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

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 4

OXT-induced uterine hypercontractility is associated with male-specific decrease in social investigation and an increase in empathy-like fear.

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OXT-induced uterine hypercontractility is associated with male-specific ...
There were no differences in ambulatory activity in the open-field test (A) and the percentage of open arm entries in the elevated plus maze (B) between the CON and OXT groups. (C) However, male OXT-exposed offspring spent significantly less time investigating a novel rat compared with CON male offspring. No differences were observed between CON and OXT female offspring. (D) OXT offspring showed significantly increased freezing levels in the OFL test during the last 2 minutes of training, suggesting an enhanced empathy-like response. However, there were no differences in the contextual fear test 24 hours later (n = 12 male and female offspring from 9 independent litters per treatment condition with exclusions as reported in supplemental materials). Data analyzed with repeated-measures ANOVA (followed by Bonferroni’s correction if required) and presented as mean ± SEM; **P < 0.01.