Potential influence of the phthalates on normal liver function and cardiometabolic risk in males

  • Nataša Milošević
  • Nataša MilićEmail author
  • Dragana Živanović Bosić
  • Ivana Bajkin
  • Ivanka Perčić
  • Ludovico Abenavoli
  • Milica Medić Stojanoska


Phthalates are ubiquitous environmental contaminants, massively used in industry as plasticizers and additives in cosmetics, which may impair the human endocrine system inducing fertility problems, respiratory diseases, obesity, and neuropsychological disorders. The aim of this study was to examine the influence of the monoethyl phthalate (MEP) and mono-(2-ethylhexyl) phthalate (MEHP) on the liver function and cardiometabolic risk factors in males. In this research, 102 male participants (51 normal weight and 51 overweight/obese) were enrolled and examined for phthalate metabolites exposure in urine samples after 12 h of fasting. MEP was found in 28.43% (29/102) volunteers, while MEHP was detected among 20.59% (21/102) participants. Statistically significant increment in transaminase serum levels was observed in MEP-positive normal weight subgroup. Linear correlation was obtained between MEP concentration in urine samples and triglyceride (TG) serum levels (r 2 = 0.33; p < 0.01), visceral adiposity index (VAI) (r 2 = 0.41; p < 0.01), lipid accumulation product (LAP) (r 2 = 0.32; p < 0.01), and TG to high-density lipoprotein (HDL) ratio (r 2 = 0.40, p < 0.01) among the obese. The MEHP-positive normal weight volunteers had statistically significant increment of body mass index (p = 0.03) compared to MEHP-negative participants. Urine MEHP concentrations were negatively correlated with HDL serum levels (r 2 = 0.31; p < 0.05) in the normal weight subgroup. The phthalates exposure may be related to statistically significant ALT and AST serum levels increment as well as with increased BMI, while the phthalate levels in the urine may be correlated with increased TG and decreased HDL cholesterol serum levels and associated with indicators of cardiometabolic risk and insulin resistance as LAP and VAI.


Phthalates Endocrine disrupting chemicals Liver damage Insulin resistance Cardiometabolic risk factors 



This research has been financially supported by the Provincial Secretariat for Science and Technological Development, AP Vojvodina, Republic of Serbia, Grant No 114-451-2216/2016.


