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Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring

Harrison, David J., Creeth, Hugo D. J., Tyson, Hannah R., Boque Sastre, Raquel, Hunter, Susan, Dwyer, Dominic M., Isles, Anthony R. and John, Rosalind M. 2021. Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring. Human Molecular Genetics , ddab154. 10.1093/hmg/ddab154

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Abstract

Abnormally elevated expression of the imprinted PHLDA2 gene has been reported in the placenta of human babies that are growth restricted in utero in several studies. We previously modelled this gene alteration in mice and found that just two-fold increased expression of Phlda2 resulted in placental endocrine insufficiency. In addition, elevated Phlda2 was found to drive fetal growth restriction (FGR) of transgenic offspring and impaired maternal care by their wild type mothers. Being born small and being exposed to suboptimal maternal care have both been associated with the increased risk of mental health disorders in human populations. In the current study we probed behavioural consequences of elevated Phlda2 for the offspring. We discovered increased anxiety-like behaviours, deficits in cognition and atypical social behaviours, with the greatest impact on male offspring. Subsequent analysis revealed alterations in the transcriptome of the adult offspring hippocampus, hypothalamus, and amygdala, regions consistent with these behavioural observations. The inclusion of a group of fully wild type controls raised in a normal maternal environment allowed us to attribute behavioural and molecular alterations to the adverse maternal environment induced by placental endocrine insufficiency rather than the specific gene change of elevated Phlda2. Our work demonstrates that a highly common alteration reported in human fetal growth restriction is associated with negative behavioural outcomes later in life. Importantly, we also establish the experimental paradigm that placental endocrine insufficiency can program atypical behaviour in offspring highlighting the under-appreciated role of placental endocrine insufficiency in driving disorders of later life behaviour.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Biosciences
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/)
Publisher: Oxford University Press
ISSN: 0964-6906
Date of First Compliant Deposit: 21 June 2021
Date of Acceptance: 14 April 2021
Last Modified: 05 Aug 2021 02:56
URI: http://orca.cardiff.ac.uk/id/eprint/142035

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