ERKEN ADÖLESAN VE ADÖLESAN DÖNEMDE FTALAT MARUZİYETİNİN EPİGENETİK MEKANİZMALAR VE METABOLİK PROFİL ÜZERİNDEKİ ETKİLERİNİN İNCELENMESİ

Bu tez çalışması TÜBİTAK-BIDEB 2214-A burs programı, Hacettepe Üniversitesi ÖYP Koordinatörlüğü ve Lokman Hekim Üniversitesi Bilimsel Araştırmalar Birimi (Proje No: 20K00301) tarafından desteklenmiştir.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.Di (2-etil hekzil) ftalat (DEHP), kişisel bakım ürünlerinden oyuncaklara kadar birçok üründe/ambalajında kullanılan ve endokrin bozucu özellikleri olan bir kimyasal maddedir. DEHP ile ilgili yapılan çalışmalar toksisitenin özellikle erkek üreme sistemini hedeflediğini göstermektedir. Bu tez çalışmasında, Sprague Dawley erkek sıçanlar, erken adölesan ve adölesan dönem boyunca 30 mg/kg/gün (DD grubu) ve 60 mg/kg/gün (YD grubu) DEHP’e maruz bırakılarak oluşan toksisitenin sonuçları yetişkinlik döneminde kontrol grubu ile karşılaştırmalı olarak değerlendirilmiştir. Bu doğrultuda, sperm parametrelerindeki değişiklikler, oksidatif stres oluşumu (total glutatyon, total antioksidan kapasite ve lipit peroksidasyonu düzeyleri), histopatolojik ve apoptotik değişiklikler incelenmiştir. Epigenetik değişiklikler irdelenmiş ve metabolomik analizler yapılmıştır. DEHP maruziyeti ile sperm sayı, motilite ve morfolojisinde anlamlı değişimler ve doku hasarına işaret eden histopatolojik değişiklikler meydana gelmiştir. Apoptoz DD ve YD grubunda sırasıyla 3,36 ve 7 kat artmıştır. Total glutatyon düzeyleri DD grubunda değişmezken YD grubunda %46,26 azalmıştır (p<0,05). DD ve YD gruplarında lipit peroksidasyonu (%41,03, %102,7, sırasıyla) ve total antioksidan kapasite (% 9,83, %19,38, sırasıyla) kontrole göre anlamlı düzeyde artmıştır (p<0,05). Metabolomik analizde lipit ve enerji metabolizmasının değiştiği saptanmış ve bu metabolik yolakların en önemli elemanlarından olan peroksizom proliferatör aktive reseptör gamma (PPAR-γ) düzeyleri doza bağlı olarak artmıştır (p<0,05). Her iki grupta da epigenetik profildeki değişimlerin en önemli göstergesi olan global DNA metilasyonlarının doza bağlı olarak azaldığı, histon metilasyon düzeylerinin ise arttığı belirlenmiştir (p<0,05). Bu sonuçlar, yaşamın erken dönemlerinde DEHP’in, oksidatif stres, PPAR-γ, ve epigenetik modifikasyonlar aracılığı ile üreme sistemi üzerinde geri dönüşsüz bir toksisiteye neden olabileceğini göstermekte ve bu etkilerin sonraki nesillere aktarılabileceğine işaret etmektedir

Selenyum, Selenoproteinler ve Hashimoto Tiroiditi

selenium is a trace element that has important functions within the body. it is suggested that there is a link between selenium levels and thyroid functions since the enzymes involved in the synthesis of thyroid hormones are selenoenzymes. selenium is also required for the normal functioning of antioxidant defense mechanisms and the reduction of oxidative stress caused by Hashimoto's thyroiditis. Although studies on selenium supplementation in autoimmune thyroid diseases are limited, the data suggest that selenium treatment may have beneficial effects. in this review the roles of selenium, an important trace element which is essential for many vital functions particularly on the oxidant/ antioxidant balance, on vital functions in the organism, effects on thyroid functions and its use as an alternative treatment or supplement in Hashimoto's thyroiditis will be emphasize

Oxidative stress markers, trace elements, and endocrine disrupting chemicals in children with Hashimoto's thyroiditis.

In this study, we aimed to investigate whether bisphenol A (BPA) and di-(2-ethylhexyl) phthalate (DEHP) exposure have any association with Hashimoto's thyroiditis (HT) and its biomarkers and to determine whether oxidative stress biomarkers and trace element levels showed any alterations in children with HT. We found that superoxide dismutase and glutathione peroxidase activities are lower in HT group from control (24% and 46%, respectively,  < 0.05). Zinc levels were significantly lower in HT group vs. control. In addition, the levels of mono-(2-ethylhexyl) phthalate (MEHP) which is the primary metabolite for DEHP, were markedly higher in HT group compared to control ( < 0.05). A negative correlation was observed between urinary BPA levels and fT4. In children with HT, oxidant/antioxidant balance is changed and these differences may be related by EDC exposure, the importance of which should be elucidated with further studies

Reply to Deng and Tang.

status: Published onlin

Oxidative Stress Parameters, Selenium Levels, DNA Damage, and Phthalate Levels in Plastic Workers.

