27-Hydroxycholesterol Inhibits Trophoblast Fusion During Placenta Development by Activating PI3K/AKT/mTOR Signaling Pathway

Overview

Journal Arch Toxicol

Specialty Toxicology

Date 2024 Jan 5

PMID 38180513

Authors

Xiaoyan Zhao

Xiaxia Cai

Haiyan Zhu

Qinyu Dang

Qian Yang

Yandi Zhu

Yadi Zhang

Mengling Zhang

Xinyin Jiang

Zhuo Hu

Yuchen Wei

Rong Xiao

Huanling Yu

Affiliations

Soon will be listed here.

Abstract

Trophoblast cell syncytialization is essential for placental and fetal development. Abnormal trophoblast cell fusion leads to pregnancy pathologies, such as preeclampsia (PE), intrauterine growth restriction (IUGR), and miscarriage. 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in human peripheral blood synthesized by sterol 27-hydroxylase (CYP27A1) and is considered a critical mediator between hypercholesterolemia and a variety of related disorders. Gestational hypercholesterolemia was associated with spontaneous preterm delivery and low birth weight (LBW) in term infants, yet the mechanism is unclear. In this study, two trophoblast cell models and CD-1 mice were used to evaluate the effects of 27-OHC on trophoblast fusion during placenta development. Two different kinds of trophoblast cells received a dosage of 2.5, 5, or 10 uM 27-OHC. Three groups of pregnant mice were randomly assigned: control, full treatment (E0.5-E17.5), or late treatment (E13.5-E17.5). All mice received daily intraperitoneal injections of saline (control group) and 27-OHC (treatment group; 5.5 mg/kg). In vitro experiments, we found that 27-OHC inhibited trophoblast cell fusion in primary human trophoblasts (PHT) and forskolin (FSK)-induced BeWo cells. 27-OHC up-regulated the expression of the PI3K/AKT/mTOR signaling pathway-related proteins. Moreover, the PI3K inhibitor LY294002 rescued the inhibitory effect of 27-OHC. Inhibition of trophoblast cell fusion by 27-OHC was also observed in CD-1 mice. Furthermore, fetal weight and placental efficiency decreased and fetal blood vessel development was inhibited in pregnant mice treated with 27-OHC. This study was the first to prove that 27-OHC inhibits trophoblast cell fusion by Activating PI3K/AKT/mTOR signaling pathway. This study reveals a novel mechanism by which dyslipidemia during pregnancy results in adverse pregnancy outcomes.

Citing Articles

Supplementation with probiotics co-cultivation improves the reproductive performance in a sow-piglet model by mother-infant microbiota transmission and placental mTOR signaling.

Li S, Lu T, Lin Z, Zhang Y, Zhou X, Li M World J Microbiol Biotechnol. 2024; 41(1):13.

PMID: 39704872 DOI: 10.1007/s11274-024-04222-5.

References

Aplin J, Myers J, Timms K, Westwood M . Tracking placental development in health and disease. Nat Rev Endocrinol. 2020; 16(9):479-494. DOI: 10.1038/s41574-020-0372-6. View

Asghari A, Umetani M . Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link. Int J Mol Sci. 2020; 21(14). PMC: 7404106. DOI: 10.3390/ijms21144822. View

Aye I, Waddell B, Mark P, Keelan J . Oxysterols inhibit differentiation and fusion of term primary trophoblasts by activating liver X receptors. Placenta. 2011; 32(2):183-91. DOI: 10.1016/j.placenta.2010.12.007. View

Bertolotti M, Del Puppo M, Corna F, Anzivino C, Gabbi C, Baldelli E . Increased appearance rate of 27-hydroxycholesterol in vivo in hypercholesterolemia: a possible compensatory mechanism. Nutr Metab Cardiovasc Dis. 2011; 22(10):823-30. DOI: 10.1016/j.numecd.2011.02.009. View

