Inflammation on day 12.5 of pregnancy gave only male mouse pups autism-like traits, a study finds

When inflammation was triggered in pregnant mice at 12.5 days of gestation, roughly one-third of the fetuses showed developmental abnormalities within 24 hours, and the pups that went on to develop autism-like traits were all male. Females in the same experiments kept developing normally. The finding comes from Lucas Cheadle’s laboratory at Cold Spring Harbor Laboratory, and it points at the placenta rather than the brain as the first place trouble shows up.

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Cheadle, an associate professor at the lab, summed up the team’s stance in a single sentence: understanding autism spectrum disorder requires looking beyond the brain. The study is in mice, and nothing in it shows the same chain of events occurs in people.

An immune trigger timed to day 12.5

The researchers injected pregnant mice with a compound that switches on the immune system the way a viral infection would, without any virus present. They repeated the experiment at different stages of pregnancy to find when the fetus is most exposed. Day 12.5 stood out as the most vulnerable point, and the one-third of fetuses with abnormal development within a day of the challenge made it, in the lab’s words, the earliest sign of disruption scientists have recorded in maternal immune activation research, according to the Cold Spring Harbor release.

The work is published in Science Advances under the paper name “Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders.” First author Irene Sanchez-Martin leads a list of nine authors that includes Bharti Kukreja, Paige Henderson, Qianyu Lin, Daniel DiMartino, Valerie Bagan, Justin Park and Brian Kalish.

Spongiotrophoblasts and a one-sided outcome

The team traced the damage to spongiotrophoblasts, cells in the part of the mouse placenta where maternal and fetal tissue meet. In pups that developed normally, that zone looked healthy. In affected males it showed visible injury. Under ordinary conditions, spongiotrophoblasts help the mother’s immune system tolerate the fetus, and after the immune challenge they appear to lose that protective role, leaving the fetus exposed to the mother’s own response, as ScienceDaily summarized the findings. Across every experiment, autism-like traits appeared only in males.

The timing is what surprised Cheadle. The window falls before the hormone surges and the sexual differentiation of the brain, so a sex-based difference this early was unexpected. The authors offer two candidate explanations. Male embryos may carry proteins that provoke an unfavorable response from the mother after immune activation, or female embryos may have a protective mechanism that males lack. Cheadle said the evidence suggests the mechanisms may well differ between the sexes, and he proposed that a protective pathway in females could eventually be borrowed to help males. Both ideas remain hypotheses that the current data point toward rather than confirm.

What a male skew in mice may say about the diagnosis gap

Autism is diagnosed far more often in boys than in girls. The National Institute of Mental Health reports, from the CDC’s 2022 monitoring of 8-year-olds in 16 U.S. communities, that 4.9 percent of boys and 1.4 percent of girls were identified with autism, making it 3.4 times as prevalent among boys, as laid out on the NIMH autism statistics page. The figures come from the CDC’s MMWR report on children aged 4 and 8, published in April 2025, which put overall prevalence among 8-year-olds at 32.2 per 1,000, or about one in 31. The survey is a record-based count in selected communities, and NIMH cautions against reading it as a national rate.

A 3.4-to-1 split has always invited the question of whether boys are simply more susceptible or girls are more often missed. The mouse data cannot settle that, but they do add a biological candidate: a placental step that goes wrong in males under the same conditions that leave females unaffected.

The Cheadle group suggests a placental route could help explain part of that gap, and that it could eventually point to new treatment targets and earlier interventions. The release also notes that genetics play a major role in autism and that other environmental factors during pregnancy contribute as well, so a single window of immune activation cannot account for the whole picture.

Funding for the lab’s work came from the Howard Hughes Medical Institute, the National Institute of Mental Health, the National Cancer Institute, the Rita Allen Foundation, the McKnight Foundation, the Klingenstein-Simons Fellowship and the Brain and Behavior Research Foundation, the lab release states. The group plans to keep studying both male and female pups, partly because the females that escaped harm may hold the more useful clue.

Spongiotrophoblasts sit at the border between two immune systems, the mother’s and the fetus’s, and the paper’s title frames the damage as a conflict between them. In the experiments, healthy pups had healthy-looking border zones, while affected males did not, which ties the outcome to a specific tissue that researchers can now examine more closely in other models.

Whether human placentas carry the same vulnerable cell population at a comparable stage remains the gap between this paper and any clinical use. Until researchers examine that directly, day 12.5 in a mouse is a clue about timing, not a calendar for people.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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