GSE137536
Adipocyte Epigenetic Alterations and Potential Therapeutic Targets in Transgenerationally Inherited Lean and Obese Phenotypes Following Ancestral Exposure to Environmental Toxicants
This study examines the transgenerational adipocyte (fat cell) epigenetic alterations in F3 generation obese and lean rats ancestrally exposed to DDT and atrazine. Adipocytes were isolated from the gonadal fat pad of F3 generation 1-year old rats ancestrally exposed to DDT, atrazine, or vehicle control in order to obtain adipocyte DNA 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. Interestingly, there were epigenetic changes that were distinct when comparing the lean and obese DMRs between the control and exposure lineage groups. DMR gene associations were identified which included common set of genes previously shown to associate with adipocyte pathology. 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. Overall design: Gestating F0 generation rats were exposed to atrazine, DDT, or control vehicle from days 8-14 of gestation. The F1 generation offspring exposed in utero were bred within the exposure lineage colony to produce the intercross F2 generation and subsequent F3 generation. No sibling or cousin crosses were used in order to prevent inbreeding artifacts. Adipocytes were isolated from the gonadal fat pad of the one-year old F3 generation of rats ancestrally exposed to DDT, atrazine, or vehicle control. Obese and lean phenotypes were defined as an increase or decrease in adipocyte area, body mass index (BMI), and observed abdominal adiposity at dissection. The lean, obese and normal (non-obese or non-lean) animals were separated for analysis. Adipocyte DNA was isolated from individuals and then pooled into 5 pools of 2-5 different individuals per phenotypic group. A genome-wide methylated DNA immunoprecipitation and next generation sequencing (MeDIP-Seq) was performed on the samples in order to investigate differences in DNA methylation within the adipocyte DNA.