Chapter 7. Impact of Phthalates on Oxidative Stress Metabolism: A Key Mechanism Contributes to the Disease Pathogenesis


Duygu Aydemir and Nuriye Nuray Ulusu
Koc University, School of Medicine, Department of Medical Biochemistry, Sariyer, Istanbul, Turkey
Koç University Research Center for Translational Medicine (KUTTAM), Sariyer, Istanbul, Turkey

Chapter DOI: 10.52305/MMXP2149
Part of the Book: Phthalates: Environmental and Health Effects


Endocrine-disrupting chemicals (EDCs) are xenobiotics found in almost all types of industrial products such as toys, pharmaceuticals, cosmetics, food wrappings, furniture, paints, solvents, plasticizer, and households. Phthalates are the most used chemicals in the industry belonging to the EDCs family. Di(2-ethylhexyl) phthalate (DEHP), di-isononyl phthalate (DiNP), di-n-octyl phthalate (DnOP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), di-n-butyl phthalate (DnBP), benzyl butyl phthalate (BzBP), di-isobutyl phthalate (DiBP) and di-isodecyl phthalate (DiDP) belong to the phthalate family and cause adverse health effects by altering hormone metabolism on human and wildlife. Phthalates have different mechanisms to alter hormone metabolism, including mimicking or antagonizing hormones, altering hormone synthesis, dysregulation of hormone transport, and activation/repression of hormone receptors. Phthalates are metabolized by skin esterases, gut, liver, and kidneys; however, metabolized products of phthalates are very harmful, and some parts of phthalates accumulate in the body without being metabolized. Besides impaired hormone metabolism, phthalates alter oxidative stress metabolism via reducing antioxidant defense, interfering with detoxification pathways, and altering energy metabolism. Peroxisome-proliferator-activated receptors (PPARs) comprise three subtypes (PPARα, δ, and γ) and main regulators of carbohydrate, protein, and oxidative stress metabolisms. Phthalates can bind to PPAR receptors and activate them, causing elevated levels of oxidative stress in the cell. Besides, phthalates may interfere with anti-oxidant enzymes, including glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione s-transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), thioredoxin family, and glutathione peroxidase (GPx) leading to the impaired redox balance in the cell. Oxidative stress is characterized by reduced antioxidant defense and enhanced reactive oxygen species (ROS) contributing to the pathogenesis of various diseases, including diabetes mellitus (DM), cancer, obesity, metabolic syndrome, infertility, cardiovascular diseases, and cancer. This chapter discusses the impact of phthalates on the oxidative stress metabolism involved in the pathogenesis of various diseases, including fertility, metabolic syndrome, diabetes mellitus, cardiovascular diseases, and cancer.

Keywords: phthalates, oxidative stress, antioxidant defense, detoxification, disease pathogenesis


Adeoye, O., Olawumi, J., Opeyemi, A., Christiania, O. 2017. “Review on the Role of Glutathione on Oxidative Stress and Infertility.” JBRA Assisted Reproduction Mar 1;22(1):61-66. doi:10.5935/1518-0557.20180003.

Adrogué, Horacio J., and Nicolaos E. Madias. 2016. “Sodium and Potassium in the Pathogenesis of Hypertension.” Current Opinion in Nephrology and Hypertension, December, 1. doi:10.1097/MNH.0000000000000301.

Amin, M. M., Ebrahimpour, K., Parastar, S., Shoshtari-Yeganeh, B., Hashemi, M., Mansourian, M., Poursafa, P., Fallah, Z., Rafiei, N., Kelishadi, R. 2018. “Association of Urinary Concentrations of Phthalate Metabolites with Cardiometabolic Risk Factors and Obesity in Children and Adolescents.” Chemosphere 211 (November): 547–56. doi:10.1016/j.chemosphere.2018.07.172.

Ashrap, P., Aung, M. T., Watkins, D. J., Mukherjee, B., Rosario-Pabón, Z., Vélez-Vega, C. M., Alshawabkeh, A., Cordero, J. F., Meeker, J. D. 2022. “Maternal Urinary Phthalate Metabolites are Associated with Lipidomic Signatures Among Pregnant Women in Puerto Rico.” J Expo Sci Environ Epidemiol Jan 24. doi: 10.1038/s41370-022-00410-3. Epub ahead of print. PMID: 35075242.

