Sex Differences in a Hypoxia Model of Preterm Brain Damage

Male sex is a well-established risk factor for poor neurodevelopmental outcome after premature birth. The mechanisms behind this sex-related difference are unknown. The damage associated with prematurity can be mimicked in rodents by prolonged exposure to sublethal postnatal hypoxia. This chronic hypoxia leads to anatomical changes in mice that strongly resemble the loss of volume, decreased myelination, and ventriculomegaly seen in pre-term newborns. However, no sex differences have been previously noted in this rodent model. We hypothesized that sex comparisons in hypoxic mice would show sex-related differences in brain volume and white matter loss in response to the same degree of hypoxic insult. Mice were placed in chronic sublethal hypoxia from postnatal day 3-11. Cortical, hippocampal, and cerebellar volumes and myelination indices were measured. We found that the male hippocampus, normally larger than the female, undergoes a greater volume loss compared with females (p < 0.05). Myelination, generally greater in males, was significantly disrupted by hypoxia in neonatal male forebrain. These results support the use of this rodent model to investigate the basis of sex-related susceptibility to brain damage and develop new sex-based neuroprotective strategies. (Pediatr Res 66: 248-253, 2009)