Association of chronic sublethal hypoxia with ventriculomegaly in the developing rat brain

Bronchopulmonary dysplasia remains a major cause of neurodevelopmental handicap in preterm infants. Because bronchopulmonary dysplasia may be associated with prolonged hypoxemia without obvious changes in systemic blood pressure, we developed an animal model of chronic sublethal hypoxia to test the hypothesis that this insult results in significant alterations in corticogenesis in the developing brain. Three groups of newborn rats were placed in a chamber with FIO2 9.5% on postnatal day 3 (P3). One group was sacrificed at P13; a second group was sacrificed at P33, and the third group was removed at P33 and reared in normoxia until sacrifice at P63. Control rats were those raised in room air for the corresponding periods of time. Rats were transcardially perfused and the brains were embedded in celloidin and prepared for morphometric analysis using standard stereology methods. Although experimental rat pups in the third group demonstrated 'catch-up' of body weight following return to normoxia, these studies demonstrated both failure of brain growth (p<0.01) and progressive cerebral ventriculomegaly (p<0.01). Decreased subcortical white matter (p<0. 05) and corpus callosum size (p<0.01) were noted at P63 in pups reared under conditions of chronic hypoxia. Decreases in cortical volume (p<0.05) were noted at all three experimental time points for hypoxic-reared pups when compared to control animals. These data suggest that chronic sublethal hypoxia may lead to severe impairments in corticogenesis in an animal model of developing brain.