Maternal and Fetal PI3K-p110α Deficiency Induces Sex-Specific Changes in Conceptus Growth and Placental Mitochondrial Bioenergetic Reserve in Mice

Fetal growth is reliant on placental formation and function, which, in turn, requires the energy produced by the mitochondria. Prior work has shown that both mother and fetus operate via the phosphoinositol 3-kinase (PI3K)-p110 alpha signalling pathway to modify placental development, function, and fetal growth outcomes. This study in mice used genetic inactivation of PI3K-p110 alpha (alpha/+) in mothers and fetuses and high resolution respirometry to investigate the influence of maternal and fetal PI3K-p110 alpha deficiency on fetal and placental growth, in relation to placental mitochondrial bioenergetics, for each fetal sex. The effect of PI3K-p110 alpha deficiency on maternal body composition was also determined to understand more about the maternal-driven changes in feto-placental development. These data show that male fetuses were more sensitive than females to fetal PI3K-p110 alpha deficiency, as they had greater reductions in fetal and placental weight, when compared to their WT littermates. Placental weight was also altered in males only of alpha/+ dams. In addition, oc/+ male, but not female, fetuses showed an increase in mitochondrial reserve capacity, when compared to their WT littermates in alpha/+ dams. Finally, alpha/+ dams exhibited reduced adipose depot masses, compared to wild-type dams. These findings, thus, demonstrate that maternal nutrient reserves and ability to apportion nutrients to the fetus are reduced in alpha/+ dams. Moreover, maternal and fetal PI3K-p110 alpha deficiency impacts conceptus growth and placental mitochondrial bioenergetic function, in a manner dependent on fetal sex.