Bolze P, Mommert M, Mallet F . Contribution of Syncytins and Other Endogenous Retroviral Envelopes to Human Placenta Pathologies. Prog Mol Biol Transl Sci. 2017; 145:111-162. DOI: 10.1016/bs.pmbts.2016.12.005. View

Busso D, Mascareno L, Salas F, Berkowitz L, Santander N, Quiroz A . Early onset intrauterine growth restriction in a mouse model of gestational hypercholesterolemia and atherosclerosis. Biomed Res Int. 2014; 2014:280497. PMC: 4176652. DOI: 10.1155/2014/280497. View

Chatuphonprasert W, Jarukamjorn K, Ellinger I . Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta. Front Pharmacol. 2018; 9:1027. PMC: 6144938. DOI: 10.3389/fphar.2018.01027. View

Chen W, Chen G, Head D, Mangelsdorf D, Russell D . Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab. 2006; 5(1):73-9. PMC: 3080013. DOI: 10.1016/j.cmet.2006.11.012. View

Coutifaris C, Kao L, Sehdev H, Chin U, Babalola G, Blaschuk O . E-cadherin expression during the differentiation of human trophoblasts. Development. 1991; 113(3):767-77. DOI: 10.1242/dev.113.3.767. View

10.

Dupressoir A, Vernochet C, Harper F, Guegan J, Dessen P, Pierron G . A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci U S A. 2011; 108(46):E1164-73. PMC: 3219115. DOI: 10.1073/pnas.1112304108. View

11.

Gibson D, Collins F, Cousins F, Esnal Zufiaurre A, Saunders P . The impact of 27-hydroxycholesterol on endometrial cancer proliferation. Endocr Relat Cancer. 2018; 25(4):381-391. PMC: 5847183. DOI: 10.1530/ERC-17-0449. View

12.

He S, Nelson E . 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas. 2017; 104:29-35. PMC: 5657610. DOI: 10.1016/j.maturitas.2017.07.014. View

13.

Ismail M, Mateos L, Maioli S, Merino-Serrais P, Ali Z, Lodeiro M . 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation. J Exp Med. 2017; 214(3):699-717. PMC: 5339669. DOI: 10.1084/jem.20160534. View

14.

Jeyarajah M, Jaju Bhattad G, Hillier D, Renaud S . The Transcription Factor OVOL2 Represses ID2 and Drives Differentiation of Trophoblast Stem Cells and Placental Development in Mice. Cells. 2020; 9(4). PMC: 7226816. DOI: 10.3390/cells9040840. View

15.

Kim M, An B, Wang L, Lee K, Bang J, Joo B . Effects of Oxysterols on Chondrogenesis of Human Adipose-derived Stem Cells. Ann Clin Lab Sci. 2020; 50(2):190-198. View

16.

Knofler M, Haider S, Saleh L, Pollheimer J, Gamage T, James J . Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell Mol Life Sci. 2019; 76(18):3479-3496. PMC: 6697717. DOI: 10.1007/s00018-019-03104-6. View

17.

Lai C, Cheng H, Lin C, Huang S, Chen T, Chung C . Activation of liver X receptor suppresses angiogenesis induction of ApoD. FASEB J. 2017; 31(12):5568-5576. DOI: 10.1096/fj.201700374R. View

18.

Leitner K, Szlauer R, Ellinger I, Ellinger A, Zimmer K, Fuchs R . Placental alkaline phosphatase expression at the apical and basal plasma membrane in term villous trophoblasts. J Histochem Cytochem. 2001; 49(9):1155-64. DOI: 10.1177/002215540104900909. View

19.

Liu Y, Fan X, Wang R, Lu X, Dang Y, Wang H . Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res. 2018; 28(8):819-832. PMC: 6082907. DOI: 10.1038/s41422-018-0066-y. View

20.

Liu C, Moten A, Ma Z, Lin H . The foundational framework of tumors: Gametogenesis, p53, and cancer. Semin Cancer Biol. 2021; 81:193-205. PMC: 9382687. DOI: 10.1016/j.semcancer.2021.04.018. View