Evidence that fetal death is associated with placental aging

Kaushik Maiti,Zakia Sultana,Robert J Aitken,Jonathan Morris,Felicity Park,Bronwyn Andrew,Simon C Riley,Roger Smith

doi:10.1016/j.ajog.2017.06.015

Abstract

The risk of unexplained fetal death or stillbirth increases late in pregnancy, suggesting that placental aging is an etiological factor. Aging is associated with oxidative damage to DNA, RNA, and lipids. We hypothesized that placentas at >41 completed weeks of gestation (late-term) would show changes consistent with aging that would also be present in placentas associated with stillbirths. We sought to determine whether placentas from late-term pregnancies and unexplained stillbirth show oxidative damage and other biochemical signs of aging. We also aimed to develop an invitro term placental explant culture model to test the aging pathways. We collected placentas from women at 37-39 weeks' gestation (early-term and term), late-term, and with unexplained stillbirth. We used immunohistochemistry to compare the 3 groups for: DNA/RNA oxidation (8-hydroxy-deoxyguanosine), lysosomal distribution (lysosome-associated membrane protein 2), lipid oxidation (4-hydroxynonenal), and autophagosome size (microtubule-associated proteins 1A/1B light chain 3B, LC3B). The expression of aldehyde oxidase 1 was measured by real-time polymerase chain reaction. Using a placental explant culture model, we tested the hypothesis that aldehyde oxidase 1 mediates oxidative damage to lipids in the placenta. Placentas from late-term pregnancies show increased aldehyde oxidase 1 expression, oxidation of DNA/RNA and lipid, perinuclear location of lysosomes, and larger autophagosomes compared to placentas from women delivered at 37-39 weeks. Stillbirth-associated placentas showed similar changes in oxidation of DNA/RNA and lipid, lysosomal location, and autophagosome size to placentas from late-term. Placental explants from term deliveries cultured in serum-free medium also showed evidence of oxidation of lipid, perinuclear lysosomes, and larger autophagosomes, changes that were blocked by the G-protein-coupled estrogen receptor 1 agonist G1, while the oxidation of lipid was blocked by the aldehyde oxidase 1 inhibitor raloxifene. Our data are consistent with a role for aldehyde oxidase 1 and G-protein-coupled estrogen receptor 1 in mediating aging of the placenta that may contribute to stillbirth. The placenta is a tractable model of aging in human tissue.

Highlights

Unexplained fetal death is a common complication of pregnancy occurring in approximately 1 in 200 pregnancies in developed countries[1] and more frequently in the developing world
Accumulation of abnormal protein is thought to play a role in aging, in the brain, for instance the accumulation of tau and amyloid protein in Alzheimer disease[13,14] and mutant huntingtin in Huntington disease.[15]
IHC showed lysosomes positioned on the apical surface of early-term placental syncytiotrophoblast (Figure 3, A, D, and E), whereas lysosomes relocated to the perinuclear and the basal surface in lateterm and stillbirth placentas (Figure 3, B, C, F, and G)

Summary

Introduction

Unexplained fetal death is a common complication of pregnancy occurring in approximately 1 in 200 pregnancies in developed countries[1] and more frequently in the developing world. While no cause has been established, the rate of fetal death rises rapidly as gestation progresses >38 weeks.[2] Johnson et al[3] proposed the operational definition of aging as an increase in risk of mortality with time, which is consistent with a role for aging in the etiology of stillbirth (Figure 1).[4] Supporting this view, a histopathological study of placentas associated with cases of unexplained intrauterine death at. The risk of unexplained fetal death or stillbirth increases late in pregnancy, suggesting that placental aging is an etiological factor. Aging is associated with oxidative damage to DNA, RNA, and lipids. OBJECTIVE: We sought to determine whether placentas from late-term pregnancies and unexplained stillbirth show oxidative damage and other biochemical signs of aging. Using a placental explant culture model, we tested the hypothesis that aldehyde oxidase 1 mediates oxidative damage to lipids in the placenta

Objectives

Methods

Results