Placental structure, function and mitochondrial phenotype relate to fetal size and sex in mice

Abstract

<jats:title>Abstract</jats:title><jats:p>Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), and mitochondrial regulators, nutrient transporters, hormone handling and signalling pathways (qPCR and western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (<jats:italic>Nrf1</jats:italic>) and fission (<jats:italic>Drp1</jats:italic> and <jats:italic>Fis1</jats:italic>) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene <jats:italic>Tfam</jats:italic> was greater in the placenta of the lightest male fetuses. Additionally, placental morphology and steroidogenic gene (<jats:italic>Cyp17a1</jats:italic> and <jats:italic>Cyp11a1</jats:italic>) expression was aberrant for the lightest females, but glucose transporter (<jats:italic>Glut1</jats:italic>) expression was lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to sex-dependent changes in the expression of hormone responsive (androgen receptor) and metabolic signalling (AMPK, AKT, PPARγ) pathways. Thus, in normal mouse pregnancy, placental structure, function and mitochondrial phenotype are differentially responsive to growth of the female and the male fetus. This study may inform the design of sex- specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring.</jats:p>