Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Dec;1(1):dvv006.
doi: 10.1093/eep/dvv006. Epub 2015 Jan 1.

Bisphenol A-associated Alterations in Genome-Wide DNA Methylation and Gene Expression Patterns Reveal Sequence-Dependent and Non-Monotonic Effects in Human Fetal Liver

Affiliations
Free PMC article

Bisphenol A-associated Alterations in Genome-Wide DNA Methylation and Gene Expression Patterns Reveal Sequence-Dependent and Non-Monotonic Effects in Human Fetal Liver

Christopher Faulk et al. Environ Epigenet. .
Free PMC article

Abstract

Bisphenol A (BPA), a high production volume chemical widely used in consumer products, is an endocrine active compound associated with complex epigenetic responses in animal models and humans. Developmental BPA exposure in mice previously revealed widespread changes in the mouse liver methylome. Here, we undertake the first epigenome-wide analysis of the effect of BPA concentration on human fetal liver DNA methylation. Enzymatic enrichment of genomic DNA for high CG density and methylation followed by next-generation sequencing yielded data for positional methylation across the genome. Comparing three groups of BPA-exposed subjects (n=18; 6 per group), high (35.44-96.76 ng/g), low (3.50 to 5.79 ng/g), and non-detect (<0.83 ng/g), revealed regions of altered methylation. Similar numbers of regions of altered methylations were detected in pairwise comparisons; however, their genomic locations were distinct between the non-detect and low or high BPA groups. In general, BPA levels were positively associated with methylation in CpG islands and negatively associated with methylation in CpG shores, shelves, and repetitive regions. DNA methylation at the SNORD imprinted cluster (15q11q13) illustrated both linear and non-monotonic associations with BPA levels. Integrated methylation and RNA-sequencing gene expression analysis revealed differential regulation of transcription at low BPA levels, as well as expression changes in RNA for ligand-binding proteins as BPA levels increase. BPA levels in human fetal liver tissue are associated with complex linear and non-monotonic as well as sequence-dependent alterations in DNA methylation. Future longitudinal studies are needed to link these changes with altered health risks.

Keywords: DNA methylation; bisphenol A; environmental epigenetics.

Figures

Figure 1
Figure 1
schematic overview of experimental design from BPA quantification in human fetal liver tissue through next-generation sequencing and analysis to identify RAMs. ND, non-detect
Figure 2
Figure 2
the chromosomal distribution of hyper-methylated (in red) and hypomethylated (in blue) sites as counted by 100 bp sliding windows per 1 million bp, normalized by chromosome length. (A) Number of windows in the non-detect vs. low groups are normalized to chromosome length and overall reflect the GC density of each chromosome. The majority of windows were hypo-methylated except for chromosome X. (B) Number of windows in the non-detect vs. high BPA groups, similar to (A). (C) Number of windows in low vs. high BPA groups shows a balanced number of hyper- to hypo-methylated regions. Overall data were not tested for significance
Figure 3
Figure 3
overlap of 100 bp windows with RAMs in non-detect vs. low, non-detect vs. high, and low vs. high BPA groups (A) Genome-wide and (B) within 5 kb of TSSs of genes
Figure 4
Figure 4
characterization of genome-wide DNA methylation patterns in CGIs, CGI shores, and CGI shelves. Increasing BPA levels were positively associated with DNA methylation in CGIs and negatively associated with DNA methylation in CGI shores and shelves
Figure 5
Figure 5
genomic distribution of RAMs. TSRs are defined genomic regions where experimentally verified transcriptional initiation has taken place. Exons are regions of coding sequence. Promoters are defined as −500 to +100 of the TSR. Gene locus encompasses the entirety of the gene, including introns. Intergenic regions are defined as regions outside genic and regulatory regions. Repeats are matched against the UCSC Genome Browser RepeatMasker track. (A) A greater percentage of RAMs overlap with exons than TSRs or promoters and have >2-fold higher RAMs overlapping in the relatively higher exposure group, for all comparisons. (B) Among gene locus, intergenic regions, introns, and repeats, only hypermethylated RAMs overlapping with repetitive regions are less in the relatively higher exposure groups
Figure 6
Figure 6
differential methylation at the SNORD gene cluster on chr15. (A) Each row in the upper panel represents the average of the six samples in the group. ND, non-detected BPA; low, low BPA level; high, high BPA level. (B) Four CpG sites within the SNORD cluster were averaged for validation using pyrosequencing. Exact locations are listed in Supplementary Material and Table S2

Similar articles

See all similar articles

Cited by 13 articles

See all "Cited by" articles

References

    1. Barker DJP, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002;31:1235–9. - PubMed
    1. Bateson P, Barker D, Clutton-Brock T, et al. Developmental plasticity and human health. Nature 2004;430:419–21. - PubMed
    1. Low FM, Gluckman PD, Hanson MA. Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases. Epigenomics 2011;3:279–94. - PubMed
    1. Rakyan VK, Blewitt ME, Druker R, et al. Metastable epialleles in mammals. Trends Genet 2002;18:348–51. - PubMed
    1. Faulk C, Dolinoy DC. Timing is everything: the when and how of environmentally induced changes in the epigenome of animals. Epigenetics 2011;6:791–7. - PMC - PubMed
Feedback