Sexing Brains Down and Up: Early aspirin dose hits male rats below the belt

Scientists have long known that testosterone regulates males’ sexual behavior and brain characteristics, although how it does so is poorly understood. New findings indicate that testosterone amps up the masculinity of the infant rat brain by inducing production of a substance that’s key to sexual development.

Male rats exposed shortly before or after birth to drugs that block manufacture of prostaglandin E2 (PGE2) exhibit impaired sexual behavior as adults, say Stuart K. Amateau and Margaret M. McCarthy, neuroscientists at the University of Maryland at Baltimore School of Medicine. In their trials, groups of newborn male rats received injections of saline or indomethacin and adult females received aspirin during pregnancy or lactation. Indomethacin and aspirin block an enzyme that’s crucial for synthesizing PGE2. Indomethacin, but not saline, impaired later sexual behavior of the injected newborns. Maternal aspirin affected sexual behavior of the offspring as adults, but to a lesser extent than indomethacin did.

If these findings are confirmed in people, the researchers say, it will raise concerns about pregnant women’s use of PGE2-blocking drugs, which also include acetaminophen. Doctors currently prescribe indomethacin to prevent premature labor.

Male rats receiving indomethacin as pups later showed signs of having unusually few neural connections in the preoptic area, an inner-brain structure previously implicated in sexual behavior, Amateau and McCarthy report in the June Nature Neuroscience. Adult female rats typically possess a comparably low number of connections, or synapses, in that area.

“What’s striking is that brief exposure to prostaglandin blockers around the time of birth has lasting effects on synapses in males’ preoptic area,” McCarthy says.

The pups that received indomethacin also displayed little sexual activity as adults, while those males whose mothers had received aspirin initiated sexual activity only after several exposures to fertile females.

A contrasting picture emerged in female rats given a male hormonal profile. When a female received injections of PGE2 shortly after birth, bolstered with testosterone during adulthood, she exhibited malelike sexual behavior, such as trying to copulate with fertile females, and a masculine-style preoptic area chock-full of synapses.

To determine the abundance of synapses in the preoptic area, Amateau and McCarthy measured spinophilin, a protein that acts on the synapse-forming spines that branch off nerve cells. A high concentration of spinophilin corresponds to a synaptic bounty typical of males.

Although PGE2 blockage affected males’ preoptic area, their blood concentrations of testosterone were similar to those of animals injected only with saline.

“These data suggest a new and unexplored mechanism . . . that directs sexual differentiation of the brain,” remark neuroscientist Erich N. Ottem of Michigan State University in East Lansing and his colleagues in a comment published with the new report.

A study of whether prenatal exposure to PGE2-sapping drugs influences people’s sexual behavior is now under way. A team led by psychologist Melissa Hines of City University in London plans to use anonymous questionnaires to monitor sexual behaviors in more than 600 youngsters, now 13 years old, who have been tracked since birth. About half of the teens’ mothers reported taking acetaminophen during pregnancy.

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