Aydemir, D., Karabulut, G., Şimşek, G., Gok, M., Barlas, N., Ulusu, N. N. 2018. “Impact of the Di(2-Ethylhexyl) Phthalate Administration on Trace Element and Mineral Levels in Relation of Kidney and Liver Damage in Rats.” Biological Trace Element Research 186 (2). doi:10.1007/s12011-018-1331-0.

Aydemir, D., Karabulut, G., Şimşek, G., Gok, M., Barlas, N., Ulusu, N. N. 2019a. “Data the DEHP Induced Changes on the Trace Element and Mineral Levels in the Brain and Testis Tissues of Rats.” Data in Brief Sep 17;26:104526. doi:10.1016/j.dib.2019. 104526.

Aydemir, D., Hashemkhani, M., Acar, H. Y., Ulusu N. N. 2019b. “In Vitro Interaction of Glutathione S-Transferase-Pi Enzyme with Glutathione-Coated Silver Sulfide Quan-tum Dots: A Novel Method for Biodetection of Glutathione S-Transferase Enzyme.” Chemical Biology and Drug Design Dec;94(6):2094-2102. doi:10.1111/ cbdd.13614.

Aydemir, D., Hashemkhani, M., Durmusoglu, E. G., Yagci-Acar, H., Ulusu, N. N. 2019c. “A New Substrate for Glutathione Reductase: Glutathione Coated Ag2S Quantum Dots.” Talanta 194 (March): 501–6. doi:10.1016/j.talanta.2018.10.049.

Aydemir, D., Sarayloo, E., Ulusu, N. N. 2019d. “Rosiglitazone-Induced Changes in the Oxidative Stress Metabolism and Fatty Acid Composition in Relation with Trace Element Status in the Primary Adipocytes.” Journal of Medical Biochemistry Sep 2;39(3):267-275. doi:10.2478/jomb-2019-0041.

Aydemir, D., Oztasci, B., Barlas, N., Ulusu, N. N. 2019e. “Effects of butylparaben on antioxidant enzyme activities and histopathological changes in rat tissues.” Arh Hig Rada Toksikol Dec 1;70(4):315-324. doi: 10.2478/aiht-2019-70-3342. PMID: 32623 865.

Aydemir, D., Oztasci, B., Barlas, N., Ulusu, N. N. 2020a. “Influence of the Butylparaben Administration on the Oxidative Stress Metabolism of Liver, Kidney and Spleen.” Turkish Journal of Biochemistry 45 (6): 689–94. doi:10.1515/tjb-2020-0048.

Aydemir, D., Ulusu, N. N. 2020b. “The Possible Role of The Glucose-6-Phosphate Dehydrogenase Enzyme Deficiency in The Polyneuropathies.” The Journal of Basic and Clinical Health Sciences 4 (3): 212-217. doi:10.30621/jbachs.2020.1151.

Aydemir, D., Malik, A. N., Kulac, I., Basak, A. N., Lazoglu, I., Ulusu, N. N. 2022. “Impact of the ALS Disease on the Biomechanical Properties and Oxidative Stress Metabolism of the Lung Tissue Correlated with the Human Mutant SOD1G93A Protein Accumulation.” Frontiers in Bioengineering and Biotechnology, 89/fbioe.2022.810243.

Baralić, K., Živančević, K., Jorgovanović, D., Javorac, D., Radovanović, J., Gojković, T., Buha Djordjevic, A., Ćurčić, M., Mandinić, Z., Bulat, Z., Antonijević, B., and Đukić-Ćosić, D. 2021. “Probiotic reduced the impact of phthalates and bisphenol A mixture on type 2 diabetes mellitus development: Merging bioinformatics with in vivo analysis.” Food and Chemical Toxicology, 154, 112325. 2021.112325.

Braun, J., M. 2017. “Early-Life Exposure to EDCs: Role in Childhood Obesity and Neurodevelopment.” Nature Reviews Endocrinology 13 (3): 161–73. doi:10.1038/ nrendo.2016.186.

Bursztyka, J., E. Perdu, K. Pettersson, I. Pongratz, M. Fernández-Cabrera, N. Olea, L. Debrauwer, D. Zalko, and J.P. Cravedi. 2008. “Biotransformation of Genistein and Bisphenol A in Cell Lines Used for Screening Endocrine Disruptors.” Toxicology in Vitro 22 (6): 1595–1604. doi:10.1016/j.tiv.2008.06.013.

