Sex-Specific Dysregulation of Placental Lipid Metabolism in Preeclampsia

Abstract

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with adverse maternal and fetal outcomes. While placental dysfunction is implicated in PE pathogenesis, the impact of PE on placental lipid metabolism and its potential sexual dimorphism remains poorly understood.

Methods: We conducted a comprehensive analysis of term placentas from PE and normotensive pregnancies with male and female fetuses. Lipid profiles were quantified using mass spectrometry, and mRNA expression of genes involved in fatty acid oxidation, esterification, and transport was assessed using qPCR.

Results: Placentas from PE pregnancies exhibited elevated lipid levels, with male placentas showing a more pronounced increase in triacylglycerols, cholesteryl esters, and free cholesterol compared to female placentas. Gene expression analysis revealed sexually dimorphic alterations, with male PE placentas exhibiting upregulation of genes involved in fatty acid uptake, oxidation, and esterification, while female PE placentas showed a more complex response with both upregulation and downregulation of certain genes. Notably, peroxisomal fatty acid oxidation was upregulated in male PE placentas but suppressed in female PE placentas.

Conclusions: Our findings reveal sexually dimorphic alterations in placental lipid metabolism in PE, suggesting that male placentas may be more vulnerable to lipotoxicity. These insights may have implications for understanding the pathogenesis of PE and developing sex-specific interventions to improve maternal and fetal outcomes.

Keywords: Preeclampsia; fatty acid esterification; fatty acid oxidation; fatty acid transport; fetal sex; gene expression; mitochondria; peroxisome; placental lipid metabolism; sexual dimorphism.

Figure 1:. Effect of preeclampsia on placental fatty acid uptake and transport in (A) male and (B) female placentas.

mRNA expression of placental genes involved in fatty acid uptake and transport was assessed in 20 placentas in each sex in normotensive (NT) control and preeclampsia (PE) groups. Data (means ± SEM) are presented as the ratio of the target gene to the reference gene GAPDH. *p<0.05 compared to respective NT controls.

Figure 2:. Effect of preeclampsia on the placental lipid esterification pathway in (A) male and (B) female placentas.

mRNA expression of placental genes involved in lipid esterification was assessed in 20 placentas in each sex in normotensive (NT) control and preeclampsia (PE) groups. Data (means ± SEM) are presented as the ratio of the target gene to the reference gene GAPDH. *p<0.05 compared to respective NT controls.

Figure 3:. Effect of preeclampsia on the placental fatty acid oxidation pathway in (A) male and (B) female placentas.

mRNA expression of placental genes involved in fatty acid oxidation was assessed in 20 placentas in each sex in normotensive (NT) control and preeclampsia (PE) groups. Data (means ± SEM) are presented as the ratio of the target gene to the reference gene GAPDH. Mitochondrial number was estimated by the ratio of CytB/β-actin DNA. *p<0.05 compared to respective NT controls.

Figure 4:. Schematic summarizing sexually dimorphic alterations in placental lipid metabolism in PE.

In male placentas, preeclampsia (PE) upregulates fatty acid (FA) transport, β-oxidation, and esterification, leading to increased triacylglycerol (TG) and cholesterol ester (CE) accumulation. In contrast, female placentas exhibit a more complex response, with altered expression of fatty acid transport and oxidation genes, but no significant changes in TG and CE levels. These findings suggest that male placentas may be more vulnerable to the lipotoxic effects of PE. Red arrows – Upregulated; Blue arrows – Downregulated.