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In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring
Arvind Palanisamy, … , Joel R. Garbow, David F. Wozniak
Arvind Palanisamy, … , Joel R. Garbow, David F. Wozniak
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(10):e133172. https://doi.org/10.1172/jci.insight.133172.
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Research Article Development Neuroscience

In utero exposure to transient ischemia-hypoxemia promotes long-term neurodevelopmental abnormalities in male rat offspring

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Abstract

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.

Authors

Arvind Palanisamy, Tusar Giri, Jia Jiang, Annie Bice, James D. Quirk, Sara B. Conyers, Susan E. Maloney, Nandini Raghuraman, Adam Q. Bauer, Joel R. Garbow, David F. Wozniak

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Figure 2

Transient OXT-induced uterine hypercontractility causes oxidative stress in the fetal brain.

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Transient OXT-induced uterine hypercontractility causes oxidative stress...
In utero exposure to OXT-induced uterine hypercontractility increased the concentration of lactate (A), 4-hydroxynonenal (B), protein carbonyl (C), and oxidized glutathione (D) in the fetal brain, strongly suggesting the presence of oxidative stress (n = 8 male and female pups from 8 dams per treatment condition). Data were analyzed with 2-way ANOVA and presented as mean ± SEM; *P < 0.05, **P < 0.01, and ****P < 0.0001.

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