Cai, X., Young, G. M., and Xie, W. 2021. “The xenobiotic receptors PXR and CAR in liver physiology, an update”. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1867(6), 166101.

Callaghan, M. A., Alatorre-Hinojosa, S., Connors, L. T., Singh, R. D., Thompson, J. A. 2021. “Plasticizers and Cardiovascular Health: Role of Adipose Tissue Dysfunction.” Frontiers in Pharmacology, 11.

Can, B., Ulusu, N. N., Kilinç, K., Leyla Acan, N., Saran, Y., and Turan, B. 2005. “Selenium Treatment Protects Diabetes-Induced Biochemical and Ultrastructural Alterations in Liver Tissue.” Biological Trace Element Research, 105(1–3), 135–150. https://doi. org/10.1385/BTER:105:1-3:135.

Chamorro-Garcia, R., Veiga-Lopez, A. 2021. “The New Kids on the Block: Emerging Obesogens.” Advances in Pharmacology, 29, 457–84. doi:10.1016/bs.apha.2021. 05. 003.

Chang, W.-H., Lee, C.-C., Yen, Y.-H., and Chen, H.-L. 2018. “Oxidative damage in patients with benign prostatic hyperplasia and prostate cancer co-exposed to phthalates and to trace elements.” Environment International, 121, 1179–1184. 10.1016/j.envint.2018.10.034.

Chou, C.-K., Yang, Y.-T., Yang, H.-C., Liang, S.-S., Wang, T.-N., Kuo, P.-L., Wang, H.-M. D., Tsai, E.-M., and Chiu, C.-C. 2018. “The Impact of Di(2-ethylhexyl)phthalate on Cancer Progression.” Archivum Immunologiae et Therapiae Experimentalis, 66(3), 183–197.

Chu, P.-C., Wu, C., and Su, T.-C. 2021. “Association between Urinary Phthalate Metabolites and Markers of Endothelial Dysfunction in Adolescents and Young Adults.” Toxics, 9(2), 33.

Cooper, A.J.L., and M.H. Hanigan. 2018. “Metabolism of Glutathione S-Conjugates: Multiple Pathways.” In Comprehensive Toxicology, 363–406. Elsevier. doi:10.1016/ B978-0-12-801238-3.01973-5.

Darbre, P. D. 2017. “Endocrine Disruptors and Obesity.” Current Obesity Reports 6 (1): 18–27. doi:10.1007/s13679-017-0240-4.

Diamanti-Kandarakis, E., Bourguignon, J.-P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., Zoeller, R. T., and Gore, A. C. 2009. “Endocrine-Disrupting Chemicals: An Endocrine Society Scientific Statement.” Endocrine Reviews, 30(4), 293–342.

Duan, Y., Wang, L., Han, L., Wang, B., Sun, H., Chen, L., Zhu, L., and Luo, Y. 2017. “Exposure to phthalates in patients with diabetes and its association with oxidative stress, adiponectin, and inflammatory cytokines.” Environment International, 109, 53–63.

Dutta, S., Haggerty, D. K., Rappolee, D. A., Ruden, D. M. 2020. “Phthalate Exposure and Long-Term Epigenomic Consequences: A Review.” Frontiers in Genetics 11 (May). doi:10.3389/fgene.2020.00405.

Du, Y., Shi, X., Ma, W., Wen, P., Yu, P., Wang, X., Fang, P., Chen, A., Gao, Z., and Cui, K. 2021. “Phthalates promote the invasion of hepatocellular carcinoma cells by enhancing the interaction between Pregnane X receptor and E26 transformation specific sequence 1.” Pharmacological Research, 169, 105648. 1016/j.phrs.2021.105648.

Eckel, R. H., Grundy, S. M., Zimmet, P.Z. 2005. “The Metabolic Syndrome.” The Lancet 365 (9468): 1415–28. doi:10.1016/S0140-6736(05)66378-7.

Engel, A., Buhrke, T., Imber, F., Jessel, S., Seidel, A., Völkel, W., and Lampen, A. 2017. “Agonistic and Antagonistic Effects of Phthalates and Their Urinary Metabolites on the Steroid Hormone Receptors ERα, ERβ, and AR.” Toxicology Letters, 277, 54–63.

Engel, A., Buhrke, T., Kasper, S., Behr, A.-C., Braeuning, A., Jessel, S., Seidel, A., Völkel, W., and Lampen, A. 2018. “The Urinary Metabolites of DINCH ® Have an İmpact on the Activities of the Human Nuclear Receptors ERα, ERβ, AR, PPARα and PPARγ.” Toxicology Letters, 287, 83–91. 02.006.

