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

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

doi:10.1038/s41598-017-06300-1

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

Tom J. Phillips
, Hannah Scott
, David A. Menassa
, Ashleigh L. Bignell
, Aman Sood
, Jude S. Morton
, Takami Akagi
, Koki Azuma
, Mark F. Rogers
, Catherine E. Gilmore
, Gareth J. Inman
, Simon Grant
, Yealin Chung
, Mais M. Aljunaidy
, Christy-Lynn Cooke
, Bruno R. Steinkraus
, Andrew Pocklington
, Angela Logan
, Gavin P. Collett
, Helena Kemp

Peter A. Holmans, Michael P. Murphy, Tudor A. Fulga, Andrew M. Coney, Mitsuru Akashi, Sandra T. Davidge, C. Patrick Case (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

81 Citations (Scopus)

290 Downloads (Pure)

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.

Original language	English
Article number	9079
Pages (from-to)	1-16
Number of pages	16
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-06300-1
Publication status	Published - 22 Aug 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Disease model
Experimental models of disease
Schizophrenia

Access to Document

10.1038/s41598-017-06300-1Licence: CC BY

Final Published Version
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Final published version, 4.52 MBLicence: CC BY

Cite this

Phillips, T. J., Scott, H., Menassa, D. A., Bignell, A. L., Sood, A., Morton, J. S., Akagi, T., Azuma, K., Rogers, M. F., Gilmore, C. E., Inman, G. J., Grant, S., Chung, Y., Aljunaidy, M. M., Cooke, C.-L., Steinkraus, B. R., Pocklington, A., Logan, A., Collett, G. P., ... Case, C. P. (2017). Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development. Scientific Reports, 7, 1-16. Article 9079. https://doi.org/10.1038/s41598-017-06300-1

@article{684cd4bdb8f4426a886d6b9a80672212,

title = "Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development",

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.",

keywords = "Disease model, Experimental models of disease, Schizophrenia",

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

note = "The work conducted in the Davidge laboratory is funded by grants from the Canadian Institutes of Health Research (CIHR); and the Women and Children{\textquoteright}s Health Research Institute (WCHRI) through the generous contributions of the Stollery Children{\textquoteright}s Hospital Foundation (SCHF) and the Royal Alexandra Hospital Foundation (RAHF). S. Davidge is a Canada Research Chair in Maternal and Perinatal Cardiovascular Health. Computing equipment was supported by an EPSRC grant (EP/K008250/1).",

year = "2017",

month = aug,

day = "22",

doi = "10.1038/s41598-017-06300-1",

language = "English",

volume = "7",

pages = "1--16",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Research",

}

Phillips, TJ, Scott, H, Menassa, DA, Bignell, AL, Sood, A, Morton, JS, Akagi, T, Azuma, K, Rogers, MF, Gilmore, CE, Inman, GJ, Grant, S, Chung, Y, Aljunaidy, MM, Cooke, C-L, Steinkraus, BR, Pocklington, A, Logan, A, Collett, GP, Kemp, H, Holmans, PA, Murphy, MP, Fulga, TA, Coney, AM, Akashi, M, Davidge, ST & Case, CP 2017, 'Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development', Scientific Reports, vol. 7, 9079, pp. 1-16. https://doi.org/10.1038/s41598-017-06300-1

TY - JOUR

T1 - Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development

AU - Phillips, Tom J.

AU - Scott, Hannah

AU - Menassa, David A.

AU - Bignell, Ashleigh L.

AU - Sood, Aman

AU - Morton, Jude S.

AU - Akagi, Takami

AU - Azuma, Koki

AU - Rogers, Mark F.

AU - Gilmore, Catherine E.

AU - Inman, Gareth J.

AU - Grant, Simon

AU - Chung, Yealin

AU - Aljunaidy, Mais M.

AU - Cooke, Christy-Lynn

AU - Steinkraus, Bruno R.

AU - Pocklington, Andrew

AU - Logan, Angela

AU - Collett, Gavin P.

AU - Kemp, Helena

AU - Holmans, Peter A.

AU - Murphy, Michael P.

AU - Fulga, Tudor A.

AU - Coney, Andrew M.

AU - Akashi, Mitsuru

AU - Davidge, Sandra T.

AU - Case, C. Patrick

N1 - The work conducted in the Davidge laboratory is funded by grants from the Canadian Institutes of Health Research (CIHR); and the Women and Children’s Health Research Institute (WCHRI) through the generous contributions of the Stollery Children’s Hospital Foundation (SCHF) and the Royal Alexandra Hospital Foundation (RAHF). S. Davidge is a Canada Research Chair in Maternal and Perinatal Cardiovascular Health. Computing equipment was supported by an EPSRC grant (EP/K008250/1).

PY - 2017/8/22

Y1 - 2017/8/22

N2 - 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.

AB - 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.

KW - Disease model

KW - Experimental models of disease

KW - Schizophrenia

U2 - 10.1038/s41598-017-06300-1

DO - 10.1038/s41598-017-06300-1

M3 - Article

C2 - 28831049

SN - 2045-2322

VL - 7

SP - 1

EP - 16

JO - Scientific Reports

JF - Scientific Reports

M1 - 9079

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

Fingerprint

Cite this