HIF-1 α may play a role in late pregnancy hypoxia-induced autism-like behaviors in offspring rats

Behav Brain Res. 2021 Aug 6:411:113373. doi: 10.1016/j.bbr.2021.113373. Epub 2021 May 26.


Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can be caused by various factors. The present study aimed to determine whether prenatal hypoxia can lead to ASD and the role of hypoxia-inducible factor-1α (HIF-1α) in this process. We constructed a prenatal hypoxia model of pregnant rats by piping nitrogen and oxygen mixed gas, with an oxygen concentration of 10 ± 0.5 %, into the self-made hypoxia chamber. Rats were subjected to different extents of hypoxia treatments at different points during pregnancy. The results showed that hypoxia for 6 h on the 17th gestation day is most likely to lead to autistic behavior in offspring rats, including social deficits, repetitive behaviors, and impaired learning and memory. The mRNA expression level of TNF-α also increased in hypoxia-induced autism group and valproic acid (VPA) group. Western blotting analysis showed increased levels of hypoxia inducible factor 1 alpha (HIF-1α) and decreased levels of phosphatase and tensin homolog (PTEN) in the hypoxic-induced autism group. Meanwhile, N-methyl d-aspartate receptor subtype 2 (NR2A) and glutamate ionotropic receptor AMPA type subunit 2 (GluR2) were upregulated in the hypoxic-induced autism group. HIF-1α might play a role in hypoxia-caused autism-like behavior and its regulatory effect is likely to be achieved by regulating synaptic plasticity.

Keywords: Autism spectrum disorder; Behavior; Hypoxia-inducible factor-1α; Prenatal hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / etiology
  • Autism Spectrum Disorder / metabolism*
  • Autism Spectrum Disorder / physiopathology
  • Disease Models, Animal
  • Female
  • Hypoxia / metabolism
  • Hypoxia / physiopathology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Male
  • PTEN Phosphohydrolase / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Social Behavior
  • Tumor Necrosis Factor-alpha / metabolism
  • Valproic Acid / adverse effects


  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Tumor Necrosis Factor-alpha
  • Valproic Acid
  • PTEN Phosphohydrolase