Sex-bias metabolism of fetal organs, and their relationship to the regulation of fetal brain-placental axis.

Introduction: The placenta plays influential role in the fetal development of mammals. But how the metabolic need of the fetal organs is related to that of the placenta, and whether this relationship is influenced by the sex of the fetus remain poorly understood.

Objectives: This study used pigs to investigate metabolomic signatures of male and female fetal organs, and determine the relevance of gene expression of the placenta and brain to the metabolism of peripheral organs.

Methods: Untargeted metabolomics analysis was performed with the day-45 placenta, kidney, heart, liver, lung and brain of male and female pig fetuses to model sex differences in the metabolism of the peripheral organs relative to that of the brain and placenta. Transcriptomic analysis was performed to investigate the expression of metabolic genes in the placenta and fetal brain of both sexes.

Results: The results of this study show that the fetoplacental metabolic regulation was not only influenced by the fetal sex but also dependent on the metabolic requirement of  the individual organs of the fetus. Neural network modeling of metabolomics data revealed differential relationship of the metabolic changes of the peripheral organs with the placenta and fetal brain between males and females. RNA sequencing further showed that genes associated with the metabolism of the peripheral organs were differentially expressed in the placenta and fetal brain.

Conclusion: The findings of this study suggest a regulatory role of the fetal brain and placenta axis in the sex-bias metabolism of the peripheral organs.