Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

Abstract

Intrauterine growth restriction (IUGR) and oxygen exposure in isolation and combination adversely affect the developing brain, putting infants at risk for neurodevelopmental disability including cerebral palsy. Rodent models of IUGR and postnatal hyperoxia have demonstrated oligodendroglial injury with subsequent white matter injury (WMI) and motor dysfunction. Here we investigate transcriptomic dysregulation in IUGR with and without hyperoxia exposure to account for the abnormal brain structure and function previously documented. We performed RNA sequencing and analysis using a mouse model of IUGR and found that IUGR, hyperoxia, and the combination of IUGR with hyperoxia (IUGR/hyperoxia) produced distinct changes in gene expression. IUGR in isolation demonstrated the fewest differentially expressed genes compared to control. In contrast, we detected several gene alterations in IUGR/hyperoxia; genes involved in myelination were strikingly downregulated. We also identified changes to specific regulators including TCF7L2, BDNF, SOX2, and DGCR8, through Ingenuity Pathway Analysis, that may contribute to impaired myelination in IUGR/hyperoxia. Our findings show that IUGR with hyperoxia induces unique transcriptional changes in the developing brain. These indicate mechanisms for increased risk for WMI in IUGR infants exposed to oxygen and suggest potential therapeutic targets to improve motor outcomes. Significance StatementThis study demonstrates that perinatal exposures of IUGR and/or postnatal hyperoxia result in distinct transcriptomic changes in the developing brain. In particular, we found that genes involved in normal developmental myelination, myelin maintenance, and remyelination were most dysregulated when IUGR was combined with hyperoxia. Understanding how multiple risk factors lead to WMI is the first step in developing future therapeutic interventions. Additionally, because oxygen exposure is often unavoidable after birth, an understanding of gene perturbations in this setting will increase our awareness of the need for tight control of oxygen use to minimize future motor disability.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function

“…This differential growth trajectory is important to highlight as we consider the neurological phenotype in this model in the following sections. But before we move on to the characterization of the IUGR hippocampal DG neurogenesis and neurobehavioral phenotype, it is worth mentioning that other organs such as the liver, small intestine, and brain white matter are also impacted by IUGR in this model (Fung et al, 2015(Fung et al, , 2016McKnight et al, 2015;Chang et al, 2018Chang et al, , 2021.…”

Being born small for gestational age (SGA) might be associated with a higher reoperation rate in proximal hypospadias

“…Thereby, we could exclude a confounding influence of these factors to the findings related to SGA. Intrauterine growth restriction and SGA have been liked with several congenital anomalies, increased morbidity in the neonatal period, neurodevelopmental issues and a higher risk of metabolic syndrome and obesity as well as a higher risk of infections [27,10,11]. This theory, similar to the thrifty gene hypothesis, may underline the observed postnatal effects, potentially also influencing surgical complication rates [12].…”