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, 8 (1), 362-378

Adipocyte Epigenetic Alterations and Potential Therapeutic Targets in Transgenerationally Inherited Lean and Obese Phenotypes Following Ancestral Exposures

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Adipocyte Epigenetic Alterations and Potential Therapeutic Targets in Transgenerationally Inherited Lean and Obese Phenotypes Following Ancestral Exposures

Stephanie E King et al. Adipocyte.

Abstract

The incidence of obesity has increased dramatically over the past two decades with a prevalence of approximately 40% of the adult population within the United States. The current study examines the potential for transgenerational adipocyte (fat cell) epigenetic alterations. Adipocytes were isolated from the gonadal fat pad of the great-grand offspring F3 generation 1-year old rats ancestrally exposed to DDT (dichlorodiphenyltrichloroethane), atrazine, or vehicle control in order to obtain adipocytes for DNA methylation analysis. Observations indicate that there were differential DNA methylated regions (DMRs) in the adipocytes with the lean or obese phenotypes compared to control normal (non-obese or lean) populations. The comparison of epigenetic alterations indicated that there were substantial overlaps between the different treatment lineage groups for both the lean and obese phenotypes. Novel correlated genes and gene pathways associated with DNA methylation were identified, and may aid in the discovery of potential therapeutic targets for metabolic diseases such as obesity. Observations indicate that ancestral exposures during critical windows of development can induce the epigenetic transgenerational inheritance of DNA methylation changes in adipocytes that ultimately may contribute to an altered metabolic phenotype.

Keywords: Adipocyte; Atrazine; DDT; Epigenetics; Etiology; Lean; Obesity; Pathology; Therapeutic Targets; Transgenerational.

Figures

Figure 1.
Figure 1.
DMR identification. The number of DMRs found using different p-value cut-off thresholds. The all window column shows all DMRs. The multiple window column shows the number of DMRs containing at least two significant 1000 bp windows. The lower table of each set shows the number of DMR having each specific number of significant windows at a p-value <1e-05. (a) Control obese female DMR. (b) Control lean female DMR. (c) Control obese male DMR. (d) Control lean male DMRs. (e) DDT obese female DMRs. (f) DDT obese male DMRs. (g) Atrazine lean female DMRs. (h) Atrazine lean male DMR.
Figure 2.
Figure 2.
DMR chromosomal locations. The DMR locations on the individual chromosomes for all DMRs at a p-value threshold of <1e-05. (a) Control obese female DMRs. (b) Control lean female DMRs. (c) Control obese male DMRs. (d) Control lean male DMRs. (e) DDT obese female DMRs. (f) DDT obese male DMRs. (g) Atrazine lean female DMRs. (h) Atrazine lean male DMRs. Red arrowheads indicate positions of DMRs and black boxes indicate clusters of DMRs.
Figure 3.
Figure 3.
DMR overlap. (a) DMR overlap for the obese and normal phenotypes within the control and DDT lineage colonies. (b) DMR overlap for the normal and lean phenotypes within the control and atrazine lineage colonies. (c) DMRs identified at p < 1e-5 overlap with other DMR sets at p-value ≤0.05. Overlap should be examined on the horizontal rows and show DMR numbers and percentages.
Figure 4.
Figure 4.
DMR gene association categories and pathways. All DMRs at a p-value threshold of <1e-05 are shown. (a) Obese versus normal DMR associated gene categories. (b) Lean versus normal DMR associated gene categories. (c) DMR associated gene pathways from KEGG.
Figure 5.
Figure 5.
Common overlap adipocyte DMR associated genes and function. DMR with ≥3 overlaps with other DMR sets/phenotypes presented. The gene name and number of phenotypic associations (DMR sets overlap comparisons) are listed. The description of gene function category and general function presented.
Figure 6.
Figure 6.
DMR gene associations with metabolic disorders. DMR associated gene symbol correlations to metabolic diseases. An arrowhead indicates positive activation and line a negative effect.
Figure 7.
Figure 7.
Gene network of DMR associated gene correlations with obesity. Potential therapeutic targets are suggested, and highly integrated genes indicated with blue circle around the gene(s).

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Grant support

This study was supported by John Templeton Foundation (50183 and 61174) grants to MKS.

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