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate. DEHP is highly used in PVC floorings and PVC windows and carpeting. The objective of this study was to determine sex hormone levels, oxidative stress parameters, selenium levels, DNA damage, and phthalate levels in plastics workers (n = 24, age = 20-58 years) working in the production of rubber mechanical goods and exposed to DEHP in workplace. The control group (n = 29, age = 25-54, all male) was selected from age-matched healthy adults. Antioxidant parameters and DNA damage were determined by spectrophotometry. Selenium levels were determined by atomic absorption spectroscopy. Plasma hormone levels were measured by chemiluminescence microparticle immunoassay. Plasma phthalate levels were determined by high-pressure liquid chromatography. Plastic workers had lower serum testosterone and free T4 levels and higher follicle-stimulating hormone levels vs. controls. Liver enzyme activities were markedly higher in workers vs. controls. There were also increases in plasma glutathione peroxidase levels and marked decreases in plasma selenium and erythrocyte total glutathione levels in plastics workers (P < 0.05 vs. control). Plasma 8-hydroxy-2'-deoxyguanosine levels were 14-fold higher in plastics workers than in controls. Plasma DEHP and mono(2-ethylhexyl)phthalate were also markedly higher in workers vs. controls. The results of this study show that occupational exposure to DEHP may lead to disturbances in sex hormones, increased liver problems, higher oxidative stress and DNA damage levels, and lower trace element concentrations in workers. More comprehensive and mechanistic studies with higher numbers of subjects are needed to show the unwanted effects of occupational exposure to DEHP

Oxidative Stress Parameters, Selenium Levels, DNA Damage, and Phthalate Levels in Plastic Workers.

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate. DEHP is highly used in PVC floorings and PVC windows and carpeting. The objective of this study was to determine sex hormone levels, oxidative stress parameters, selenium levels, DNA damage, and phthalate levels in plastics workers (n = 24, age = 20-58 years) working in the production of rubber mechanical goods and exposed to DEHP in workplace. The control group (n = 29, age = 25-54, all male) was selected from age-matched healthy adults. Antioxidant parameters and DNA damage were determined by spectrophotometry. Selenium levels were determined by atomic absorption spectroscopy. Plasma hormone levels were measured by chemiluminescence microparticle immunoassay. Plasma phthalate levels were determined by high-pressure liquid chromatography. Plastic workers had lower serum testosterone and free T4 levels and higher follicle-stimulating hormone levels vs. controls. Liver enzyme activities were markedly higher in workers vs. controls. There were also increases in plasma glutathione peroxidase levels and marked decreases in plasma selenium and erythrocyte total glutathione levels in plastics workers (P < 0.05 vs. control). Plasma 8-hydroxy-2'-deoxyguanosine levels were 14-fold higher in plastics workers than in controls. Plasma DEHP and mono(2-ethylhexyl)phthalate were also markedly higher in workers vs. controls. The results of this study show that occupational exposure to DEHP may lead to disturbances in sex hormones, increased liver problems, higher oxidative stress and DNA damage levels, and lower trace element concentrations in workers. More comprehensive and mechanistic studies with higher numbers of subjects are needed to show the unwanted effects of occupational exposure to DEHP

Bisphenol A and phthalate levels in adolescents with polycystic ovary syndrome

Endocrine disruptors have been proposed in the etiology of polycystic ovary syndrome (PCOS) as they have the potency to interfere with hormone-sensitivity systems. The aim of this study was to evaluate the levels of bisphenol A (BPA) and phtalates in adolescents with PCOS. Sixty-two girls with PCOS and 33 controls, age 12–18 years were enrolled in the study. The diagnosis of PCOS was made using modified Rotterdam criteria. Urinary BPA levels were measured using high-performance liquid chromatography. Di-(2-ethylhexyl)-phthalate (DEHP), the most commonly used phthalate and mono-(2-ethylhexyl)-phthalate (MEHP), its main metabolite were measured by using high-performance liquid chromatography. Adolescents with PCOS had markedly increased BPA levels (15.89 μg/g creatine ± 1.16) when compared with the control group (7.30 μg/g creatine ± 1.38) (p =.016). In adolescents with PCOS, BPA was significantly correlated with polycystic morphology on ultrasound but not with obesity androgen levels, or other metabolic parameters. Patients with PCOS (DEHP: 0.40 ppm ± 0.24, MEHP: 0.13 ppm ± 0.23) and controls (DEHP: 0.49 ppm ± 0.27, MEHP: 0.14 ppm ± 0.3) had similar serum phtalate concentrations (p =.7 and p =.3, respectively). Exposure to specific endocrine disruptors such as BPA could modify neuroendocrine, reproductive, and metabolic regulation favoring PCOS development in adolescents. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group