期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 352, 期 -, 页码 77-86出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2018.05.029
关键词
Prenatal ethanol exposure; Glucocorticoids; Placenta; 11 beta-Hydroxysteroid dehydrogenase type 2; cAMP/PKA pathway; Early growth response factor 1
资金
- National Natural Science Foundation of China [81430089, 81673524]
- National Key Research and Development Program of China [2017YFC1001300]
- Hubei Province Health and Family Planning Scientific Research Project [WJ2017C0003]
It is known that inhibiting 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) expression in the placenta can cause fetal over-exposure to maternal glucocorticoids and induce intrauterine growth restriction (IUGR); these effects ultimately increase the risk of adult chronic diseases. This study aimed to investigate the molecular mechanism of the prenatal ethanol exposure (PEE)-induced inhibition of placental 11 beta-HSD2 expression. Pregnant Wistar rats were intragastrically administered ethanol (4 g/kg/d) from gestational days 9 to 20. The levels of maternal and fetal serum corticosterone and placental 11 beta-HSD2-related gene expression were analyzed. Furthermore, we investigated the mechanism of reduced placental 11 beta-HSD2 expression induced by ethanol treatment (15-60 mM) in HTR-8/SVneo cells. In vivo, PEE decreased fetal body weights and increased maternal and fetal serum corticosterone and early growth response factor 1 (EGR1) expression levels. Moreover, histone modification changes (decreased acetylation and increased di-methylation of H3K9) to the HSD11B2 promoter and lower 11 beta-HSD2 expression levels were observed. In vitro, ethanol decreased cAMP/PKA signaling and 11 beta-HSD2 expression and increased EGR1 expression in a concentration-dependent manner. A cAMP agonist and EGR1 siRNA reversed the ethanol-induced inhibition of 11 beta-HSD2 expression. Together, PEE reduced placental 11 beta-HSD2 expression, and the underlying mechanism is associated with ethanol-induced histone modification changes to the HSD11B2 promoter through the cAMP/PKA/EGR1 pathway.
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