Sex-Dependent Regulation of Placental Oleic Acid and Palmitic Acid Metabolism by Maternal Glycemia and Associations with Birthweight.

Pregnancy complications such as maternal hyperglycemia increase perinatal mortality and morbidity, but risks are higher in males than in females. We hypothesized that fetal sex-dependent differences in placental palmitic-acid (PA) and oleic-acid (OA) metabolism influence such risks. Placental explants ( n = 22) were incubated with isotope-labeled fatty acids ( 13 C-PA or 13 C-OA) for 24 or 48 h and the production of forty-seven 13 C-PA lipids and thirty-seven 13 C-OA lipids quantified by LCMS. Linear regression was used to investigate associations between maternal glycemia, BMI and fetal sex with 13 C lipids, and between 13 C lipids and birthweight centile. Placental explants from females showed greater incorporation of 13 C-OA and 13 C-PA into almost all lipids compared to males. Fetal sex also influenced relationships with maternal glycemia, with many 13 C-OA and 13 C-PA acylcarnitines, 13 C-PA-diacylglycerols and 13 C-PA phospholipids positively associated with glycemia in females but not in males. In contrast, several 13 C-OA triacylglycerols and 13 C-OA phospholipids were negatively associated with glycemia in males but not in females. Birthweight centile in females was positively associated with six 13 C-PA and three 13 C-OA lipids (mainly acylcarnitines) and was negatively associated with eight 13 C-OA lipids, while males showed few associations. Fetal sex thus influences placental lipid metabolism and could be a key modulator of the impact of maternal metabolic health on perinatal outcomes, potentially contributing toward sex-specific adaptions in which females prioritize survival.