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

Darina Czamara; Linda Dieckmann; Simone Röh; Sarah Kraemer; Rebecca C. Rancourt; Sara Sammallahti; Eero Kajantie; Hannele Laivuori; Johan G. Eriksson; Katri Räikkönen; Wolfgang Henrich; Andreas Plagemann; Elisabeth B. Binder; Thorsten Braun; Sonja Entringer

doi:10.1186/s13148-021-01153-y

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

Darina Czamara, Linda Dieckmann, Simone Röh, Sarah Kraemer, Rebecca C. Rancourt, Sara Sammallahti, Eero Kajantie, Hannele Laivuori, Johan G. Eriksson, Katri Räikkönen, Wolfgang Henrich, Andreas Plagemann, Elisabeth B. Binder, Thorsten Braun, Sonja Entringer^*

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › Academic › peer-review

17 Citations (Scopus)

Abstract

Background: 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. Results: 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. Conclusions: 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.

Original language	English
Article number	165
Journal	Clinical Epigenetics
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13148-021-01153-y
Publication status	Published - 26 Aug 2021

Bibliographical note

Funding Information:
AP and TB disclose receipt of financial support for the research, authorship, and/or publication of this article, supported by DFG (BR2925/3-1,-2,-3 and PL241/8-2,-3). EK reports support from Academy of Finland, Foundation for Pediatric Research, Sigrid Juselius Foundation and Novo Nordisk Foundation. Open Access funding enabled and organized by Projekt DEAL.

Funding Information:
EB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from Böhringer Ingelheim for a collaboration on functional investigations of FKBP5. Otherwise, the authors declare that they have no competing interests.

Funding Information:
We would like to thank the midwifes, Dr. A. Gusarova, Dr. F. Braun-Tavares and A. K. Hardt at the Department for Obstetrics, Charit? for valuable assistance in recruiting study participants. We would also like to thank L. Ehrlich at the Department for Obstetrics, Charit? for her assistance in placental tissue preparation. We would like to thank all of the midwives, obstetricians, and other medical staff, laboratory and research personnel, and administrative staff working in hospitals, antenatal and child wellbeing clinics, municipalities, national registers, and other institutions, whose efforts have made research in the ITU cohort possible. We would also like to thank research nurse Eija Lahdensuo and a number of research assistants who during the study period participated in ITU and PREDO study data collection. We thank?Susann Sauer, Maik K?del, Monika Rex-Haffner and Eija Lahdensuo for technical?support and Jessica Keverne for language editing.

Publisher Copyright:
© 2021, The Author(s).

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10.1186/s13148-021-01153-y

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Czamara, D., Dieckmann, L., Röh, S., Kraemer, S., Rancourt, R. C., Sammallahti, S., Kajantie, E., Laivuori, H., Eriksson, J. G., Räikkönen, K., Henrich, W., Plagemann, A., Binder, E. B., Braun, T., & Entringer, S. (2021). Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation. Clinical Epigenetics, 13(1), Article 165. https://doi.org/10.1186/s13148-021-01153-y

@article{3a31bc6c54624c3aa90ac27f885af96c,

title = "Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation",

abstract = "Background: 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. Results: 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. Conclusions: 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.",

author = "Darina Czamara and Linda Dieckmann and Simone R{\"o}h and Sarah Kraemer and Rancourt, {Rebecca C.} and Sara Sammallahti and Eero Kajantie and Hannele Laivuori and Eriksson, {Johan G.} and Katri R{\"a}ikk{\"o}nen and Wolfgang Henrich and Andreas Plagemann and Binder, {Elisabeth B.} and Thorsten Braun and Sonja Entringer",