Erkekoglu, P., Rachidi, W., Yuzugullu, O. G., Giray, B., Favier, A., Ozturk, M., and Hincal, F. 2010. “Evaluation of Cytotoxicity and Oxidative DNA Damaging Effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig Cells and Protection by Selenium.” Toxicology and Applied Pharmacology, 248(1), 52–62.

Fénichel, P., and Chevalier, N. 2017. “Environmental Endocrine Disruptors: New Diabetogens?” Comptes Rendus Biologies 340 (9–10): 446–52. doi:10.1016/j.crvi. 2017.07.003.

Fernandez-Marcos, P. J., and Nóbrega-Pereira, S. 2016. “NADPH: New Oxygen for the ROS Theory of Aging.” Oncotarget 7 (32): 50814–15. doi:10.18632/oncotarget.107 44.

Forman, H. J., Zhang, H., Rinna, A. 2009a. “Glutathione: Overview of Its Protective Roles, Measurement, and Biosynthesis.” Molecular Aspects of Medicine 30 (1–2): 1–12. doi:10.1016/j.mam.2008.08.006.

Gök, M., Ulusu, N. N., Tarhan, N., Tufan, C., Ozansoy, G., Arı, N., and Karasu, Ç. 2016. “Flaxseed Protects Against Diabetes-Induced Glucotoxicity by Modulating Pentose Phosphate Pathway and Glutathione-Dependent Enzyme Activities in Rats.” Journal of Dietary Supplements, 13(3), 339–351. 1036188.

Gore, A. C., V. A. Chappell, S. E. Fenton, J. A. Flaws, A. Nadal, G. S. Prins, J. Toppari, and R. T. Zoeller. 2015. “EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals.” Endocrine Reviews 36 (6): E1–150. doi:10.1210/er.2015-1010.

Grundy, S. M. 2006. “Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds.” Journal of the American College of Cardiology 47 (6): 1093–1100. doi:10.1016/j.jacc.2005.11.046.

Guo, Y., Weck, J., Sundaram, R., Goldstone, A. E., Buck Louis, G., and Kannan, K. 2014. “Urinary Concentrations of Phthalates in Couples Planning Pregnancy and Its Association with 8-Hydroxy-2′-deoxyguanosine, a Biomarker of Oxidative Stress: Longitudinal Investigation of Fertility and the Environment Study.” Environmental Science & Technology, 48(16), 9804–9811.

Güven, C., Dal, F., Aydoğan Ahbab, M., Taskin, E., Ahbab, S., Adin Çinar, S., Sırma Ekmekçi, S., Güleç, Ç., Abacı, N., Akçakaya, H. 2016. “Low dose monoethyl phthalate (MEP) exposure triggers proliferation by activating PDX-1 at 1.1B4 human pancreatic beta cells.” Food and Chemical Toxicology, 93, 41–50. 10.1016/j.fct.2016.04.023.

Hannon, P. R., Flaws, J.A. 2015. “The Effects of Phthalates on the Ovary.” Frontiers in Endocrinology 6 (February). doi:10.3389/fendo.2015.00008.

Harris, R., Turan, N., Kirk, C., Ramsden, D., and Waring, R. 2007. “Effects of Endocrine Disruptors on Dehydroepiandrosterone Sulfotransferase and Enzymes Involved in PAPS Synthesis: Genomic and Nongenomic Pathways.” Environmental Health Perspectives, 115(Suppl 1), 51–54.

Haverinen, E., Paalanen, L., Palmieri, L., Padron-Monedero, A., Noguer-Zambrano, I., Sarmiento Suárez, R., and Tolonen, H. 2021. “Comparison of Metabolic Syndrome Prevalence Using Four Different Definitions – A Population-Based Study in Finland.” Archives of Public Health, 79(1), 231.

Hsieh, T.-H., Hsu, C.-Y., Yang, P.-J., Chiu, C.-C., Liang, S.-S., Ou-Yang, F., Kan, J.-Y., Hou, M.-F., Wang, T.-N., and Tsai, E.-M. 2022. “DEHP Mediates Drug Resistance by Directly Targeting AhR in Human Breast Cancer.” Biomedicine & Pharma-cotherapy, 145, 112400.

