Placental hypoxia-regulating network in relation to birth weight and ponderal index: the ENVIRONAGE Birth Cohort Study

Karen Vrijens,Narjes Madhloum,Wilfried Gyselaers,Maria Tsamou,Tim S Nawrot

doi:10.1186/s12967-017-1375-5

Karen Vrijens, Narjes Madhloum + Show 3 more

Open Access

https://doi.org/10.1186/s12967-017-1375-5

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Abstract

BackgroundHIF1α, miR-210 and its downstream targets ISCU, COX-10, RAD52 and PTEN are all part of the placental hypoxia-responsive network. Tight regulation of this network is required to prevent development of maternal–fetal complications such as fetal growth restriction. HIF1α expression is increased in preeclamptic placentae, but little is known about its association with birth weight in normal pregnancies.MethodsWe measured placental levels of HIF1α, miR-20a, miR-210, ISCU, COX-10, RAD52 and PTEN in 206 mother–newborn pairs of the ENVIRONAGE birth cohort.ResultsPlacental HIF1α gene expression was inversely associated with the ponderal index (PI): for a doubling in placental HIF1α expression, PI decreased by 6.7% (95% confidence interval [CI] 1.3 to 12.0%, p = 0.01). Placental RAD52 expression also displayed an inverse association with PI, a doubling in gene expression was associated with a 6.2% (CI 0.2 to 12.1% p = 0.04) decrease in PI. As for birth weight, we observed a significant association with placental miR-20a expression only in boys, where a doubling in miR-20a expression is associated with a 54.2 g (CI 0.6 to 108 g, p = 0.05) increase in birth weight.ConclusionsThe decrease in fetal growth associated with expression of hypoxia-network members HIF1a, RAD52 and miR-20a indicates that this network is important in potential intrauterine insults.

Highlights

Hypoxia-inducible factor 1α (HIF1α), miR-210 and its downstream targets iron sulfur-cluster assembly enzyme (ISCU), C oxidase-10 (COX-10), RAD52 and phosphatase and tensin homolog (PTEN) are all part of the placental hypoxia-responsive network
Placental HIF1α gene expression was inversely associated with ponderal index (PI): for a doubling in placental HIF1α expression, PI decreased by 6.7% (95% confidence interval [CI] 1.3 to 12.0%, p = 0.01) when analyzing both sexes together, with similar estimates in boys and girls
Placental RAD52 expression displayed an inverse association with PI for boys and girls, a doubling in gene expression was associated with a 6.2% (CI 0.2 to 12.1% p = 0.04) decrease in PI

Summary

Introduction

HIF1α, miR-210 and its downstream targets ISCU, COX-10, RAD52 and PTEN are all part of the placental hypoxia-responsive network. Tight regulation of this network is required to prevent development of maternal–fetal complications such as fetal growth restriction. HIF1α expression is increased in preeclamptic placentae, but little is known about its association with birth weight in normal pregnancies. Little is known on the relation between HIF1α expression in placental tissue from normal term pregnancies and fetal growth. As tight regulation of oxygen levels is essential for proper fetal-placental development, we hypothesize placental expression levels of the hypoxia-responsive network are associated with measures of fetal growth in normal pregnancies. We analyzed expression of 7 members from the hypoxia-regulation network in placental tissue (Fig. 1), by examining miR-20a and miR-210 and mRNA HIF1α, cytochrome C oxidase-10 (COX-10), ISCU, phosphatase and tensin homolog (PTEN), and DNA repair protein RAD52 expression levels

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