Inflammation during pregnancy may affect the developing placenta in ways that leave male fetuses particularly vulnerable to developmental abnormalities, according to a new study published in Science Advances.
The findings offer a possible explanation for sex differences in neurodevelopmental disorders such as autism, although researchers caution that the results come from experiments in mice and do not establish the same mechanism in humans.
The study, titled ‘Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders’, examined how maternal immune activation affects fetal development. This refers to an inflammatory response in the mother, such as one triggered by an infection during pregnancy.
Researchers at Cold Spring Harbor Laboratory induced an immune response in pregnant mice using poly(I:C), a substance that mimics the immune system’s response to a viral infection without introducing an actual virus. They found that approximately 30% of exposed embryos developed abnormalities within 24 hours. These included reduced fetal weight and changes in the development of sensory organs.
The abnormalities appeared exclusively in a subset of male embryos. Female embryos did not show the same developmental disruptions.
The placenta’s role
The researchers found that affected male embryos also had damage to specialised placental cells called spongiotrophoblast. These cells help maintain the immune environment at the boundary between the mother and the developing fetus, which carries genetic material from both parents.
Following maternal immune activation, these cells showed increased inflammatory activity and reduced expression of genes involved in maintaining placental structure and hormone production. The researchers also detected inflammatory molecules in the amniotic fluid. One of these, interleukin-6 (IL-6), was necessary for the developmental abnormalities to occur.
“To truly understand autism spectrum disorder, we have to look beyond the brain,” Lucas Cheadle, an associate professor at Cold Spring Harbor Laboratory, told ScienceDaily. “Our work suggests that maternal immune activation and changes within the placenta are a gateway to autism for some unique individuals.”
The researchers suggest that male embryos may produce proteins that trigger a stronger maternal immune response when the placenta’s normal protective mechanisms are disrupted. They also propose that female embryos may have protective mechanisms that help them withstand inflammation.
Why are males more frequently diagnosed?
The findings add to a long-running debate about why autism is diagnosed more frequently in males. A 2011 review published in PLOS Biology, titled ‘Why Are Autism Spectrum Conditions More Prevalent in Males?’, examined possible explanations, including prenatal testosterone exposure and genetic differences involving the X and Y chromosomes. It also discussed the possibility that autism is underdiagnosed in females because its presentation may differ.
None of these explanations has been conclusively established, and the review emphasised that autism has multiple contributing factors.
The new study offers another possible avenue of investigation by identifying the placenta as an early site of vulnerability. However, its findings should not be interpreted as evidence that maternal infections cause autism in humans. Further research is needed to determine whether similar placental mechanisms operate during human pregnancy.
(Edited By Raunaq Lekhi)