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Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood

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Abstract

Aims/hypothesis

Perinatal exposure to bisphenol A (BPA), a widely distributed environmental endocrine disruptor, is associated with insulin resistance and diabetes in offspring. The underlying molecular mechanisms could involve epigenetics, as adverse effects induced by environmental exposure in early life are suggested through DNA methylation. In this study we sought to elucidate the relationship between perinatal BPA exposure and alteration of hepatic DNA methylation.

Methods

Pregnant Wistar rats were administered BPA (50 μg/kg/day) or corn oil by oral gavage throughout gestation and lactation. Variables associated with insulin resistance and hepatic DNA methylation were examined at postnatal week 3 and week 21 in male offspring.

Results

In BPA-treated offspring, serum insulin and HOMA-insulin resistance were increased, and the insulin sensitivity index and hepatic glycogen storage were decreased compared with controls at week 21. At week 3, none of these variables were significantly changed. However, hepatic global DNA methylation was decreased, accompanied by overexpression of DNA methyltransferase 3B mRNA at week 3. Meanwhile, perinatal exposure to BPA induced promoter hypermethylation and a reduction in gene expression of hepatic glucokinase. Moreover, increased promoter hypermethylation of Gck became more pronounced in BPA-treated offspring at week 21.

Conclusions/interpretation

Abnormal DNA methylation in hepatic tissue precedes development of insulin resistance induced by perinatal BPA exposure. These findings support the potential role of epigenetics in fetal reprogramming by BPA-induced metabolic disorders.

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Abbreviations

BPA:

Bisphenol A

CpG:

Cytosine phosphate guanine

DNMT3B:

DNA methyltransferase 3B

DNMT1:

DNA (cytosine-5-)-methyltransferase

G6p:

Glucose 6-phosphate

GCK:

Glucokinase

GD:

Gestation day

HNF-1:

Hepatic nuclear factor 1

HOMA-IR:

HOMA-insulin resistance

ISI:

Insulin sensitivity index

LXRα:

Liver X receptor α

PAS:

Periodic acid Schiff

PPARγ:

Peroxisome proliferator-activated receptor γ

SP1:

Sp1 transcription factor

SREBP-1c:

Sterol regulatory element-binding protein 1c

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Acknowledgements

We thank Z. W. Cai (Department of Chemistry, Hong Kong Baptist University, Hong Kong, China) for help with revision and Y. Lin and J. Wei (School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for their help with animal studies.

Funding

This work was supported by the National Program on Key Basic Research Project of China (973 Program) (2012CB722401); the National Natural Science Foundation of China (81030051, 21177046); the R&D Special Fund for Public Welfare Industry (Environment) (201309048); the National Basic Research Development Program of China (2008CB418206); the Fundamental Research Funds for the Central Universities; HUST (2012QN240, 2012TS072) and the Doctoral Fund of Ministry of Education of China (20120142120017).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

SQX conceived and designed the study. YM and WX participated in the acquisition of experimental data and data analyses and drafted the manuscript. DQW determined mRNA and protein levels. YYL participated in the analysis of global DNA methylation. YJW carried out the bisulphite-sequencing of Gck promoter and relative data analyses. BX and XC participated in keeping rats, data processing and statistical analyses. All authors were involved in preparing the analyses and interpretation of the data and critical revision of the manuscript and approved the final manuscript for publication.

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Authors and Affiliations

  1. Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Y. Ma, W. Xia, D. Q. Wang, Y. J. Wan, B. Xu, X. Chen, Y. Y. Li & S. Q. Xu

  2. State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Y. Ma, W. Xia, D. Q. Wang, Y. J. Wan, B. Xu, X. Chen, Y. Y. Li & S. Q. Xu

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  1. Y. Ma
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  2. W. Xia
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  3. D. Q. Wang
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Corresponding authors

Correspondence to Y. Y. Li or S. Q. Xu.

Additional information

Y. Ma and W. Xia contributed equally to this study

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Ma, Y., Xia, W., Wang, D.Q. et al. Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia 56, 2059–2067 (2013). https://doi.org/10.1007/s00125-013-2944-7

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  • DOI: https://doi.org/10.1007/s00125-013-2944-7

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