Scientists at Cold Spring Harbor Laboratory say the placenta, not only the developing brain, may hold a clue to one of autism research's oldest puzzles: why autism spectrum disorder is diagnosed in boys several times more often than in girls.
In a study published in Science Advances, a team led by CSHL associate professor Lucas Cheadle triggered an immune response in pregnant mice at different points in gestation, mimicking the body's reaction to a viral infection without introducing an actual virus. Fetuses were most vulnerable when the inflammation occurred 12.5 days into pregnancy: within 24 hours, researchers say, about a third of fetuses showed developmental abnormalities. Autism-like traits later appeared only in male offspring across every experiment the team ran; female littermates developed normally.
A damaged gatekeeper
The affected male fetuses also showed visible damage to spongiotrophoblasts, specialized placental cells that help the mother's immune system tolerate the fetus rather than attack it as foreign tissue. The researchers propose that maternal immune activation disrupts that protective function specifically around male fetuses, though they stop short of proving why. One possibility, they suggest, is that male embryos produce proteins that provoke a stronger maternal immune response; another is that female embryos carry some protective mechanism males lack. Neither explanation has been confirmed, and the team says further work in both sexes is planned.
"To truly understand autism spectrum disorder, we have to look beyond the brain," Cheadle said, describing the placenta as a potential alternate route into the condition's biology alongside the neural mechanisms that have dominated autism research for decades.
The findings come with caveats the researchers themselves emphasize. The work was done entirely in mice, and the authors are explicit that it "does not establish that the same mechanisms cause autism in humans." The behaviors measured are autism-like traits in rodents, not a diagnosis of autism itself, and the 12.5-day window is a mouse-specific gestational stage that does not map directly onto any particular point in human pregnancy. The placental damage and the developmental abnormalities were observed together, not shown to cause one another in a strict experimental sense.
Autism's sex skew — boys are diagnosed roughly three to four times more often than girls in most population studies — has long been attributed mainly to genetic and neurological differences. If placental injury turns out to play a comparable role in humans, it could eventually open a second avenue of research into prenatal risk factors, though that possibility remains speculative until the mechanism is tested beyond mouse models.