The Critical Window, Epigenetics, and Stress — and Maybe Mental Health too

The past few weeks have been good for stress. Two labs published studies supporting the idea that stress during sensitive periods in early development can cause epigenetic changes affecting how an organism turns out. These studies look at mice and humans, respectively. I’m diving into the mouse study today — it’s got two kinds of epigenetics: an inherited, probably chromatin-mark imprinting angle; and an miRNA angle. I’ll get to the human study from the Kobor lab next time.

As an aside, I find “stress and epigenetics”  especially interesting because I’m always looking for clues about how this new-ish field is perceived and represented by the lay public, and “stress” is a lay-public magnet. As I’ve talked about before, aside from pharma and diagnostics companies, life-science professionals, and general science dorks (ahem), the other folks who’re most interested in epigenetics are the all-around mystics. Anyway, it’s the stress connection that they seem to love. But these two recent articles seem like they’ve escaped that attention, while picking up some mainstream coverage here, here, and here. Still, it’s not much, which surprises me.

Anyway, in the mouse study, Christopher Morgan and Tracy Bale at the University of Pennsylvania School of Veterinary Medicine followed up their lab’s previous finding that stressing out pregnant mice during the first week of gestation — with constant light, the smell of foxes, and other painless irritations — dysmasculinized male offspring.

That is, compared to the sons of unstressed moms, this first crop of males showed female-like behavioral responses when hung by the tail and when forced to learn a maze, and they reacted more strongly to being trapped in a small cage, as judged by corticosterone levels. They also showed shorter anogenital distances, which I won’t need to detail, right?

Well, in Morgan’s and Bale’s newest work in the Journal of Neuroscience, they find that the second-generation offspring of stressed pregnant moms were dysmasculinized compared to control mice too. And through the male line — these were the sons of sons of stressed moms — these males inherited the same tail-hanging behavior and reduced anogenital distances. But they weren’t statistically different from controls in the maze or in corticosterone response to stress. Each group had fewer than 10 mice, so a large study might prove more statistical differences.

Only gametes appeared to transmit these traits, but not through genetics — the authors don’t go into it, but that leaves epigenetic chromatin marks, and possible environmental effects.

The other epigenetic connection is really the point of the whole experiment. The U Penn scientists found three miRNAs with much lower expression in second-gen dysmasculinized mice, all of which target ß-glycan, a member of the TGFß family. That’s important because Morgan and Bale were looking for connections to in utero brain masculinization — there’s evidence that’s part of what’s behind many sexually dimorphic neurological and behavioral problems, including schizophrenia and autism.

Interestingly, in pituitary gonadotrophs and gonadal Leydig or theca cells, ß-glycan is involved in regulating the release of gonadal hormones (MacConell et al., 2002; Chapman and Woodruff, 2003; Wiater et al., 2009). As a role for ß-glycan in neurodevelopment has not been identified, our data suggest that it may serve an unappreciated role in the organization of the sexually dimorphic brain.

It’s not a smoking gun, but it ties in nicely with a lot of recent interest in epigenetics and glucocorticoids, which are the human analog of rodent corticosterones (here’s a free review of epigenetics in glucocorts).  In case you missed a big part of this, McGill University’s Michael Meaney and colleagues recently reported (full text) in Nature Neuroscience that suicide victims who experienced childhood abuse showed greater promoter methylation of the glucocorticosteroid gene, with lower mRNA levels, than did suicide victims who hadn’t been abused.

That study went a long way toward revealing a bit in humans what others previously found in rodents — that there’s an early life stage when the glucocorticoid pathway is susceptible to epigenetic regulation, and that affects mental health. In the rodent paper, maternal care epigenetically reprogrammed pups at the glucocort receptor in their hippocampuses.

So, stress, glucocorticoids, mental health, and critical developmental windows. The paper from the Kobor lab goes into the developmental window a bit more — in humans.

(Image “staircase window 2″ by Flickr user extranoise reproduced here under a Creative Commons license.)
# Christopher P. Morgan, & # Tracy L. Bale (2011). Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage Journal of Neuroscience : 10.1523/​JNEUROSCI.1887-11.2011