Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Altered placental formation and functional capacity are major contributors to FGR pathogenesis. Relating placental structure to function across the placenta in healthy and FGR pregnancies remains largely unexplored but could improve understanding of placental diseases. We investigated integration of these parameters spatially in the term human placenta using predictive modelling. Systematic sampling was able to overcome heterogeneity in placental morphological and molecular features. Defects in villous development, elevated fibrosis, and reduced expression of growth and functional marker genes (IGF2, VEGA, SLC38A1, and SLC2A3) were seen in age-matched term FGR versus healthy control placentas. Characteristic histopathological changes with specific accompanying molecular signatures could be integrated through computational modelling to predict if the placenta came from a healthy or FGR pregnancy. Our findings yield new insights into the spatial relationship between placental structure and function and the etiology of FGR.

Adverse maternal environments such as small size, malnutrition, and metabolic conditions are known to influence fetal growth outcomes. Similarly, fetal growth and metabolic alterations may alter the intrauterine environment and affect all fetuses in multiple gestation/litter-bearing species. The placenta is the site of convergence between signals derived from the mother and the developing fetus/es. Its functions are fuelled by energy generated by mitochondrial oxidative phosphorylation (OXPHOS). The aim of this study was to delineate the role of an altered maternal and/or fetal/intrauterine environment in feto-placental growth and placental mitochondrial energetic capacity. To address this, in mice, we used disruptions of the gene encoding phosphoinositol 3-kinase (PI3K) p110α, a growth and metabolic regulator to perturb the maternal and/or fetal/intrauterine environment and study the impact on wildtype conceptuses. We found that feto-placental growth was modified by a perturbed maternal and intrauterine environment, and effects were most evident for wildtype males compared to females. However, placental mitochondrial complex I+II OXPHOS and total electron transport system (ETS) capacity were similarly reduced for both fetal sexes, yet reserve capacity was additionally decreased in males in response to the maternal and intrauterine perturbations. These were also sex-dependent differences in the placental abundance of mitochondrial-related proteins (e.g., citrate synthase and ETS complexes), and activity of growth/metabolic signalling pathways (AKT and MAPK) with maternal and intrauterine alterations. Our findings thus identify that the mother and the intrauterine environment provided by littermates modulate feto-placental growth, placental bioenergetics, and metabolic signalling in a manner dependent on fetal sex. This may have relevance for understanding the pathways leading to reduced fetal growth, particularly in the context of suboptimal maternal environments and multiple gestation/litter-bearing species.

Pregnancy is characterized by adaptations in the function of several maternal body systems that ensure the development of the fetus whilst maintaining health of the mother. The renal system is responsible for water and electrolyte balance, as well as waste removal. Thus, it is imperative that structural and functional changes occur in the kidney during pregnancy. However, our knowledge of the precise morphological and molecular mechanisms occurring in the kidney during pregnancy is still very limited. Here, we investigated the changes occurring in the mouse kidney during pregnancy by performing an integrated analysis involving histology, gene and protein expression assays, mass spectrometry profiling and bioinformatics. Data from non-pregnant and pregnant mice were used to identify critical signalling pathways mediating changes in the maternal kidneys. We observed an expansion of renal medulla due to proliferation and infiltration of interstitial cellular constituents, as well as alterations in the activity of key cellular signalling pathways (e.g., AKT, AMPK and MAPKs) and genes involved in cell growth/metabolism (e.g., Cdc6, Foxm1 and Rb1) in the kidneys during pregnancy. We also generated plasma and urine proteomic profiles, identifying unique proteins in pregnancy. These proteins could be used to monitor and study potential mechanisms of renal adaptations during pregnancy and disease.

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.