Physiological and pathological functions of sphingolipids in pregnancy

Fakhr, Yuliya; Brindley, David N.; Hemmings, Denise G.

doi:10.1016/j.cellsig.2021.110041

Cited by 30 publications

(29 citation statements)

References 237 publications

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“…Though our previous study has demonstrated a significant association between PG 36:1 and increased gestational age ( 32 ), there is no clear evidence that suggests a link between SM 43:3 and adverse birth outcomes. A recent study, however, has demonstrated the role of SM on regulating placental vascularization and facilitating placental-uterine invasion ( 33 ), suggesting the impact of lipids on birth outcomes. Next, we observed significant negative associations of Mn with poly-unsaturated PA and poly-unsaturated PLPE, and Zn with poly-unsaturated PLPE ( Figure 2 ; Supplementary Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

Maternal Metals/Metalloid Blood Levels Are Associated With Lipidomic Profiles Among Pregnant Women in Puerto Rico

Kim

Ashrap

Watkins

et al. 2022

Front. Public Health

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Background/Aim: The association between heavy metal exposure and adverse birth outcomes is well-established. However, there is a paucity of research identifying biomarker profiles that may improve the early detection of heavy metal-induced adverse birth outcomes. Because lipids are abundant in our body and associated with important signaling pathways, we assessed associations between maternal metals/metalloid blood levels with lipidomic profiles among 83 pregnant women in the Puerto Rico PROTECT birth cohort.Methods: We measured 10 metals/metalloid blood levels during 24–28 weeks of pregnancy. Prenatal plasma lipidomic profiles were identified by liquid chromatography–mass spectrometry-based shotgun lipidomics. We derived sums for each lipid class and sums for each lipid sub-class (saturated, monounsaturated, polyunsaturated), which were then regressed on metals/metalloid. False discovery rate (FDR) adjusted p-values (q-values) were used to account for multiple comparisons.Results: A total of 587 unique lipids from 19 lipid classes were profiled. When controlling for multiple comparisons, we observed that maternal exposure to manganese and zinc were negatively associated with plasmenyl-phosphatidylethanolamine (PLPE), particularly those containing polyunsaturated fatty acid (PUFA) chains. In contrast to manganese and zinc, arsenic and mercury were positively associated with PLPE and plasmenyl-phosphatidylcholine (PLPC).Conclusion: Certain metals were significantly associated with lipids that are responsible for the biophysical properties of the cell membrane and antioxidant defense in lipid peroxidation. This study highlighted lipid-metal associations and we anticipate that this study will open up new avenues for developing diagnostic tools.

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Section: Discussionmentioning

confidence: 99%

Maternal Metals/Metalloid Blood Levels Are Associated With Lipidomic Profiles Among Pregnant Women in Puerto Rico

Kim

Ashrap

Watkins

et al. 2022

Front. Public Health

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“…One of the mediators of TNF-α signaling in non-placental endothelial and epithelial cells is sphingosine 1-phosphate (S1P) [ 24 , 25 , 26 , 27 ]. S1P is a bioactive sphingolipid that regulates cellular processes such as angiogenesis, proliferation, differentiation, and apoptosis [ 28 ]. S1P acts intracellularly, or it can exert its effects extracellularly through its specific receptors, S1P receptors 1–5 (S1PR1-5), which are variably expressed in all placental cell types and have multiple functions as summarized in Fakhr et al [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…S1P is a bioactive sphingolipid that regulates cellular processes such as angiogenesis, proliferation, differentiation, and apoptosis [ 28 ]. S1P acts intracellularly, or it can exert its effects extracellularly through its specific receptors, S1P receptors 1–5 (S1PR1-5), which are variably expressed in all placental cell types and have multiple functions as summarized in Fakhr et al [ 28 ]. Briefly, S1PR1 and S1PR3 activation in trophoblasts leads to the secretion of IL-8.…”

