Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development. Issue 18 (18th September 2022)

• Record Type: Journal Article
• Authors: Capatina, Nadejda; Burton, Graham J.; Yung, Hong Wa
• Is Part Of: Physiological reports. Volume 10:Issue 18(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-18
• Subjects: endoplasmic reticulum stress -- hyperhomocysteinemia -- placenta -- pregnancy -- trophoblast stem cells -- unfolded protein response; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.15467
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Hyperhomocysteinemia may arise from folate/vitamin B12 deficiency, genetic polymorphisms, kidney disease, or hypothyroidism. It is associated with an increased risk of early pregnancy loss and placenta‐related complications of pregnancy, including pre‐eclampsia and fetal growth restriction. While the majority of studies of hyperhomocysteinemia focus on epigenetic changes secondary to metabolic disruption, the effects of homocysteine toxicity on placental development remain unexplored. Here, we investigated the influence of hyperhomocysteinemia on early blastocyst development and trophoblast differentiation. Exposure of cultured blastocysts to high homocysteine levels reduces cell number in the trophectoderm layer, most likely through increased apoptosis. Homocysteine also promotes differentiation of a trophoblast stem cell line. Both effects diminish the stem cell pool, and are mediated in an endoplasmic reticulum (ER) unfolded protein response (UPR ER )‐dependent manner. Targeted alleviation of UPR ER may therefore provide a new therapeutic intervention to improve pregnancy outcome in women with hyperhomocysteinemia. Abstract : High concentration of homocysteine reduces cell number and activates endoplasmic reticulum unfolded protein response (UPRER) pathways exclusively in trophectoderm (TE) layer of mouse blastocyst. Tauroursodeoxycholic acid (TUDCA), a bile acid, attenuates homocysteine‐mediated UPRER and abolishes apoptotic death in TE layer of blastocyst. High homocysteine activates UPRER pathways in mouse trophoblast stem cells and promotes trophoblast differentiation.