Huang, P. L. 2009. “A Comprehensive Definition for Metabolic Syndrome.” Disease Models & Mechanisms 2 (5–6): 231–37. doi:10.1242/dmm.001180.

Huang, Y.-C., Huang, P.-R., Lo, Y.-T. C., Sun, C.-W., Pan, W.-H., Wang, S.-L., and Huang, H.-B. 2021. “Food Processing and Phthalate Exposure: The Nutrition and Health Survey in Taiwan (1993–1996 and 2005–2008).” Frontiers in Nutrition, 8.

Huffman, A. M., Wu, H., Rosati, A., Rahil, T., Sites, C. K., Whitcomb, B. W., and Richard Pilsner, J. 2018. “Associations of urinary phthalate metabolites and lipid peroxidation with sperm mitochondrial DNA copy number and deletions.” Environmental Research, 163, 10–15.

Jadhao, M., Tsai, E.-M., Yang, H.-C., Chen, Y.-F., Liang, S.-S., Wang, T.-N., Teng, Y.-N., Huang, H.-W., Wang, L.-F., and Chiu, C.-C. 2021. “The Long-Term DEHP Exposure Confers Multidrug Resistance of Triple-Negative Breast Cancer Cells through ABC Transporters and Intracellular ROS.” Antioxidants, 10(6), 949. 3390/antiox10060949.

Jaimes, R., Swiercz, A., Sherman, M., Muselimyan, N., Marvar, P. J., and Posnack, N. G. 2017. “Plastics and Cardiovascular Health: Phthalates May Disrupt Heart Rate Variability and Cardiovascular Reactivity.” American Journal of Physiology-Heart and Circu-latory Physiology, 313(5), H1044–H1053. art.00364.2017.

James, M. O. 2021. “Drug Metabolism: Phase II Enzymes.” In Reference Module in Biomedical Sciences. Elsevier. doi:10.1016/B978-0-12-820472-6.00123-7.

James-Todd, T., Ponzano, M., Bellavia, A., Williams, P. L., Cantonwine, D. E., Calafat, A. M., Hauser, R., Quinn, M. R., Seely, E. W., and McElrath, T. F. 2022. “Urinary Phthalate and DINCH Metabolite Concentrations and Gradations of Maternal Glucose İntolerance.” Environment International, 161, 107099. nt.2022.107099.

Katsikantami, I., Sifakis, S., Tzatzarakis, M. N., Vakonaki, E., Kalantzi, O.-I., Tsatsakis, A. M., and Rizos, A. K. 2016. “A Global Assessment of Phthalates Burden and Related Links to Health Effects.” Environment International, 97, 212–236. 10.1016/j.envint.2016.09.013.

Kim, T. 2013. “Peroxisome-Proliferator-Activated Receptors Regulate Redox Signaling in the Cardiovascular System.” World Journal of Cardiology 5 (6): 164. doi:10.4330/ wjc.v5.i6.164.

Klaassen, C. D., Boles, J. W. 1997. “The Importance of 3‘‐phosphoadenosine 5‘‐phosphosulfate (PAPS) in the Regulation of Sulfation.” The FASEB Journal 11 (6): 404–18. doi:10.1096/fasebj.11.6.9194521.

Klöting, N., Hesselbarth, N., Gericke, M., Kunath, A., Biemann, R., Chakaroun, R., Kosacka, J., Kovacs, P., Kern, M., Stumvoll, M., Fischer, B., Rolle-Kampczyk, U., Feltens, R., Otto, W., Wissenbach, D. K., von Bergen, M., and Blüher, M. 2015. “Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites.” Plos One 10(12), e0143190. pone.0143190.

Ko, N.-Y., Lo, Y.-T. C., Huang, P.-C., Huang, Y.-C., Chang, J.-L., and Huang, H.-B. 2019. “Changes in İnsulin Resistance Mediate the Associations between Phthalate Exposure and Metabolic Syndrome.” Environmental Research, 175, 434–441. 10.1016/j.envres.2019.04.022.

Kobo, O., Leiba, R., Avizohar, O., and Karban, A. 2019. “Normal Body Mass İndex (BMI) Can Rule Out Metabolic Syndrome.” Medicine, 98(9), e14712. 97/MD.0000000000014712.

Kondolot, M., Ozmert, E. N., Ascı, A., Erkekoglu, P., Oztop, D. B., Gumus, H., Kocer-Gumusel, B., and Yurdakok, K. 2016. “Plasma Phthalate and Bisphenol A Levels and Oxidant-Antioxidant Status in Autistic Children.” Environmental Toxicology and Pharmacology, 43, 149–158.

