Adipocyte Epigenetic Alterations and Potential Therapeutic Targets in Transgenerationally Inherited Lean and Obese Phenotypes Following Ancestral Exposure to Environmental Toxicants
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ABSTRACT:
PROVIDER: PRJNA565793 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10126700_1.fastq.gz | Fastqsanger.gz | |||
| SRR10126700_2.fastq.gz | Fastqsanger.gz | |||
| SRR10126701_1.fastq.gz | Fastqsanger.gz | |||
| SRR10126701_2.fastq.gz | Fastqsanger.gz | |||
| SRR10126702_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. Methylated sperm DNA was isolated from rats ancestrally exposed to plastics (Bip), vinclozolin (Vip), pesticides (Pip), dioxin (Hip), jet fuel (Jip) or control vehicle (Cip). Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. For each treatment, treated samples were paired with control samples and hybridized together on arrays (Bip1/Cip1, Bip2/Cip2, Bip3/Cip3, Vip1/Cip1, etc.), resulting in three arrays per treatment group.
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