Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition
Abstract Background Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental fu...
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-022-02610-y |
| _version_ | 1828318254638039040 |
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| author | Lucile Broséus Daniel Vaiman Jörg Tost Camino Ruano San Martin Milan Jacobi Joel D. Schwartz Rémi Béranger Rémy Slama Barbara Heude Johanna Lepeule |
| author_facet | Lucile Broséus Daniel Vaiman Jörg Tost Camino Ruano San Martin Milan Jacobi Joel D. Schwartz Rémi Béranger Rémy Slama Barbara Heude Johanna Lepeule |
| author_sort | Lucile Broséus |
| collection | DOAJ |
| description | Abstract Background Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. Methods Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. Results At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure—but not pulsatile pressure—and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. Conclusions This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy. |
| first_indexed | 2024-04-13T17:39:21Z |
| format | Article |
| id | doaj.art-13a3a51580db4d4792fadb0ba7b57d25 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-13T17:39:21Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-13a3a51580db4d4792fadb0ba7b57d252022-12-22T02:37:13ZengBMCBMC Medicine1741-70152022-10-0120111510.1186/s12916-022-02610-yMaternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type compositionLucile Broséus0Daniel Vaiman1Jörg Tost2Camino Ruano San Martin3Milan Jacobi4Joel D. Schwartz5Rémi Béranger6Rémy Slama7Barbara Heude8Johanna Lepeule9University Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB)From Gametes to Birth, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes UniversityLaboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA – Institut de Biologie François Jacob, University Paris SaclayFrom Gametes to Birth, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes UniversityUniversity Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB)Department of Environmental Health, Harvard T.H. Chan School of Public HealthUniv. Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR 1085University Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB)Univ. Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAEUniversity Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB)Abstract Background Maternal blood pressure levels reflect cardiovascular adaptation to pregnancy and proper maternal-fetal exchanges through the placenta and are very sensitive to numerous environmental stressors. Maternal hypertension during pregnancy has been associated with impaired placental functions and with an increased risk for children to suffer from cardiovascular and respiratory diseases later on. Investigating changes in placental DNA methylation levels and cell-type composition in association with maternal blood pressure could help elucidate its relationships with placental and fetal development. Methods Taking advantage of a large cohort of 666 participants, we investigated the association between epigenome-wide DNA methylation patterns in the placenta, measured using the Infinium HumanMethylation450 BeadChip, placental cell-type composition, estimated in silico, and repeated measurements of maternal steady and pulsatile blood pressure indicators during pregnancy. Results At the site-specific level, no significant association was found between maternal blood pressure and DNA methylation levels after correction for multiple testing (false discovery rate < 0.05), but 5 out of 24 previously found CpG associations were replicated (p-value < 0.05). At the regional level, our analyses highlighted 64 differentially methylated regions significantly associated with at least one blood pressure component, including 35 regions associated with mean arterial pressure levels during late pregnancy. These regions were found enriched for genes implicated in lung development and diseases. Further mediation analyses show that a significant part of the association between steady blood pressure—but not pulsatile pressure—and placental methylation can be explained by alterations in placental cell-type composition. In particular, elevated blood pressure levels are associated with a decrease in the ratio between mesenchymal stromal cells and syncytiotrophoblasts, even in the absence of preeclampsia. Conclusions This study provides the first evidence that the association between maternal steady blood pressure during pregnancy and placental DNA methylation is both direct and partly explained by changes in cell-type composition. These results could hint at molecular mechanisms linking maternal hypertension to lung development and early origins of childhood respiratory problems and at the importance of controlling maternal blood pressure during pregnancy.https://doi.org/10.1186/s12916-022-02610-yPlacentaDNA methylationBlood pressurePregnancyCell-type heterogeneityMesenchymal stromal cells |
| spellingShingle | Lucile Broséus Daniel Vaiman Jörg Tost Camino Ruano San Martin Milan Jacobi Joel D. Schwartz Rémi Béranger Rémy Slama Barbara Heude Johanna Lepeule Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition BMC Medicine Placenta DNA methylation Blood pressure Pregnancy Cell-type heterogeneity Mesenchymal stromal cells |
| title | Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition |
| title_full | Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition |
| title_fullStr | Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition |
| title_full_unstemmed | Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition |
| title_short | Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition |
| title_sort | maternal blood pressure associates with placental dna methylation both directly and through alterations in cell type composition |
| topic | Placenta DNA methylation Blood pressure Pregnancy Cell-type heterogeneity Mesenchymal stromal cells |
| url | https://doi.org/10.1186/s12916-022-02610-y |
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