Lucile Broséus1, Daniel Vaiman2, Jörg Tost3, Camino Ruano San Martin2, Milan Jacobi4, Joel D Schwartz5, Rémi Béranger6, Rémy Slama4, Barbara Heude7, Johanna Lepeule8. 1. University Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB), Grenoble, France. lucile.broseus@univ-grenoble-alpes.fr. 2. From Gametes to Birth, Institut Cochin, U1016 INSERM, UMR 8104 CNRS, Paris-Descartes University, Paris, France. 3. Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, University Paris Saclay, Evry, France. 4. University Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB), Grenoble, France. 5. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 6. Univ. Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), UMR 1085, Rennes, France. 7. Univ. Paris, Centre for Research in Epidemiology and Statistics (CRESS), INSERM, INRAE, Paris, France. 8. University Grenoble Alpes, INSERM, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences (IAB), Grenoble, France. johanna.lepeule@univ-grenoble-alpes.fr.
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.
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.
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