Alonso-Alconada Daniel, Chillida Marc, Catalan Ana, Gressens Pierre, Robertson Nicola J
Department of Cell Biology & Histology, School of Medicine & Nursing, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
Psychiatry Department, OSI Bilbao-Basurto, Basurto University Hospital, Bilbao, Spain.
Pediatr Res. 2025 Apr 16. doi: 10.1038/s41390-025-04046-5.
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.
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.
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.
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.
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.
临床数据表明，女性可能比男性对缺氧更具抵抗力，男性被认为是患终身神经后遗症的一个风险因素。然而，缺氧缺血在某些脑区的影响及其与基因性别之间的关联仍不清楚。
利用新生仔猪脑损伤模型，对15头仔猪（8头雌性和7头雄性）进行全脑缺氧缺血损伤。48小时后，对五个脑区的总细胞死亡以及坏死、凋亡和裂解型半胱天冬酶-3阳性细胞的数量进行定量分析。
暴露于缺氧缺血的雄性仔猪比雌性仔猪更易受影响（总细胞死亡，p<0.01），并且根据性别对脑损伤表现出区域特异性反应，雄性在深部灰质（尾状核，p<0.01；丘脑，p<0.0001）和白质（p<0.01）中受影响更大。尽管坏死是两性细胞死亡的主要形式，但细胞死亡模式有所不同：雄性仔猪坏死更多（p<0.0001），而雌性的凋亡（p<0.0001）和半胱天冬酶-3激活（p<0.0001）更高。
我们的结果表明，雄性仔猪在缺氧缺血后比雌性在整体和区域上更易受影响；此外，细胞死亡模式和凋亡分子机制均存在性别差异。
临床数据表明，女性可能比男性新生儿对围产期窒息更具抵抗力。缺氧缺血在某些脑区的影响以及细胞死亡模式与性别的关联仍不清楚。缺氧缺血的雄性仔猪比雌性更易受影响，在深部灰质和白质区域也表现出更高的区域易损性。尽管坏死是两性细胞死亡的主要形式，但雄性仔猪坏死更多，而雌性的凋亡和半胱天冬酶-3激活更高。由于细胞死亡模式和分子机制的差异，新生儿脑损伤和治疗反应可能存在性别依赖性。
