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Here, we explore the mechanism by which CA induces FGR. Pregnant mice except controls were orally administered with CA daily from gestational day 13 (GD13) to GD17. Results found that CA exposure decreased fetal weight and crown\u2010rump length, and increased the incidence of FGR in a dose\u2010dependent manner. Furthermore, CA caused placental glucocorticoid (GC) barrier dysfunction via down\u2010regulating the protein but not the mRNA level of placental 11\u03b2\u2010Hydroxysteroid dehydrogenase\u20102 (11\u03b2\u2010HSD2). Additionally, CA activated placental GCN2\/eIF2\u03b1 pathway. GCN2iB, an inhibitor of GCN2, significantly inhibited CA\u2010induced down\u2010regulation of 11\u03b2\u2010HSD2 protein. We further found that CA caused excessive reactive oxygen species (ROS) production and oxidative stress in mouse placentas and human trophoblasts. NAC significantly rescued CA\u2010induced placental barrier dysfunction by inhibiting activation of GCN2\/eIF2\u03b1 pathway and subsequent down\u2010regulation of 11\u03b2\u2010HSD2 protein in placental trophoblasts. Importantly, NAC rescued CA\u2010induced FGR in mice. Overall, our results suggest that CA exposure during late pregnancy induces placental GC barrier dysfunction and subsequent FGR may be via ROS\u2010mediated placental GCN2\/eIF2\u03b1 activation. This study provides valuable insight for understanding the mechanism of cholestasis\u2010induced placental dysfunction and subsequent FGR.<\/jats:p>","DOI":"10.1096\/fj.202202126r","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T13:05:31Z","timestamp":1676984731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cholic acid exposure during late pregnancy causes placental dysfunction and fetal growth restriction by reactive oxygen species\u2010mediated activation of placental\n                    <scp>GCN2<\/scp>\n                    \/\n                    <scp>eIF2\u03b1<\/scp>\n                    pathway"],"prefix":"10.1096","volume":"37","author":[{"given":"Shuai","family":"Lin","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Anhui Medical University  Hefei 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