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Lab mice fear men but not women, and that's a big problem for science

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(Alexander H. Tuttle)

The history of science is one chock-full of mice and men. Historically, biological and medical research has largely depended on rodents, which provide scientists with everything from cells and organs to behavioral data. That's why a new study in which researchers found that mice actually fear men, but not women, has the potential to be so disruptive. It might mean that a number of researchers have published mouse studies in which their results reflect this male-induced stress effect — and they know nothing about it.

"it may have confounded, to whatever degree, some very large subset of existing research."

"People have not paid attention to this in the entire history of scientific research of animals," says Jeffrey Mogil, a pain researcher at McGill University and lead author of the study. "I think that it may have confounded, to whatever degree, some very large subset of existing research." Moreover, the effect probably isn't limited to behavioral studies, because the organs and cells that are used in medical research, such as in cancer studies, often originate in rodents. "If you're doing a liver cell study, the cells came from a rat that was sacrificed either by a man or a woman," Mogil says. As a result, "its stress levels would be in very different states." This, he says, could have an effect on the functioning of the liver cell in that later experiment.

In the study, published today in Nature Methods, researchers used the "mouse grimace scale" to measure pain responses in rodents exposed to men, women, or their respective smells. Pain is a proxy for stress because stress can, to a large extent, numb pain. So when the mice were confronted with the smell of men, they experienced less pain, whereas the presence of women — or their smell, Mogil says — "did nothing at all."

This might seem like a positive effect, but think of it this way: when athletes get hurt during a stressful game, they often don't feel the injury right away, and they keep pushing. From an evolutionary standpoint, this is supposed to keep them alive by helping them focus on something other than pain. Yet in reality, it mostly just ends up making the injury worse.

But pain wasn't the only indicator of stress in this study. Further experiments showed that the rodents also had increased body temperatures and levels of corticosterone, a stress hormone, in response to the smell of men. And the effect wasn't just prompted by human males, either. Rats and mice "are afraid of the smell of males of any species," Mogil says, because the mice in this study reacted to the smell of male dogs, guinea pigs, and cats as well.

competition, not predation

The researchers think that mice react this way because of competition, and not predation. Male mice are territorial, Mogil says, even when it comes to females entering their domain. They also compete with males for mating opportunities, "so it's probably a little bit evolutionarily adaptive to have this effect until you can determine that a male that's around doesn't actually mean you any harm," he says. In all likelihood, mice just haven't developed a way to discriminate between the smell of a male mouse and the smell of other male mammals, so men also elicit a fear response.

Interestingly, the stress response isn't only dependent on the sex of an intruder, but also on the circumstances of his or her approach. "If you put a male-worn T-shirt and a female-worn T-shirt in the same room, the female T-shirt counteracts the effect of a male T-shirt." This, Mogil says, indicates that solitary males represent the real threat. "A lone male is up to no good — either hunting or defending his territory." Fortunately, the male-induced stress effect becomes less pronounced over time, eventually disappearing altogether. This, and the fact that women counteract the effect, means there are a number of ways that researchers could prevent it from showing up in data.

"Fire all the men — or have them chaperoned by a woman."

One option, Mogil says jokingly, "is fire all the men — or have them chaperoned by a woman." A more realistic approach, however, would be to have male experimenter sit in a room for 45 minutes before collecting data. That makes the problem go away. But the Mogil doubts that anyone will want to do that because "it's just too boring."

Instead, Mogil hopes that his research — and other studies like it — will prompt researchers to report the gender of the experimenter in their publications. "You don't have to go back very far to see studies where people didn't think the strain of mouse mattered or the sex of the mouse mattered," Mogil says. "But these things all matter," and could be addressed in statistical analyses.

For now, Mogil is looking forward to hearing from fellow researchers who might now have an answer for unusual results. "I expect to hear stories, to hear people telling me that this sort of explains mysteries about experimenters not replicating each other, or having effects and then losing them," Mogil says. Because studies are so large these days, the graduate students who start them often don't see them through to completion, Mogil explains. So, women and men often end up taking on the same work in succession. Whether scientists will want to go back and check if their results were tainted by a male-induced stress response, however, is anybody's guess. As Mogil puts it, "we will have to see."

The Verge
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