Persistent overexpression of DNA methyltransferase 1 attenuating GABAergic inhibition in basolateral amygdala accounts for anxiety in rat offspring exposed perinatally to low-dose bisphenol A

J Psychiatr Res. 2013 Oct;47(10):1535-44. doi: 10.1016/j.jpsychires.2013.05.013. Epub 2013 Jun 20.


Substantial evidence indicates that predisposition to diseases can be acquired during early stages of development and interactions between environmental and genetic factors may be implicated in the onset of many pathological conditions. We have shown that perinatal exposure to bisphenol A (BPA) at environmental dose level causes long-term anxiety-like behaviors in rats. The aim of this study was to examine epigenetic reprogramming effect of BPA on anxiety-related neurobehavior in the rat offspring. The results of real-time RT-PCR displayed that the overexpression of DNA methyltransferase 1 (DNMT1) mRNA was accompanied by the reduction of glutamic acid decarboxylase 67 (GAD67) mRNA level in the basolateral amygdala (BLA) of postnatal day 45 BPA-exposed female rats. Chronic intro-BLA injection with 5-ada-CdR could rectify the GAD67 mRNA expression. Behavioral data showed that the anxiety-like behaviors in BPA-exposed rats were reversed by intro-BLA treatment with 5-ada-CdR which could be further blocked by PTX. Electrophysiological study revealed behavioral alterations were associated with the increase of postsynaptic neuronal excitability in the cortical-BLA pathway which appeared as multispike responses, paired-pulse facilitation instead of paired-pulse inhibition and long-term potentiation and 5-aza-CdR treatment restored the increased synaptic transmission in the BLA via improving GABAergic system. The above results suggest that the overexpression of DNMT1 in the BLA is responsible for the etiology of anxiety associated with BPA exposure via GABAergic disinhibition. In addition, we also find these long-term neurobehavioral effects of developmental BPA exposure are reversible in adolescent period.

Keywords: Anxiety; BLA; BPA; DNMT1; Epigenetic; GABAergic dysinhibition; GAD67.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Air Pollutants, Occupational / toxicity*
  • Amygdala / enzymology*
  • Amygdala / pathology
  • Animals
  • Anxiety / etiology*
  • Anxiety / pathology*
  • Benzhydryl Compounds / toxicity*
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • Disease Models, Animal
  • Evoked Potentials / drug effects
  • Female
  • GABA Antagonists / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • In Vitro Techniques
  • Indolizines / pharmacology
  • Male
  • Methionine / pharmacology
  • Neural Inhibition / drug effects
  • Neurons / drug effects
  • Neurons / physiology
  • Phenols / toxicity*
  • Picrotoxin / pharmacology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • gamma-Aminobutyric Acid / metabolism*


  • 5-azacastanospermine
  • Air Pollutants, Occupational
  • Benzhydryl Compounds
  • GABA Antagonists
  • Indolizines
  • Phenols
  • Picrotoxin
  • gamma-Aminobutyric Acid
  • Methionine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • Dnmt1 protein, rat
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • bisphenol A