Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development

Tom J Phillips,Mark F Rogers,Gareth J Inman,Michael P Murphy,Catherine E Gilmore,Peter Holmans ,Helena Kemp,Mitsuru Akashi,Andrew Pocklington,Yealin Chung,Gavin Collett ,Ashleigh L Bignell,David A Menassa,Takami Akagi,Mais M Aljunaidy,Christy Lynn M Cooke ,Andrew M Coney,Anubhuti Sood ,Bruno R Steinkraus,Sandra T Davidge,Angela Logan,K Azuma ,Tudor A Fulga,Jude S Morton,Hannah Scott,Simon Grant,C P Case

doi:10.1038/s41598-017-06300-1

Abstract

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life.

Highlights

The hypothesis for the fetal origin of adult diseases was first proposed in 1990 by David Barker[1]
MitoQ-NPs were most effective at reducing the effects of in vitro hypoxia, compared to NP-bound Gap[26] or PPADS (Supplementary Fig. S2)
When NPs were applied to BeWo barriers for up to 24 h, they were predominantly located in the top layer of the barrier (Fig. 1a)[40]

Summary

Introduction

The hypothesis for the fetal origin of adult diseases was first proposed in 1990 by David Barker[1]. Evidence has accumulated lending credence to the hypothesis that some neuropsychiatric diseases that become symptomatic during adolescence or in adulthood have a neurodevelopmental origin[2, 3] Psychological disorders such as schizophrenia, attention deficit hyperactivity disorder and autism have been associated with episodes of altered oxygen during pregnancy, as early as the end of the first trimester[3,4,5,6,7]. We noted that soluble drugs such as MitoQ, a mitochondrial antioxidant, Gap[26], which blocks connexin hemichannels and gap junctions, PPADS, a purinergic receptor antagonist, and C17, an antagonist of pannexin channels, could inhibit intercellular signalling between the layers of the barrier and prevent the secretion of DNA damaging factors from the barrier[40, 41] These observations suggest that secreted placental factors may be candidate effectors for fetal programming of disease. They present an opportunity to treat the placenta via the mother to prevent harmful signalling to the fetus

Methods

Results

Conclusion