targets for explaining them.
__
Related: Heritability of Substance Abuse Meets Epigenetics?

*The speaker identified himself as a first year graduate student. I think he did a bang up job of the presentation and of handling the questions.

4 responses so far

  • Mytchondria says:

    Anyone ask if the worms teeth fall out from meth? Lots of explosions from cooking meth in worm community?

  • drugmonkey says:

    No, I do not believe those are problems for the nematode community.

  • Jessica Tollkuhn says:

    H3K4me3 is a histone modification found at the promoters of genes that are actively expressed. Less H3K4me3 means less gene expression overall. I'm assuming they just went ahead and did the ChIPs on the whole animal (puh-leez don't tell me they did Westerns). What genes had decreased methylation? Did they look at changes in RNA levels of those genes too?

    Also, if the cells they claim are affected by the treatment are 8/302, then it's pretty unlikely that whatever change in H3K4me3 they are seeing is coming from those few cells. Sounds like they just really screwed up the animals. The Interwebs tell me that all of worm embryogenesis (fertilization to larval hatching) takes 14 hours and they treated for 15. Intense.

    Everybody go read Kevin Mitchell now.
    http://www.wiringthebrain.com/2014/04/the-trouble-with-epigenetics-part-3.html

  • mh says:

    yeah both the histone modifications and behavior changes sound...non-specific. general sickness/toxicity seems like it should be the default interpretation here barring more specific data. there are only so many ways that worms break, but sick worms tend to do everything wrong.

    nematodes with teeth: https://www.youtube.com/watch?v=jkGdKN3D3aE

Leave a Reply