Section: Introductionmentioning

confidence: 99%

“…S1PR2 activation decreases trophoblast migration that is important for attaching the placenta to the maternal decidua. S1PR4 and S1PR5 are mainly expressed in placental cells of immune origin [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…S1P is synthesized by sphingosine kinases 1/2 (SphK1, SphK2) and is degraded by S1P lyase (SPL) or dephosphorylated by S1P phosphatases (SPP) and lipid phosphate phosphatases (LPPs) [ 28 ]. SphK1 activation and S1P are implicated downstream of TNF-α signaling [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Tumor Necrosis Factor-α Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation

Fakhr

Koshti

Habibyan

et al. 2022

IJMS

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Preeclampsia (PE) involves inadequate placental function. This can occur due to elevated pro-inflammatory tumor necrosis factor-α (TNF-α). In other tissues, TNF-α signals via sphingosine kinase 1 (SphK1). SphK1 hinders syncytial formation. Whether this occurs downstream of TNF-α signaling is unclear. We hypothesized that placental SphK1 levels are higher in PE and elevated TNF-α decreases syncytial function, increases syncytial shedding, and increases cytokine/factor release via SphK1 activity. Term placental biopsies were analyzed for SphK1 using immunofluorescence and qRT-PCR. Term placental explants were treated after 4 days of culture, at the start of syncytial regeneration, with TNF-α and/or SphK1 inhibitors, PF-543. Syncytialization was assessed by measuring fusion and chorionic gonadotropin release. Cell death and shedding were measured by lactate dehydrogenase release and placental alkaline phosphatase-positive shed particles. Forty-two cytokines were measured using multiplex assays. Placental SphK1 was increased in PE. Increased cell death, shedding, interferon-α2, IFN-γ-induced protein 10, fibroblast growth factor 2, and platelet-derived growth factor-AA release induced by TNF-α were reversed upon SphK1 inhibition. TNF-α increased the release of 26 cytokines independently of SphK1. TNF-α decreased IL-10 release and inhibiting SphK1 reversed this effect. Inhibiting SphK1 alone decreased TNF-α release. Hence, SphK1 partially mediates the TNF-α-induced PE placental phenotype, primarily through cell damage, shedding, and specific cytokine release.

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Lipid profile of circulating placental extracellular vesicles during pregnancy identifies foetal growth restriction risk

Klemetti,

Pettersson,

Ahmad Khan

et al. 2024

J of Extracellular Vesicle

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Small‐for‐gestational age (SGA) neonates exhibit increased perinatal morbidity and mortality, and a greater risk of developing chronic diseases in adulthood. Currently, no effective maternal blood‐based screening methods for determining SGA risk are available. We used a high‐resolution MS/MSALL shotgun lipidomic approach to explore the lipid profiles of small extracellular vesicles (sEV) released from the placenta into the circulation of pregnant individuals. Samples were acquired from 195 normal and 41 SGA pregnancies. Lipid profiles were determined serially across pregnancy. We identified specific lipid signatures of placental sEVs that define the trajectory of a normal pregnancy and their changes occurring in relation to maternal characteristics (parity and ethnicity) and birthweight centile. We constructed a multivariate model demonstrating that specific lipid features of circulating placental sEVs, particularly during early gestation, are highly predictive of SGA infants. Lipidomic‐based biomarker development promises to improve the early detection of pregnancies at risk of developing SGA, an unmet clinical need in obstetrics.

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Physiological and pathological functions of sphingolipids in pregnancy

Cited by 30 publications

References 237 publications

Maternal Metals/Metalloid Blood Levels Are Associated With Lipidomic Profiles Among Pregnant Women in Puerto Rico

Maternal Metals/Metalloid Blood Levels Are Associated With Lipidomic Profiles Among Pregnant Women in Puerto Rico

Tumor Necrosis Factor-α Induces a Preeclamptic-like Phenotype in Placental Villi via Sphingosine Kinase 1 Activation

Lipid profile of circulating placental extracellular vesicles during pregnancy identifies foetal growth restriction risk

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