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.