Sexual Dimorphism in Placental mTORC1 Signaling, Amino Acid Transport, and Mitochondrial Respiration at Term

Male fetuses generally grow faster in utero and are heavier at birth than females, whereas the rates of perinatal mortality and morbidity are often higher in boys than in girls. Sexual dimorphism in placental function is believed to contribute to these differences. However, evidence for sex-specific differences in placental function remains limited. We hypothesized that placental nutrient-sensing signaling activity, amino acid transport capacity, and mitochondrial respiration are higher in male than female placentas. Placentas were collected from 46 women (BMI 18.5-29.9 kg/m²) with uncomplicated pregnancies delivering appropriate-for-gestational-age infants (n = 23 female; n = 23 male). In homogenates of male placentas, the phosphorylation of S6RP (Ser235/236) was increased and total 4E-BP1 protein expression was reduced compared with female placentas, indicating enhanced mTORC1 signaling. In vitro System A amino acid transport activity was also greater in microvillous plasma membranes isolated from male placentas. Placental mitochondrial respiratory capacity was assessed in villous tissue using high-resolution respirometry with carbohydrate and lipid substrate-uncoupler-inhibitor titration (Carb SUIT and Lipid SUIT) protocols on the Oroboros O2k platform. Male placentas exhibited greater maximal oxidative phosphorylation capacity, enhanced complex II-linked respiration, and higher maximal electron transport system capacity compared with female placentas under both carbohydrate- and lipid-supported respiratory conditions. Although placental weight did not differ between sexes, the birth weight-to-placental weight ratio was significantly higher in male pregnancies, consistent with greater placental functional efficiency. In conclusion, placental mTORC1 signaling activity, System A amino acid transport activity, and mitochondrial respiratory capacity are greater in male than female placentas and are associated with greater placental functional efficiency and fetal growth in male pregnancies.