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

Abstract

Simple SummaryThe placenta is responsible for materno-fetal resource allocation. Placental insufficiency may disrupt fetal growth trajectory, with negative consequences for maternal and fetal health. By manipulating a growth-controlling protein named PI3K-p110α, this work, performed on mice, shows the relevance of the maternal environment and fetal genotype in determining the conceptus growth and mitochondria bioenergetic reserve in the placental transport zone. Interestingly, the disruption of maternal and/or fetal PI3K-p110α exerted these effects in a sex-specific manner, with male fetuses more affected than females. These data highlight the importance of the sex of the fetus and placental mitochondrial function in the regulation of fetal growth.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)-p110α signalling pathway to modify placental development, function, and fetal growth outcomes. This study in mice used genetic inactivation of PI3K-p110α (α/+) in mothers and fetuses and high resolution respirometry to investigate the influence of maternal and fetal PI3K-p110α deficiency on fetal and placental growth, in relation to placental mitochondrial bioenergetics, for each fetal sex. The effect of PI3K-p110α 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-p110α 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 α/+ dams. In addition, α/+ male, but not female, fetuses showed an increase in mitochondrial reserve capacity, when compared to their WT littermates in α/+ dams. Finally, α/+ 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 α/+ dams. Moreover, maternal and fetal PI3K-p110α deficiency impacts conceptus growth and placental mitochondrial bioenergetic function, in a manner dependent on fetal sex.