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Deleterious effect of hyperoxia at birth on white matter damage in the newborn rat
Gaelle Vottier1, Hoa Pham, Julien Pansiot
1INSERM, AVENIR R05230HS (U676), Université Paris 7, Faculté de Médecine Denis Diderot, IFR 02, Paris, France.
Insights
High oxygen exposure after birth harms developing white matter in premature infants, increasing the risk of cerebral palsy. Gradual oxygen reintroduction, not high oxygen, protects against this damage.
Area of Science:
- Neonatal neuroscience
- Developmental neurobiology
- Perinatal medicine
Background:
- White matter damage (WMD) is a primary cause of cerebral palsy in premature infants.
- Reactive oxygen species during reoxygenation are implicated in WMD pathogenesis.
- The impact of postnatal oxygen exposure on immature white matter requires further investigation.
Purpose of the Study:
- To investigate the hypothesis that free radical injury during reoxygenation at birth harms immature white matter.
- To determine the effects of postnatal hyperoxia and progressive reoxygenation on white matter development in a rat model.
- To assess the exacerbation of antenatal hypoxia-induced WMD by postnatal hyperoxia.
Main Methods:
- A rat model was used, involving antenatal hypoxia (E5-E21) or normoxia.
- Postnatal exposures included normoxia, hyperoxia (60% FiO2), or slow reoxygenation (15% to 21% FiO2 by P7).
- White matter inflammation (microglial cells), cell death (TUNEL), myelin content, and oligodendrocyte maturation were analyzed.
Main Results:
- Postnatal hyperoxia significantly increased microglial activation and cell death in developing white matter.
- Hyperoxia decreased myelin content and mature oligodendrocyte density, worsening antenatal hypoxia-induced WMD.
- Progressive reoxygenation prevented WMD and did not alter white matter inflammation or cell death compared to controls.
Conclusions:
- Postnatal hyperoxia has a deleterious effect on the developing white matter in rat pups.
- Hyperoxia at birth exacerbates white matter damage, particularly in the context of antenatal hypoxia.
- Avoiding hyperoxia at birth is recommended for preterm infants at risk of white matter damage and cerebral palsy.
Abstract:
White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO(2) = 10%) or maintained normoxia (FiO(2) = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO(2) = 21%), hyperoxia (FiO(2) = 60%) or slowly reoxygenated (FiO(2) from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (-31%) and mature oligodendrocyte density (-37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD.
