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Mechanisms for establishment of the placental glucocorticoid barrier, a guard for life

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Abstract

The fetus is shielded from the adverse effects of excessive maternal glucocorticoids by 11β-HSD2, an enzyme which is expressed in the syncytial layer of the placental villi and is capable of converting biologically active cortisol into inactive cortisone. Impairment of this placental glucocorticoid barrier is associated with fetal intrauterine growth restriction (IUGR) and development of chronic diseases in later life. Ontogeny studies show that the expression of 11β-HSD2 is initiated at a very early stage after conception and increases with gestational age but declines around term. The promoter for HSD11B2, the gene encoding 11β-HSD2, has a highly GC-rich core. However, the pattern of methylation on HSD11B2 may have already been set up in the blastocyst when the trophoblast identity is committed. Instead, hCG-initiated signals appear to be responsible for the upsurge of 11β-HSD2 expression during trophoblast syncytialization. By activating the cAMP/PKA pathway, hCG not only alters the modification of histones but also increases the expression of Sp1 which activates the transcription of HSD11B2. Adverse conditions such as stress, hypoxia and nutritional restriction can cause IUGR of the fetus. It appears that different causes of IUGR may attenuate HSD11B2 expression differentially in the placenta. While stress and nutritional restriction may reduce HSD11B2 expression by increasing its methylation, hypoxia may decrease HSD11B2 expression via alternative mechanisms rather than by methylation. Herein, we summarize the advances in the study of mechanisms underlying the establishment of the placental glucocorticoid barrier and the attenuation of this barrier by adverse conditions during pregnancy.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (31671566 and 81330018), National Key R&D Program of China (2017YFC1001403) and National Key Basic Research Projects (2014CB943302). The authors would like to thank Dr. Dev Sooranna, Imperial College London, for editing the manuscript.

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  1. Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200135, People’s Republic of China

    Ping Zhu, Wangsheng Wang, Rujuan Zuo & Kang Sun

  2. Department of Obstetrics and Gynecology, No. 401 Hospital, Qingdao, People’s Republic of China

    Ping Zhu

  3. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People’s Republic of China

    Wangsheng Wang, Rujuan Zuo & Kang Sun

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Zhu, P., Wang, W., Zuo, R. et al. Mechanisms for establishment of the placental glucocorticoid barrier, a guard for life. Cell. Mol. Life Sci. 76, 13–26 (2019). https://doi.org/10.1007/s00018-018-2918-5

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