Women with polycystic ovary syndrome (PCOS) have elevated levels of testosterone and its chemical relatives. They also have an increased risk of anxiety and depression. Both sons and daughters of women with PCOS have similar symptoms, so it might be transmitted through traditional genetic means. But the idea is gaining traction that it is the fetal environment—specifically, the fact that the fetuses of mothers with PCOS are gestating in high levels of testosterone—that's associated with the problems.

Elevated levels of maternal testosterone are known to affect the brain morphology and function of their offspring and have been linked to anxiety in both humans and rats. To try to determine how, an international team of researchers looked at the levels of androgen receptors in different brain regions associated with anxiety and depression. They worked in a rat model of PCOS where pregnant rats were injected with testosterone.

The team found that offspring of pregnant rats with elevated testosterone were anxious, although this behavior was much more apparent in the baby girl rats than in the baby boy ones. They went on to show that the excess testosterone in the womb diminished the ability of the next generation to respond to it. Levels of the messenger RNAs that encode receptors for testosterone and similar molecules were lower in the amygdalae and hippocampuses of the offspring. The effect was larger in female offspring than in the male offspring.

The amygdala in particular is important in processing emotions, and its dysfunction has been implicated in other anxiety disorders. To confirm that testosterone can have these effects, the researchers recapitulated both the anxiety and the diminished receptor levels in adult female mice by injecting them with testosterone.

The authors write that in their rat model at least, “the maternal testosterone dose used may masculinize the brain of female offspring.” But it's not all about masculinization. Levels of a receptor for the neurotransmitter serotonin were similar in the amygdalae and hippocampuses of testosterone treated mice of both sexes (they had less of the receptor than control animals).

The authors suggest that high testosterone levels in women with PCOS cause anxiety in two generations. In addition to making the women themselves anxious, they can alter the brain morphology of the children and render the children anxious too. The children do not inherit higher levels of testosterone, but they have lower receptor levels in the brain, which influences their behavior.

(The lowering of the receptor levels in their amygdalae is presumably a compensatory response to the high levels of testosterone they were exposed to in utero.)

Taken together with the recent finding that paternal microRNAs delivered by sperm can alter the offspring as well, the mechanisms by which the environment of the parents can influence the behavior of offspring into their adulthood are becoming clearer. This is a level of transmission that is not genetic, but it's clearly heritable.

PNAS, 2015. DOI: 10.1073/pnas.1507514112 (About DOIs).

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