Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development

Hyperhomocysteinemia may arise from folate/vitamin B(12) 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.