note = "Funding Information: AP and TB disclose receipt of financial support for the research, authorship, and/or publication of this article, supported by DFG (BR2925/3-1,-2,-3 and PL241/8-2,-3). EK reports support from Academy of Finland, Foundation for Pediatric Research, Sigrid Juselius Foundation and Novo Nordisk Foundation. Open Access funding enabled and organized by Projekt DEAL. Funding Information: EB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from B{\"o}hringer Ingelheim for a collaboration on functional investigations of FKBP5. Otherwise, the authors declare that they have no competing interests. Funding Information: We would like to thank the midwifes, Dr. A. Gusarova, Dr. F. Braun-Tavares and A. K. Hardt at the Department for Obstetrics, Charit? for valuable assistance in recruiting study participants. We would also like to thank L. Ehrlich at the Department for Obstetrics, Charit? for her assistance in placental tissue preparation. We would like to thank all of the midwives, obstetricians, and other medical staff, laboratory and research personnel, and administrative staff working in hospitals, antenatal and child wellbeing clinics, municipalities, national registers, and other institutions, whose efforts have made research in the ITU cohort possible. We would also like to thank research nurse Eija Lahdensuo and a number of research assistants who during the study period participated in ITU and PREDO study data collection. We thank?Susann Sauer, Maik K?del, Monika Rex-Haffner and Eija Lahdensuo for technical?support and Jessica Keverne for language editing. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = aug,

day = "26",

doi = "10.1186/s13148-021-01153-y",

language = "English",

volume = "13",

journal = "Clinical Epigenetics",

issn = "1868-7075",

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Czamara, D, Dieckmann, L, Röh, S, Kraemer, S, Rancourt, RC, Sammallahti, S, Kajantie, E, Laivuori, H, Eriksson, JG, Räikkönen, K, Henrich, W, Plagemann, A, Binder, EB, Braun, T & Entringer, S 2021, 'Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation', Clinical Epigenetics, vol. 13, no. 1, 165. https://doi.org/10.1186/s13148-021-01153-y

TY - JOUR

T1 - Betamethasone administration during pregnancy is associated with placental epigenetic changes with implications for inflammation

AU - Czamara, Darina

AU - Dieckmann, Linda

AU - Röh, Simone

AU - Kraemer, Sarah

AU - Rancourt, Rebecca C.

AU - Sammallahti, Sara

AU - Kajantie, Eero

AU - Laivuori, Hannele

AU - Eriksson, Johan G.

AU - Räikkönen, Katri

AU - Henrich, Wolfgang

AU - Plagemann, Andreas

AU - Binder, Elisabeth B.

AU - Braun, Thorsten

AU - Entringer, Sonja

N1 - Funding Information: AP and TB disclose receipt of financial support for the research, authorship, and/or publication of this article, supported by DFG (BR2925/3-1,-2,-3 and PL241/8-2,-3). EK reports support from Academy of Finland, Foundation for Pediatric Research, Sigrid Juselius Foundation and Novo Nordisk Foundation. Open Access funding enabled and organized by Projekt DEAL. Funding Information: EB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from Böhringer Ingelheim for a collaboration on functional investigations of FKBP5. Otherwise, the authors declare that they have no competing interests. Funding Information: We would like to thank the midwifes, Dr. A. Gusarova, Dr. F. Braun-Tavares and A. K. Hardt at the Department for Obstetrics, Charit? for valuable assistance in recruiting study participants. We would also like to thank L. Ehrlich at the Department for Obstetrics, Charit? for her assistance in placental tissue preparation. We would like to thank all of the midwives, obstetricians, and other medical staff, laboratory and research personnel, and administrative staff working in hospitals, antenatal and child wellbeing clinics, municipalities, national registers, and other institutions, whose efforts have made research in the ITU cohort possible. We would also like to thank research nurse Eija Lahdensuo and a number of research assistants who during the study period participated in ITU and PREDO study data collection. We thank?Susann Sauer, Maik K?del, Monika Rex-Haffner and Eija Lahdensuo for technical?support and Jessica Keverne for language editing. Publisher Copyright: © 2021, The Author(s).

PY - 2021/8/26

Y1 - 2021/8/26

N2 - Background: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Results: 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. Conclusions: 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.

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U2 - 10.1186/s13148-021-01153-y

DO - 10.1186/s13148-021-01153-y

M3 - Article

AN - SCOPUS:85113480381

SN - 1868-7075

VL - 13

JO - Clinical Epigenetics

JF - Clinical Epigenetics

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M1 - 165

ER -

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

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