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Our previous studies showed that prenatal caffeine exposure (PCE) led to fetal overexposure to maternal glucocorticoids (GCs) and increased serum total cholesterol levels in adult rat offspring. This study further confirms the intrauterine programming of PCE\u2010induced hypercholesterolemia in female adult rat offspring. Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 120 mg\/kg\/d) from gestational day (GD)9 to 20. Female rat offspring were euthanized at GD20 and postnatal wk 12; several adult rat offspring were additionally subjected to ice\u2010water swimming stimulation to induce chronic stress prior to death. The effects of GCs on cholesterol metabolism and epigenetic regulation were verified using the L02 cell line. The results showed that PCE induced hypercholesterolemia in adult offspring, which manifested as significantly higher levels of serum total cholesterol and LDL cholesterol (LDL\u2010C) as well as higher ratios of LDL\u2010C\/HDL cholesterol. We further found that the cholesterol levels were increased in fetal livers but were decreased in fetal blood, accompanied by increased maternal blood cholesterol levels and reduced placental cholesterol transport. Furthermore, analysis of PCE offspring in the uterus and in a postnatal basal\/chronic stress state and the results of\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments showed that hepatic cholesterol metabolism underwent GC\u2010dependent changes and was associated with cholesterol synthase\n                    <jats:italic>via<\/jats:italic>\n                    abnormalities in 3\u2010hydroxy\u20103\u2010methylglutaryl\u2010CoA reductase (HMGCR) histone acetylation. We concluded that, to compensate for intrauterine placentally derived decreases in fetal blood cholesterol levels, high intrauterine GC levels activated fetal hepatic CCAAT enhancer binding protein \u03b1 signaling and down\u2010regulated Sirtuin1 expression, which mediated the high levels of histone acetylation\n                    <jats:italic>(via<\/jats:italic>\n                    H3K9ac and H3K14ac) and expression of HMGCR. This GC\u2010 dependent cholesterol metabolism programming effect was sustained through adulthood, leading to the occurrence of hypercholesterolemia.\u2014Xu, D., Luo, H. W., Hu, W., Hu, S. W., Yuan, C., Wang, G. H., Zhang, L., Yu, H., Magdalou, J., Chen, L. B., Wang, H. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine\u2010exposed female adult rat offspring.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    32, 5563\u20135576 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201701557r","type":"journal-article","created":{"date-parts":[[2018,5,2]],"date-time":"2018-05-02T16:09:25Z","timestamp":1525277365000},"page":"5563-5576","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine\u2010exposed female adult rat offspring"],"prefix":"10.1096","volume":"32","author":[{"given":"Dan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pharmacology Basic Medical School, and 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