Sperm Epimutation Biomarkers of Obesity and Pathologies following DDT Induced Epigenetic Transgenerational Inheritance of Disease

Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination and the incidence of adult onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the F3 generation males were investigated. No pathology was observed in the F1 generation DDT lineage males or females compared with F1 generation controls (vehicle exposure). There was an increase of testis disease and early onset puberty in the F2 generation DDT lineage males. The F3 generation DDT males had significant increases in testis disease, prostate disease, and late onset puberty. The F3 generation DDT females had significant increases in ovarian and kidney disease. Both the F3 generation males and females had significant increases in the frequency of obesity and multiple disease. The F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, kidney disease, and multiple disease pathologies. Outbred gestating female rats were transiently exposed to a vehicle control or DDT The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F3 generation control and DDT lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the DDT lineage sperm from samples with different disease outcomes. MeDIP-seq was used to measure methylation in each sample.