Cortisol Induces Aromatase Expression in Human Placental Syncytiotrophoblasts Through the cAMP/Sp1 Pathway

Author:

Wang Wangsheng1,Li Jianneng1,Ge Yuchun2,Li Wenjiao3,Shu Qun3,Guan Haiyan4,Yang Kaiping4,Myatt Leslie5,Sun Kang5

Affiliation:

1. School of Life Sciences (W.W., J.L., K.S.) Fudan University, Shanghai 200433, People's Republic of China

2. Shanghai First Maternity and Infant Health Hospital (Y.G.), School of Medicine, Tongji University, Shanghai 200040, People's Republic of China

3. Maternity and Infant Health Hospital of Changning District (W.L., Q.S.), Shanghai 200051, People's Republic of China

4. Department of Obstetrics and Gynecology (H.G., K.Y.) University of Western Ontario, London, Ontario, Canada N6C 2V5

5. Center for Pregnancy and Newborn Research (L.M., K.S.), Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, Texas 78229

Abstract

One of the dominant effects of glucocorticoids in triggering parturition in certain animal species is to drive the placental conversion of progesterone to estrogen. However, in the human placenta, estrogen is formed using dehydroepiandrosterone from the fetal adrenal glands rather than progesterone as precursor. Although aromatization of dehydroepiandrosterone is crucial in estrogen synthesis in human placenta, it is not known whether glucocorticoids affect aromatase expression. Human term placental syncytiotrophoblasts were used to examine the effect of cortisol on aromatase expression. The signaling pathway and transcription factors involved were identified in this study. Results showed that cortisol induced aromatase expression in a concentration-dependent manner, which was mediated indirectly by glucocorticoid receptor and required the participation of other proteins. The induction of aromatase by cortisol could be blocked by either specificity protein 1 (Sp1) antagonist mithramycin or knockdown of Sp1 expression. The induction of aromatase and Sp1 by cortisol could be prevented by inhibitors of the cAMP pathway, whereas activators of the cAMP pathway induced Sp1 and aromatase expression as well as Sp1 binding to aromatase promoter. Concomitantly, cortisol treatment and activation of the cAMP pathway led to increased acetylation and decreased methylation of histone 3 at the aromatase promoter. In conclusion, cortisol stimulates aromatase expression through the cAMP/Sp1 pathway in human placental syncytiotrophoblasts. These findings reveal a novel role of cortisol in increasing the local level of estrogen within the placenta that would help transform the myometrium to a contractile state, thereby contributing to a cascade of events leading to human parturition.

Publisher

The Endocrine Society

Subject

Endocrinology

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