Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation,Clinical Epigenetics

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Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation
Clinical Epigenetics ( IF 4.8 ) Pub Date : 2021-08-26 , DOI: 10.1186/s13148-021-01153-y
Darina Czamara ₁ , Linda Dieckmann _{1,

2} , Simone Röh ₁ , Sarah Kraemer ₃ , Rebecca C Rancourt ₄ , Sara Sammallahti ₅ , Eero Kajantie _{6,

7,

8,

9} , Hannele Laivuori _{10,

11,

12} , Johan G Eriksson _{13,

14,

15,

16} , Katri Räikkönen ₁₇ , Wolfgang Henrich ₁₈ , Andreas Plagemann _{4,

18} , Elisabeth B Binder _{1,

19} , Thorsten Braun _{4,

18} , Sonja Entringer _{3,

20}

Affiliation

Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, 80804, Munich, Germany.
International Max Planck Research School for Translational Psychiatry, München, Germany.
Institute of Medical Psychology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Luisenstr. 57, 10117, Berlin, Germany.
Department of Experimental Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Augustenburger Platz 1, 13353, Berlin, Germany.
Department of Child and Adolescent Psychiatry, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
Finnish Institute for Health and Welfare, Helsinki, Finland.
Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Faculty of Medicine, PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland.
Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.
Department of General Practice and Primary Care, University of Helsinki, Helsinki, Finland.
Folkhälsan Research Center, Helsinki, Finland.
Department of Obstetrics and Gynaecology and Human Potential Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Department of Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Augustenburger Platz 1, 13353, Berlin, Germany.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30329, USA.
Development, Health, and Disease Research Program, University of California, Irvine, Orange, CA, USA.

Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans. We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response. Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.

中文翻译：

怀孕期间服用倍他米松与胎盘表观遗传变化有关，并对炎症产生影响

糖皮质激素（GC）在胎儿编程中发挥着关键作用。对有早产危险的个体使用合成 GC (sGC) 进行产前治疗是常见做法。产前 sGC 的短期和长期不良影响已有报道，但其对胎盘表观遗传特征的影响从未在人类中进行过系统研究。我们在 52 名暴露病例和 84 名胎龄匹配对照中测试了 sGC 倍他米松 (BET) 暴露与胎盘 DNA 甲基化 (DNAm) 之间的关联。我们使用靶向亚硫酸氢盐测序对相关基因座进行精细定位。在包括 494 个胎盘的独立队列中进行了胎盘 DNAm 与基因表达的关联以及相关基因的共表达分析。暴露于 BET 与 FKBP5 增强子的胎盘 DNAm 降低显着相关。 FKBP5（FK506 结合蛋白 51）是一种调节糖皮质激素受体活性的共伴侣。该增强子位点的 DNAm 较低与 FKBP5 和共表达基因模块的较高表达相关。该模块富含与先兆子痫相关并参与炎症和免疫反应的基因。我们的研究结果表明，怀孕期间接触 BET 与胎盘 DNAm 的少量但持久的变化有关，并可能促进与胎盘功能障碍和炎症增加相关的基因表达谱。这可能代表了介导 GC 相关的负面长期后果和后代健康结果的途径。

更新日期：2021-08-26

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