Sex-dependent impairments in oligodendrocyte maturation and myelination in offspring mice exposed to preeclampsia

Abstract

Preeclampsia, a prevalent obstetric complication with systemic implications for maternal and fetal health, has been increasingly linked to altered neurodevelopment and long-term neuropsychological sequelae in offspring. While existing evidence highlights its potential to disrupt brain development, the sex-specific effects of preeclampsia on white matter development and oligodendrocyte maturation remain poorly characterized. This study focused on assessing the effects of preeclampsia on offspring oligodendrocyte maturation, myelination and neurobehavioral outcomes. A preeclampsia mouse model was established by continuously subcutaneous injecting 125 mg/kg/day of N(G)-Nitro-L-arginine methyl ester (L-NAME) into pregnant mice from gestational day 10.5 to 17.5, with concurrent monitoring systolic blood pressure and urinary protein levels. Postnatal reflex assessments were followed by comprehensive behavioral testing and neurohistological analyses in offspring. Behavioral results indicated that male offspring exposed to preeclampsia demonstrated sex-specific deficits in anxiety-related behaviors, cognitive function, and social exploration, alongside disruptions in white matter development. These included impaired oligodendrocyte maturation, reduced myelination, and axonal damage, likely attributable to diminished oligodendrocyte lineage cells proliferation. It is inspiring that environmental enrichment during adolescence ameliorated behavioral deficits and partially restored white matter development in preeclampsia-exposed offspring. In conclusion, our findings suggest that male mice exposed to preeclampsia are more likely to experience alterations in long-term behavior and white matter development than in female mice. Environmental enrichment warrants further investigation as a potential preventive or therapeutic approach to address neurodevelopmental risks associated with prenatal preeclampsia exposure.