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. 2023 Sep 28;14(1):66.
doi: 10.1186/s13293-023-00548-1.

Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity

Theresa L Powell  1   2 , Charis Uhlson  2 , Lana Madi  1 , Karin Zemski Berry  3 , Stephanie S Chassen  2 , Thomas Jansson  1 , Veronique Ferchaud-Roucher  4   5
Affiliations

Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity

Theresa L Powell et al. Biol Sex Differ. .

Abstract

Background: We have previously reported that maternal obesity reduces placental transport capacity for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA), a preferred form for transfer of DHA (omega 3) to the fetal brain, but only in male fetuses. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC), have either sn-1 ester, ether or vinyl ether (plasmalogen) linkages to primarily unsaturated and monounsaturated fatty acids and DHA or arachidonic acid (ARA, omega 6) in the sn-2 position. Whether ether and plasmalogen PC and PE metabolism in placenta impacts transfer to the fetus is unexplored. We hypothesized that ether and plasmalogen PC and PE containing DHA and ARA are reduced in maternal-fetal unit in pregnancies complicated by obesity and these differences are dependent on fetal sex.

Methods: In maternal, umbilical cord plasma and placentas from obese women (11 female/5 male infants) and normal weight women (9 female/7 male infants), all PC and PE species containing DHA and ARA were analyzed by LC-MS/MS. Placental protein expression of enzymes involved in phospholipid synthesis, were determined by immunoblotting. All variables were compared between control vs obese groups and separated by fetal sex, in each sample using the Benjamini-Hochberg false discovery rate adjustment to account for multiple testing.

Results: Levels of ester PC containing DHA and ARA were profoundly reduced by 60-92% in male placentas of obese mothers, while levels of ether and plasmalogen PE containing DHA and ARA were decreased by 51-84% in female placentas. PLA2G4C abundance was lower in male placentas and LPCAT4 abundance was lower solely in females in obesity. In umbilical cord, levels of ester, ether and plasmalogen PC and PE with DHA were reduced by 43-61% in male, but not female, fetuses of obese mothers.

Conclusions: We found a fetal sex effect in placental PE and PC ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

Keywords: De novo placental phospholipid synthesis; Maternal obesity; Remodeling phospholipid pathway; Sexual dimorphism.

Plain language summary

Docosahexaenoic acid (DHA) is a critical omega 3 long chain polyunsaturated fatty acid (LCPUFA) for fetal brain development. We have recently reported that maternal obesity reduces placental transport capacity for LysophosPhatidylCholine-DHA (LPC-DHA), a preferred form for transfer of DHA to the fetal brain, but only in male fetuses. Other important lipids, the plasmalogen phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are considered DHA reservoirs, but its roles in the maternal–fetal unit are largely unexplored. We examined these lipid species in maternal and fetal circulation and in placental tissue to uncover potential novel roles for ether and plasmalogen lipids in the regulation of placenta delivery of these vital nutrients in pregnancies complicated by obesity depending of fetal sex. We demonstrated for the first time, that female fetuses of obese mothers decrease placental ether and plasmalogen PE containing DHA and arachidonic acid (ARA, omega 6), and show a high fetal–placental adaptability and placental reserve capacity that can maintain the PC-LCPUFA synthesis and the transfer of these crucial species to the fetus to preserve brain development. Our study also demonstrated that male fetuses, in response to maternal obesity, reduce the placental ester PC species containing DHA and ARA and reduce the ether and plasmalogen PE reservoir of DHA and ARA in fetal circulation. Our findings support a fetal sex effect in placental ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

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Conflict of interest statement

The authors have no disclosures.

Figures

Fig. 1
Fig. 1
Differences in PC and PE containing DHA and ARA variables in maternal plasma between the two groups (control/obese) of mothers including both male and female fetuses. A Significant differences in PC and PE containing DHA in maternal plasma between control and obese groups. B PC and PE species containing ARA were not changed between control and obese mothers. Relative levels are expressed in mean ± SD and significant differences pass at false-discovery rate-adjusted p value (Benjamini–Hochberg false discovery rate adjustment to account for multiple testing). *p < 0.05
Fig. 2
Fig. 2
Representative image of capillary electrophoresis bands and relative protein abundance A of fatty acyl-CoA reductase 1 (FAR1) in placental homogenates in obese vs control women in male and female groups obtained by simple West, B of PhosphoLipase A2 Group IVC (PLA2G4C or iPLA2) and C of LysophosPhatidylCholine Acyl Transferase 4 (LPCAT4). B and C were analyzed by western blot. Ctr-M = control-Male, Ob-M = Obese-Male, Ctr-F = control-Female, Ob-F = Obese-Female. Data are means ± SD. *p < 0.05
Fig. 3
Fig. 3
Inverse correlations between maternal BMI and levels of ether and plasmalogen linked PE with DHA and ARA in placentas of female fetus. Spearman test was performed to assess correlations, r and p values are in the figure, *p < 0.05, **p < 0.01, ***p < 0.005
Fig. 4
Fig. 4
Inverse correlations between maternal BMI and levels of ether and plasmalogen linked PE with DHA and ARA in umbilical cord venous plasma of male fetus. Spearman test was performed to assess correlations, r and p values are in the figure, *p < 0.05, **p < 0.01, ***p < 0.005
Fig. 5
Fig. 5
Summary of the influence of fetal sex in ester, ether and plasmalogen PC and PE containing DHA and ARA in the maternal–fetal unit in response to maternal obesity. The phenotype of obese mothers includes reduced ester, ether and plasmalogen PC and PE containing DHA but not those phospholipids containing ARA regardless of fetal sex. In obese mother carrying a male baby: in placenta, all the ester linked PC containing DHA and ARA are decreased by obesity and only one ether PC with DHA species while all ester linked PE were unchanged suggesting downregulated PEMT enzyme activity to convert PE into PC. In addition, decreased LPC-DHA is likely due to decreased iPLA2 protein expression. In fetal circulation, several ester PC DHA and ARA species and ester, ether and plasmalogen PE with DHA and ARA were reduced suggesting a defect of LCPUFA transfer capacity. In obese mother carrying a female baby: in placenta, all PE species with DHA and ARA were decreased but not PC species and LPCAT4 expression was lower. These results suggest an upregulated PEMT activity to maintain PC production. No change was observed in female umbilical cord. By decreasing all ether and plasmalogen PE, species considered as reservoir for DHA and ARA in the placenta, female fetuses of obese mothers show a high fetal–placental adaptability and placental reserve capacity that can maintain the PC-LCPUFA synthesis and the transfer of these crucial species to the fetus to preserve growth and brain development
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