Investigation of effects of phthalate exposure on epigenetic mechanisms and metabolic profile in early adolescent and adolescent periods

Di (2-ethyl hexyl) phthalate (DEHP) is a chemical that has endocrine disrupting properties and is widely used in many customer products. Studies on DEHP show that toxicity specifically targets the male reproductive system. In this thesis, preadolescent Sprague Dawley male rats were exposed to 30 mg/kg/day (DD group) and 60 mg/kg/day (YD group) DEHP until the end of adolescence period and the toxicity were evaluated in adulthood by measuring sperm parameters, histopathologic and apoptotic changes, oxidative stress parameters (total glutathione, total antioxidant capacity and lipid peroxidation levels), epigenetic mechanisms and changes in metabolic profile. Significant alterations in sperm count, motility, and morphology in both study group and histopathological changes were observed by DEHP exposure compared to control. Testicular apoptosis increased 3.36 and 7 times in the DD and YD groups, vs control respectively. Total glutathione levels did not change in the DD group, it decreased by 46.26% in the DD group (p <0.05). Lipid peroxidation (41.03%, 102.7%, respectively) and total antioxidant capacity (9.83%, 19.38%, respectively) increased significantly in DD and YD groups compared to control (p <0.05). Metabolomic analysis revealed an altered lipid and energy metabolism. Peroxisome proliferator activated receptor gamma (PPAR-γ) levels as one of the most important elements of these metabolic pathways, were increased depending on the dose (p <0.05). Global DNA hypomethylation and increased histone methylation levels which are the most important indicator of the changes in epigenetic profile, were also observed in both groups (p <0.05). These results indicate that DEHP exposure in the early stages of life causes an irreversible reproductive system toxicity through oxidative stress, PPAR-γ, and epigenetic modifications and these effects may be transgenerationally inherited.