期刊
JCI INSIGHT
卷 5, 期 10, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.133172
关键词
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资金
- Department of Anesthesiology, Washington School of Medicine
- NIH R01 grant [NS102870]
- NIH [R01 HD086323, U54 HD087011]
- NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54 HD087011]
- National Cancer Institute Cancer Center Support grant [P30 CA91842]
- Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award from the National Center for Research Resources, a component of the NIH [UL1TR002345]
- NIH Roadmap for Medical Research
The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.
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