Sex dimorphism in brain cell death after hypoxia-ischemia in newborn piglets.

Background: Clinical data suggest that females might be more resistant to hypoxia than males, with male sex recognized as a risk factor for suffering life-long neurological sequelae. However, the impact of hypoxia-ischemia in certain brain regions and its association with genetic sex remains unclear.

Methods: Using the piglet model of neonatal brain injury, fifteen piglets (8 females and 7 males) were subjected to a global cerebral hypoxic-ischemic insult. After 48 h, total cell death and the number of necrotic, apoptotic and cleaved-caspase-3 positive cells was quantified in five brain regions.

Results: Male piglets exposed to hypoxia-ischemia were more vulnerable than females (total cell death p < 0.01), also showing a region-specific response to brain injury depending on sex, with males being more affected in both deep gray (caudate p < 0.01; THAL p < 0.0001) and white (p < 0.01) matter. Despite necrosis was the primary form of cell death for both sexes, the pattern of cell death differed: while male piglets showed more necrosis (p < 0.0001), apoptosis (p < 0.0001) and caspase-3 activation (p < 0.0001) were higher in females.

Conclusion: Our results suggest that male piglets were globally and regionally more vulnerable than females after HI; further, both the pattern of cell death and the apoptotic molecular mechanisms were sexually dimorphic.

Impact: Clinical data suggest that females might be more resistant to perinatal asphyxia than male newborns. The impact of hypoxia-ischemia in certain brain regions and the association of cell death patterns with sex remain unclear. Hypoxic-ischemic male piglets were more vulnerable than females, showing also increased regional vulnerability in both deep gray and white matter areas. Although necrosis was the primary form of cell death for both sexes, male piglets showed more necrosis, whereas apoptosis and caspase-3 activation were higher in females. Neonatal brain injury and therapeutic responses may be sex-dependent due to differences in cell death patterns and molecular mechanisms.