Küblbeck, J., Niskanen, J., Honkakoski, P. 2020. “Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR.” Cells 9 (10): 2306. doi:10.3390/cells 9102306.

Lee, H.-R., Hwang, K.-A., and Choı, K.-C. 2014. “The Estrogen Receptor Signaling Pathway Activated by Phthalates is Linked with Transforming Growth Factor-Β in the Progression of LNCaP Prostate Cancer Models.” International Journal of Oncology, 45(2), 595–602.

Liang, Q.-X., Lin, Y., Fang, X.-M., Gao, Y.-H., and Li, F. 2022. “Association Between Phthalate Exposure in Pregnancy and Gestational Diabetes: A Chinese Cross-Sect-ional Study.” International Journal of General Medicine, Volume 15, 179–189.

Liu, G., Cai, W., Liu, H., Jiang, H., Bi, Y., and Wang, H. 2021. “The Association of Bisphenol A and Phthalates with Risk of Breast Cancer: A Meta-Analysis.” Inter-national Journal of Environmental Research and Public Health, 18(5), 2375.

Lock, E.A. 2010. “Renal Xenobiotic Metabolism.” In Comprehensive Toxicology, 55–79. Elsevier. doi:10.1016/B978-0-08-046884-6.00803-4.

Lu, X., Xu, X., Lin, Y., Zhang, Y., and Huo, X. 2018. “Phthalate Exposure as a Risk Factor for Hypertension.” Environmental Science and Pollution Research, 25(21), 20550–20561.

Mariana, M., and Cairrao, E. 2020. “Phthalates Implications in the Cardiovascular System.” Journal of Cardiovascular Development and Disease, 7(3), 26. 3390/jcdd7030026.

Meli, R., Monnolo, A., Annunziata, C., Pirozzi, C., and Ferrante, M. C. 2020. “Oxidative Stress and BPA Toxicity: An Antioxidant Approach for Male and Female Reproductive Dysfunction.” Antioxidants, 9(5), 405. 9050405.

Monserrat-Mesquida, M., Quetglas-Llabrés, M., Capó, X., Bouzas, C., Mateos, D., Pons, A., Tur, J. A., and Sureda, A. 2020. “Metabolic Syndrome is Associated with Oxidative Stress and Proinflammatory State.” Antioxidants, 9(3), 236. 10.3390/antiox9030236.

Moolna, A., Bowsher, C. G. 2010. “The Physiological Importance of Photosynthetic Ferredoxin NADP+ Oxidoreductase (FNR) Isoforms in Wheat.” Journal of Experimental Botany 61 (10): 2669–81. doi:10.1093/jxb/erq101.

Oesch-Bartlomowicz, B., Oesch, F. 2007. “Mechanisms of Toxification and Detoxification Which Challenge Drug Candidates and Drugs.” In Comprehensive Medicinal Chemistry II, 193–214. Elsevier. doi:10.1016/B0-08-045044-X/00124-3.

Ozcan, M., Aydemir, D., Bacanlı, M., Anlar, H. G., Ulusu, N. N., and Aksoy, Y. 2021. “Protective Effects of Antioxidant Chlorophyllin in Chemically Induced Breast Cancer Model In vivo.” Biological Trace Element Research, 199(12), 4475–4488.

Panagiotou, E. M., Ojasalo, V., Damdimopoulou, P. 2021. “Phthalates, Ovarian Function and Fertility in Adulthood.” Best Practice & Research Clinical Endocrinology & Metabolism, 35(5), 101552.

Patel, R., Parmar, N., Pramanik Palit, S., Rathwa, N., Ramachandran, A. V., and Begum, R. 2022. “Diabetes Mellitus and Melatonin: Where Are We?” Biochimie. https://doi. org/10.1016/j.biochi.2022.01.001.

Philips, Elise M., Vincent W.V. Jaddoe, and Leonardo Trasande. 2017. “Effects of Early Exposure to Phthalates and Bisphenols on Cardiometabolic Outcomes in Pregnancy and Childhood.” Reproductive Toxicology 68 (March): 105–18. doi:10.1016/j.rep rotox.2016.08.015.

