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DNA methylation patterns reveal cellular mechanisms underlying neurologic risk in inflammation-sensitized hypoxic ischemic encephalopathy

ABSTRACT: Neonatal hypoxic ischemic encephalopathy (HIE) is a common birth complication that can cause death or lifelong disability due to cerebral palsy, epilepsy, and autism. Maternal infection or inflammation is a leading risk factor for diagnosis of HIE and cerebral palsy. However, the reasons for this increase in neurological risk to the offspring remain unknown. Inflammation or infection are known to cause epigenetic changes and may contribute to the increased risk of neurodevelopmental disability in exposed offspring. We hypothesized that differential methylation occurs in brain monocytes in a mouse model of inflammation-sensitized hypoxic ischemic encephalopathy. We compared DNA methylation in brain monocytes isolated from control, maternal immune activation (MIA), and inflammation sensitized HIE at postnatal day 7 (P7). Maternal inflammation induced significant methylation differences relative to control samples. MIA samples showed FDR-significant enrichment at loci involving craniofacial development and transcription factors important for regulating neurodevelopment and immune function. MIA and HIE samples were not significantly different. These results suggest that maternal inflammation or infection may increase the risk of HIE or neurological sequelae via gene methylation resulting in altered neurodevelopment.

ORGANISM(S): Mus musculus

PROVIDER: GSE319589 | GEO | 2026/02/19

REPOSITORIES: GEO

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Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.

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DNA methylation patterns reveal cellular mechanisms underlying neurologic risk in inflammation-sensitized hypoxic ischemic encephalopathy

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