Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring.
Placental endocrine insufficiency programs anxiety, deficits in cognition and atypical social behaviour in offspring.
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DOI：
10.1093/hmg/ddab154
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发表时间：
2021-09-15
影响因子：
3.5
通讯作者：
John RM
中科院分区：
文献类型：
--
作者：
Harrison DJ;Creeth HDJ;Tyson HR;Boque-Sastre R;Hunter S;Dwyer DM;Isles AR;John RM
在几项研究中，已报告了在子宫内生长受限的人类婴儿胎盘中印记PHLDA2基因的异常升高表达。我们先前在小鼠中模拟了这种基因改变，发现Phlda2表达增加2倍会导致胎盘内分泌功能不全。此外，发现Phlda2升高会导致转基因后代的胎儿生长受限（FGR），并损害其野生型母亲的母亲护理。出生时身材矮小和暴露于次优的孕产妇护理都与人口中心理健康障碍的风险增加有关。在目前的研究中，我们探讨了Phlda2升高对后代的行为后果。我们发现焦虑样行为、认知缺陷和非典型社会行为增加，对雄性后代的影响最大。随后的分析显示，成年后代海马体、下丘脑和杏仁核的转录组发生了变化，这些区域与这些行为观察结果一致。包括一组完全野生型控制提出了一个正常的母体环境，使我们能够属性的行为和分子的变化，不利的母体环境引起的胎盘内分泌功能不全，而不是特定的基因变化升高Phlda2。我们的工作表明，在人类FGR中报告的一种非常常见的改变与以后生活中的负面行为结果有关。重要的是，我们还建立了胎盘内分泌功能不全可以在后代中编程非典型行为的实验范式，突出了胎盘内分泌功能不全在驾驶后期生活行为障碍中的作用。
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 2-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 wildtype 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 wildtype 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 FGR 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.
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