Pigini, D., Caporossi, L., Paci, E., Capanna, S., Viganò, P., Alteri, A., Rabellotti, E., Buonaurio, F., Papaleo, B., and Tranfo, G. 2022. “Phthalate Exposure and Biomarkers of Oxidation of Nucleic Acids: Results on Couples Attending a Fertility Center.” Toxics, 10(2), 61.

Predieri, B., Bruzzi, P., Bigi, E., Ciancia, S., Madeo, S. F., Lucaccioni, L., and Iughetti, L. 2020. “Endocrine Disrupting Chemicals and Type 1 Diabetes.” International Journal of Molecular Sciences, 21(8), 2937.

Rengarajan, S., Parthasarathy, C., Anitha, M., Balasubramanian, K. 2007. “Diethylhexyl Phthalate İmpairs İnsulin Binding and Glucose Oxidation in Chang Liver Cells.” Toxicology in Vitro, 21(1), 99–102.

Reuter, S., Gupta, S. C., Chaturvedi, M. M., and Aggarwal, B. B. 2010. “Oxidative Stress, İnflammation, and Cancer: How Are They Linked?” Free Radical Biology and Medicine, 49(11), 1603–1616.

Rusyn, I., Peters, J. M., and Cunningham, M. L. 2006. “Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver.” Critical Reviews in Toxicology, 36(5), 459–479.

Saccoccia, F., Angelucci, F., Boumis, G., Carotti, D., Desiato, G., Miele, A., and Bellelli, A. 2014. “Thioredoxin Reductase and Its Inhibitors.” Current Protein & Peptide Science, 15(6), 621–646.

Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K., Shaw, J. E., Bright, D., and Williams, R. 2019. “Global and Regional Diabetes Prevalence Estimates for 2019 and Projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.” Diabetes Research and Clinical Practice, 157, 107843. 10.1016/j.diabres.2019.107843.

Saklayen, M. G. 2018. “The Global Epidemic of the Metabolic Syndrome.” Current Hypertension Reports 20 (2): 12. doi:10.1007/s11906-018-0812-z.

Schmidt, J.-S., Schaedlich, K., Fiandanese, N., Pocar, P., and Fischer, B. 2012. “Effects of Di(2-ethylhexyl) Phthalate (DEHP) on Female Fertility and Adipogenesis in C3H/N Mice.” Environmental Health Perspectives, 120(8), 1123–1129. 89/ehp.1104016.

Schmidt, N., Page, D., Tiehm, A. 2017. “Biodegradation of Pharmaceuticals and Endocrine Disruptors with Oxygen, Nitrate, Manganese (IV), Iron (III) and Sulfate as Electron Acceptors.” Journal of Contaminant Hydrology 203 (August): 62–69. doi:10.1016/ j.jconhyd.2017.06.007.

Serrano, S. E., Braun, J., Trasande, L., Dills, R., and Sathyanarayana, S. 2014. “Phthalates and Diet: A Review of the Food Monitoring and Epidemiology Data.” Environmental Health, 13(1), 43.

Stojanoska, M. M., Milosevic, N., Milic, N., and Abenavoli, L. 2017. “The İnfluence of Phthalates and Bisphenol A on the Obesity Development and Glucose Metabolism Disorders.” Endocrine, 55(3), 666–681.

Sui, Y., Meng, Z., Chen, J., Liu, J., Hernandez, R., Gonzales, M. B., Gwag, T., Morris, A. J., and Zhou, C. 2021. “Effects of Dicyclohexyl Phthalate Exposure on PXR Acti-vation and Lipid Homeostasis in Mice.” Environmental Health Perspectives, 129(12).

Tandoğan, B., Kuruüzüm-Uz, A., Sengezer, C., Güvenalp, Z., Demirezer, L. Ö., and Nuray Ulusu, N. 2011. “In vitro Effects of Rosmarinic Acid on Glutathione Reductase and Glucose 6-Phosphate Dehydrogenase.” Pharmaceutical Biology, 49(6), 587–594.

Tandoğan, B., Ulusu, N. N. 2007. “The Inhibition Kinetics of Yeast Glutathione Reductase by Some Metal Ions.” Journal of Enzyme Inhibition and Medicinal Chemistry 22 (4): 489–95. doi:10.1080/14756360601162147.

Tandoğan, B., Ulusu, N. N. 2010. “Purification and Kinetics of Bovine Kidney Cortex Glutathione Reductase.” Protein & Peptide Letters 17 (5): 667–74. doi:10.2174/09298 6610791112684.

