Abstract
Placental cortisol is inactivated in normotensive pregnancies, but is frequently present in pre-eclampsia associated placentae. Since glucocorticoids are strongly associated with the programming of long-term health, we assessed DNA methylation of genes involved in cortisol signalling and bioavailability, and hormonal signalling in the placenta of normotensive and hypertensive pregnancies. Candidate genes/CpG sites were selected through analysis of Illumina Infinium HumanMethylation450 BeadChip array data on control (n = 19) and early onset pre-eclampsia (EOPET; n = 19) placental samples. DNA methylation was further quantified by bisulfite pyrosequencing in a larger cohort of control (n = 111) cases, in addition to EOPET (n = 19), late onset pre-eclampsia (LOPET; n = 18) and normotensive intrauterine growth restriction (nIUGR; n = 13) cases. DNA methylation (percentage points) was increased at CpG sites within genes encoding the glucocorticoid receptor (NR3C1 exon 1D promoter; +8.46%; P<0.01) and corticotropin releasing hormone (CRH) binding protein (CRHBP intron 3; +9.14%; P<0.05), and decreased within CRH (5′ UTR; −4.30%; P = 0.11) in EOPET-associated placentae, but not in LOPET nor nIUGR cases, compared to controls. Differential DNA methylation was not observed among groups at the 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene promoter. Significant hypomethylation was observed in pre-eclampsia but not nIUGR placentae for steroidogenic genes, including CYP11A1 (exon1; EOPET; −9.66%; P<0.00001, and LOPET; −5.77%; P<0.001), 3β-hydroxy-delta-5-steroid dehydrogenase type 1 (HSD3B1 exon 2; EOPET; −12.49%; P<0.00001, and LOPET; −6.88%; P<0.001), TEA domain family member 3 (TEAD3 intron 1; EOPET; −12.56%; P<0.00001) and CYP19 (placental-specific exon 1.1 promoter; EOPET; −10.62%, P<0.0001). These data represent dysregulation of the placental epigenome in pre-eclampsia related to genes involved in maintaining the hormonal environment during pregnancy and highlights particular susceptibility in the early onset syndrome.
Highlights
Maternal stress and/or elevated glucocorticoid exposure in utero is associated with low birth weight, exaggerated infant stress response and adult disease in the offspring [1]
Multiple genes associated with stress pathways and steroid production were associated with differentially methylated CpG sites in EOPET cases compared with controls based on the Illumina DNA methylation array (Table 2)
A CpG island associated with CRH binding protein (CRHBP) (Fig. S1) was significantly hypermethylated in EOPET, whereas non-CpG island regions associated with corticotropin releasing hormone (CRH), CYP11A1, HSD3B1, TEAD3 and CYP19 were hypomethylated in EOPET versus control placentae (Fig. S2-6, respectively)
Summary
Maternal stress and/or elevated glucocorticoid exposure in utero is associated with low birth weight, exaggerated infant stress response and adult disease in the offspring [1]. Disorders during pregnancy which alter maternal physiology and induce systemic inflammatory response are likely to augment stress-signalling pathways, and may be associated with adverse developmental programming. Pre-eclampsia, that of early onset, is largely the result of poor placentation, leading to hypoxic and inflammatory insult to surrounding tissue as well as underperfusion of essential materials from mother to fetus [2,3,4]. Pre-eclampsia is a common obstetrical complication in developed countries and remains a leading cause of maternal death [6], its aetiology is poorly understood. In this study we aim to determine how placental stress-pathways might be altered in preeclampsia and related pregnancy complications
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