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 (¹³C-PA or ¹³C-OA) for 24 or 48 h and the production of forty-seven ¹³C-PA lipids and thirty-seven ¹³C-OA lipids quantified by LCMS. Linear regression was used to investigate associations between maternal glycemia, BMI and fetal sex with ¹³C lipids, and between ¹³C lipids and birthweight centile. Placental explants from females showed greater incorporation of ¹³C-OA and ¹³C-PA into almost all lipids compared to males. Fetal sex also influenced relationships with maternal glycemia, with many ¹³C-OA and ¹³C-PA acylcarnitines, ¹³C-PA-diacylglycerols and ¹³C-PA phospholipids positively associated with glycemia in females but not in males. In contrast, several ¹³C-OA triacylglycerols and ¹³C-OA phospholipids were negatively associated with glycemia in males but not in females. Birthweight centile in females was positively associated with six ¹³C-PA and three ¹³C-OA lipids (mainly acylcarnitines) and was negatively associated with eight ¹³C-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.