Tang, X., Wu, S., Shen, L., Wei, Y., Cao, X., Wang, Y., Long, C., Zhou, Y., Li, D., Huang, F., Liu, B., and Wei, G. 2018. “Di-(2-ethylhexyl) Phthalate (DEHP)-İnduced Testicular Toxicity through Nrf2-Mediated Notch1 Signaling Pathway in Sprague-Dawley Rats.” Environmental Toxicology, 33(7), 720–728. 1002/tox.22559.

Tsai, C.-F., Hsieh, T.-H., Lee, J.-N., Hsu, C.-Y., Wang, Y.-C., Lai, F.-J., Kuo, K.-K., Wu, H.-L., Tsai, E.-M., and Kuo, P.-L. 2014. “Benzyl Butyl Phthalate İnduces Migration, İnvasion, and Angiogenesis of Huh7 Hepatocellular Carcinoma Cells through Nongenomic AhR/G-Protein Signaling.” BMC Cancer, 14(1), 556. 1186/1471-2407-14-556.

Turan, B., Acan, N. L., Ulusu, N. N., and Tezcan, E. F. 2001. “A Comparative Study on Effect of Dietary Selenium and Vitamin E on Some Antioxidant Enzyme Activities of Liver and Brain Tissues.” Biological Trace Element Research, 81(2), 141–152.

Ulusu, N. N., Acan, N. L., Turan, B., and Tezcan, E. F. 2003. “Inhibition of Glutathione Reductase by Cadmium Ion in Some Rabbit Tissues and the Protective Role of Dietary Selenium.” Biological Trace Element Research, 91(2), 151–156. 85/BTER:91:2:151.

Ulusu, N. N., Turan, B. 2005. “Beneficial Effects of Selenium on Some Enzymes of Diabetic Rat Heart.” Biological Trace Element Research 103 (3): 207–16. doi:10.13 85/BTER:103:3:207.

Wallner, P., Kundi, M., Hohenblum, P., Scharf, S., and Hutter, H.-P. 2016. “Phthalate Metabolites, Consumer Habits and Health Effects.” International Journal of Environ-mental Research and Public Health, 13(7), 717. 70717.

Wang, Y.-X., Zeng, Q., Sun, Y., You, L., Wang, P., Li, M., Yang, P., Li, J., Huang, Z., Wang, C., Li, S., Dan, Y., Li, Y.-F., and Lu, W.-Q. 2016. “Phthalate Exposure in Association with Serum Hormone Levels, Sperm DNA Damage and Spermatozoa Apoptosis: A Cross-Sectional Study in China.” Environmental Research, 150, 557–565.

Xia, B., Zhu, Q., Zhao, Y., Ge, W., Zhao, Y., Song, Q., Zhou, Y., Shi, H., and Zhang, Y. 2018. “Phthalate Exposure and Childhood Overweight and Obesity: Urinary Meta-bolomic Evidence.” Environment International, 121, 159–168. 16/j.envint.2018.09.001.

Yuan, X.-Q., Du, Y.-Y., Liu, C., Guo, N., Teng, X.-M., Hua, X., Yao, Y.-C., Deng, Y.-L., Zeng, Q., Deng, T.-R., and Li, Y.-F. 2020. “Phthalate Metabolites and Biomarkers of Oxidative Stress in the Follicular Fluid of Women Undergoing İn vitro Fertilization.” Science of The Total Environment, 738, 139834. 2020.139834.

Zhang, H., Ben, Y., Han, Y., Zhang, Y., Li, Y., Chen, X. 2022. “Phthalate Exposure and Risk of Diabetes Mellitus: Implications from a Systematic Review and Meta-Analysis.” Environmental Research, 204, 112109. 2021. 112109.

Zhong, L., Holmgren, A. 2000. “Essential Role of Selenium in the Catalytic Activities of Mammalian Thioredoxin Reductase Revealed by Characterization of Recombinant Enzymes with Selenocysteine Mutations.” Journal of Biological Chemistry, 275(24), 18121–18128.

Zhu, M., Huang, C., Ma, X., Wu, R., Zhu, W., Li, X., Liang, Z., Deng, F., Wu, J., Geng, S., Xie, C., and Zhong, C. 2018. “Phthalates Promote Prostate Cancer Cell Prolif-eration through Activation of ERK5 and p38.” Environmental Toxicology and Pharmacology, 63, 29–33.



Categories: ,