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Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation

Huixi Chen1, Sisi Luo2, Xiuyu Deng3

  • 1The International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China; Shanghai Key Laboratory of Reproduction and Development, Shanghai 200011, China; Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200030, China; Key Laboratory of Reproductive Genetics (Ministry of Education), Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; State Key Laboratory of Cardiology, Shanghai 200000, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|April 22, 2024
PubMed

Insights

Maternal pre-eclampsia (PE) leads to offspring metabolic disorders, including obesity, due to epigenetic changes affecting lipid metabolism. Early interventions may mitigate these lifelong health risks.

Area of Science:

  • Developmental biology
  • Epigenetics
  • Metabolic disorders

Background:

  • The "gamete and embryo-foetal origins of adult diseases" hypothesis links early life conditions to adult chronic disorders.
  • Maternal pre-eclampsia (PE) is a pregnancy complication that may program offspring for metabolic dysfunction.

Purpose of the Study:

  • To investigate developmental changes and underlying epigenetic mechanisms of metabolic disorders in offspring from a pre-eclampsia (PE) programmed pregnancy.
  • To characterize the long-term metabolic consequences in offspring following maternal PE.

Main Methods:

  • Utilized a pre-eclampsia-like mouse model induced by Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME).
  • Performed lipid profiling, histology, indirect calorimetry, mRNA sequencing, and pyrosequencing on offspring at young and elderly ages.
  • Analyzed gene expression and DNA methylation in fetal and adult livers of offspring.

Main Results:

  • Offspring from PE pregnancies exhibited increased weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance persisting into adulthood.
  • RNA sequencing revealed altered expression of genes involved in lipid metabolism (e.g., Gpat3, Cpt1a) in PE offspring livers.
  • Pyrosequencing identified promoter hypomethylation and hypermethylation in Gpat3 and Cpt1a, correlating with altered gene expression, indicating persistent epigenetic changes from fetal to adult stages.

Conclusions:

  • Findings suggest a methylation-mediated epigenetic mechanism driving intergenerational lipid accumulation and metabolic dysfunction in offspring of PE pregnancies.
  • These epigenetic alterations contribute to impaired energy balance and obesity, increasing susceptibility to metabolic disorders later in life.
  • Early interventions in offspring exposed to maternal PE may offer potential benefits in reducing their risk of developing metabolic disorders.
Abstract

Keywords:
DNA methylationIntergenerational inheritanceLipid metabolismMetabolic disorderPre-eclampsia

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