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
Abstract
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 res…
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An increase in Dnmt1 correlated with a decrease in GAD67 mRNA in BPA rats.
“Researchers believed that the GABAergic pathway was affected, because an increase in Dnmt1 correlated with a decrease in glutamine decarboxylase (GAD67) mRNA, the enzyme responsible for the production of GABA from glutamate, though GABA and glutamate levels were not directly measured (Valenzuela et al., 2011; Zhou et al., 2013).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhou et al., 2013
In rat dams fed BPA, newborns showed an increase in Dnmt1 mRNA expression levels in their basolateral amygdala in tandem with increased anxiety behavior observations.
“In one study using rat dams fed BPA, newborns showed an increase in Dnmt1 mRNA expression levels in their BLA in tandem with increased anxiety behavior observations (Zhou et al., 2013).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhou et al., 2013
The rescuing effect of 5-ada-Cdr was later inhibited by use of picrotoxin, an antagonist of GABAA receptors.
“The rescuing effect of 5-ada-Cdr was then later inhibited by use of picrotoxin, an antagonist of the GABAA receptors (Zhou et al., 2013).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhou et al., 2013
GABA and glutamate levels were not directly measured in the BPA study.
“though GABA and glutamate levels were not directly measured (Valenzuela et al., 2011; Zhou et al., 2013).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhou et al., 2013
Reversal of decreased GAD67 mRNA expression and subsequent anxiety-like behaviors in BPA rats is possible by administering 5-ada-Cdr, a hypomethylating agent.
“Researchers also showed that the reversal of decreased GAD67 mRNA expression and subsequent anxiety-like behaviors in BPA rats is possible by administering 5-ada-Cdr, a hypomethylating agent (Zhou et al., 2013).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Zhou et al., 2013
BPA increases expression of DNA methyltransferase 1 in the amygdala, a change associated with increased anxiety-like behavior in rat offspring.
“BPA further increases expression of DNA methyltransferase 1 in the amygdala, a change associated with increased anxiety-like behavior in rat offspring (Zhou et al., 2013).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Zhou et al., 2013
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“A subsequent decrease in GABA is observed (Zhou et al., 2013; Zhu et al., 2018).”
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“BPA further increases expression of DNA methyltransferase 1 in the amygdala, a change associated with increased anxiety-like behavior in rat offspring (Zhou et al., 2013).”
- Authors
- Zhou, R., Chen, F., Chang, F., Bai, Y., & Chen, L.
- Affiliations
- Nanjing Medical University (CN)
- Corresponding author
- Chen, Ling
- Venue
- Journal of Psychiatric Research
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 47
- Issue
- 10
- Pages
- 1535-1544
- ISSN
- 0022-3956 (ISSN-L)
- OpenAlex
- W1997632778
- Cited by
- 54
- References
- 3
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 8 · 2015: 9 · 2014: 1
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Psychiatric Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- bisphenol A, perinatal exposure, DNMT1, GABAergic inhibition, basolateral amygdala, anxiety-like behavior, epigenetic reprogramming, GAD67, postsynaptic excitability, synaptic transmission, developmental neurotoxicity
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Bisphenol A Compounds, Air Pollutants, Occupational, Amygdala, Animals, Anxiety, Benzhydryl Compounds, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferases, Evoked Potentials, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Indolizines, Male, Methionine, Neural Inhibition, Neurons, Phenols, Picrotoxin, Pregnancy, Prenatal Exposure Delayed Effects, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, GABA Antagonists, Rats, In Vitro Techniques
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