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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 1

Placental perfusion is significantly impaired after OXT-induced aberrant uterine contractility.

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Placental perfusion is significantly impaired after OXT-induced aberrant...
(A) Middle and right show the initial area under the curve (IAUC) from the baseline and post-OXT dynamic contrast-enhanced MRI experiments overlaid onto the corresponding anatomical T2-weighted images from 1 slice shown on the left. (B) Left: Placental relative signal enhancement after Dotarem injection is significantly decreased after OXT compared with baseline. Right: Comparison of the changes in IAUC (averaged across all placentas) from baseline after either saline or OXT showing an approximately 45% decrease after OXT, confirming that OXT-induced uterine hypercontractility was associated with significantly reduced uteroplacental perfusion (n = 3 per group). Data were analyzed with 2-tailed Student’s t test and presented as mean ± SEM; **P < 0.01. (C) OXT-induced hypercontractility significantly decreases placental R2*. Left: Illustrative fast spin echo (FSE) images from an OXT-treated dam showing placental regions of interest (ROIs). Right: Placental R2* was measured in 29 and 38 placentas from saline-treated (n = 3) or OXT-treated (n = 6) dams, respectively. OXT treatment decreased placental R2* by approximately 40%, suggesting either severe uteroplacental perfusion or profound placental squeeze draining all blood, including deoxygenated blood, away from the placenta. Data were analyzed with Mann-Whitney U test and presented as mean ± SEM; ****P < 0.0001.

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