  1. Amato, M. C., & Giordano, C. (2014). International Journal of Endocrinology, Article ID 730827, 7 pages.Google Scholar
  2. Barr, D. B., Wilder, L. C., Caudill, S. P., Gonzalez, A. J., Needham, L. L., & Pirkle, J. L. (2005). Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environmental Health Perspectives, 113(2), 192–200.CrossRefGoogle Scholar
  3. Barrett, J. R. (2005). Chemical exposures: the ugly side of beauty products. Environmental Health Perspectives, 113(1), A24. Scholar
  4. Blount, B. C., Silva, M. J., Caudill, S. P., Needham, L. L., Pirkle, J. L., Sampson, E. J., Lucier, G. W., Jackson, R. J., & Brock, J. W. (2000). Levels of seven urinary phthalate metabolites in a human reference population. Environmental Health Perspectives, 108(10), 979–982. Scholar
  5. Braga-Basaria, M., Dobs, A. S., Muller, D. C., Carducci, M. A., John, M., Egan, J., & Basaria, S. (2006). Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 24(24), 3979–3983. Scholar
  6. Burgert, T. S., Taksali, S. E., Dziura, J., Goodman, T. R., Yeckel, C. W., Papademetris, X., Constable, R. T., Weiss, R., Tamborlane, W. V., Savoye, M., Seyal, A. A., & Caprio, S. (2006). Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. The Journal of Clinical Endocrinology and Metabolism, 91(11), 4287–4294. Scholar
  7. Buser, M. C., Murray, H. E., & Scinicariello, F. (2014). Age and sex differences in childhood and adulthood obesity association with phthalates: analyses of NHANES 2007-2010. International Journal of Hygiene and Environmental Health, 217(6), 687–694. Scholar
  8. Campins Falcó, P., Tortajada Genaro, L. A., Meseger Lloret, S., Blasco Gomez, F., Sevillano Cabeza, A., & Molins Legua, C. (2001). Creatinine determination in urine samples by batchwise kinetic procedure and flow injection analysis using the Jaffé reaction: chemometric study. Talanta, 55(6), 1079–1089. Scholar
  9. Chaturvedi, N. K., Kumar, S., Negi, S., & Tyagi, R. K. (2010). Endocrine disruptors provoke differential modulatory responses on androgen receptor and pregnane and xenobiotic receptor: potential implications in metabolic disorders. Molecular and Cellular Biochemistry, 345(1–2), 291–308. Scholar
  10. Chen, H., Zhang, W., Rui, B. B., Yang, S. M., Xu, W. P., & Wei, W. (2016). Di(2-ethylhexyl) phthalate exacerbates non-alcoholic fatty liver in rats and its potential mechanisms. Environmental Toxicology and Pharmacology, 42, 38–44. Scholar
  11. Clark, J. M., Brancati, F. L., & Diehl, A. M. (2003). The prevalence and etiology of elevated aminotransferase levels in the United States. The American Journal of Gastroenterology, 98(5), 960–967. Scholar
  12. De Lorenzo, A., Soldati, L., Sarlo, F., Calvani, M., Di Lorenzo, N., & Di Renzo, L. (2016). New obesity classification criteria as a tool for bariatric surgery indication. World Journal of Gastroenterology, 22(2), 681–703. Scholar
  13. Du, T., Yuan, G., Zhang, M., Zhou, X., Sun, X., & Yu, X. (2014). Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance. Cardiovascular Diabetology, 13(1), 146. Scholar
  14. Erkekoglu, P., Giray, B. K., Kizilgun, M., Hininger-Favier, I., Rachidi, W., Roussel, A. M., Favier, A., & Hincal, F. (2012). Thyroidal effects of di-(2-ethylhexyl) phthalate in rats of different selenium status. Journal of Environmental Pathology, Toxicology and Oncology: Official Organ of the International Society for Environmental Toxicology and Cancer, 31(2), 143–153. Scholar
  15. Fei, C., McLaughlin, J. K., Tarone, R. E., & Olsen, J. (2007). Perfluorinated chemicals and fetal growth: a study within the Danish national birth cohort. Environmental Health Perspectives, 115(11), 1677–1682. Scholar
  16. Foster, P. M. (2006). Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. International Journal of Andrology, 29(1), 140–147. Scholar
  17. Foster, P. M., Mylchreest, E., Gaido, K. W., & Sar, M. (2001). Effects of phthalate esters on the developing reproductive tract of male rats. Human Reproduction Update, 7(3), 231–235. Scholar
  18. Frederiksen, H., Skakkebaek, N. E., & Andersson, A. M. (2007). Metabolism of phthalates in humans. Molecular Nutrition & Food Research, 51(7), 899–911. Scholar
  19. Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., Nakayama, O., Makishima, M., Matsuda, M., & Shimomura, I. (2004). Increased oxidative stress in obesity and its impact on metabolic syndrome. The Journal of Clinical Investigation, 114(12), 1752–1761. Scholar
  20. Genuis, S. J., Beesoon, S., Lobo, R. A., & Birkholz, D. (2012). Human elimination of phthalate compounds: blood, urine, and sweat (BUS) study. The Scientific World Journal, 2012, 615068.CrossRefGoogle Scholar
  21. Giboney, P. T. (2005). Mildly elevated liver transaminase levels in the asymptomatic patient. American Family Physician, 71(6), 1105–1110.Google Scholar
  22. Giulivo, M., Lopez de Alda, M., Capri, E., & Barceló, D. (2016). Human exposure to endocrine disrupting compounds: their role in reproductive systems, metabolic syndrome and breast cancer. A review. Environmental Research, 151, 251–264. Scholar
  23. Goodman, M., Lakind, J. S., & Mattison, D. R. (2014). Do phthalates act as obesogens in humans? A systematic review of the epidemiological literature. Critical Reviews in Toxicology, 44(2), 151–175. Scholar
  24. Gray Jr., L. E., Ostby, J., Furr, J., Price, M., Veeramachaneni, D. N., & Parks, L. (2000). Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicological Sciences: an Official Journal of the Society of Toxicology, 58(2), 350–365. Scholar
  25. Guerrero-Romero, F., Simental-Mendia, L. E., Gonzalez-Ortiz, M., Martinez-Abundis, E., Ramos-Zavala, M. G., Hernandez-Gonzalez, S. O., et al. (2010). The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. The Journal of Clinical Endocrinology and Metabolism, 95(7), 3347–3351. Scholar
  26. Han, S. W., Lee, H., Han, S. Y., Lim, D. S., Jung, K. K., Kwack, S. J., et al. (2009). An exposure assessment of di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in human semen. Journal of Toxicology and Environmental Health Part A, 72(21–22), 1463–1469.CrossRefGoogle Scholar
  27. Hanley, A. J., Williams, K., Festa, A., Wagenknecht, L. E., D'Agostino Jr., R. B., Kempf, J., et al. (2004). Elevations in markers of liver injury and risk of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes, 53(10), 2623–2632. Scholar
  28. Hassanein, T., & Frederick, T. (2004). Mitochondrial dysfunction in liver disease and organ transplantation. Mitochondrion, 4(5–6), 609–620. Scholar
  29. Hatch, E. E., Nelson, J. W., Qureshi, M. M., Weinberg, J., Moore, L. L., Singer, M., & Webster, T. F. (2008). Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999-2002. Environmental Health: a Global Access Science Source, 7(1), 27. Scholar
  30. Hatch, E. E., Nelson, J. W., Stahlhut, R. W., & Webster, T. F. (2010). Association of endocrine disruptors and obesity: perspectives from epidemiological studies. International Journal of Andrology, 33(2), 324–332. Scholar
  31. Hauser, R., Duty, S., Godfrey-Bailey, L., & Calafat, A. M. (2004a). Medications as a source of human exposure to phthalates. Environmental Health Perspectives, 112(6), 751–753. Scholar
  32. Hauser, R., Meeker, J. D., Park, S., Silva, M. J., & Calafat, A. M. (2004b). Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environmental Health Perspectives, 112(17), 1734–1740. Scholar
  33. Hauser, R., Meeker, J. D., Duty, S., Suva, M. J., & Calafat, A. M. (2006). Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology, 17(6), 682–691. Scholar
  34. Hernández-Díaz, S., Mitchell, A. A., Kelley, K. E., Calafat, A. M., & Hauser, R. (2009). Medications as a potential source of exposure to phthalates in the U.S. population. Environmental Health Perspectives, 117(2), 185–189. Scholar
  35. Huang, T., Saxena, A. R., Isganaitis, E., & James-Todd, T. (2014). Gender and racial/ethnic differences in the associations of urinary phthalate metabolites with markers of diabetes risk: National Health and Nutrition Examination Survey 2001-2008. Environmental Health: a Global Access Science Source, 13(1), 6. Scholar
  36. Hurst, C. H., & Waxman, D. J. (2003). Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicological Sciences: an Official Journal of the Society of Toxicology, 74(2), 297–308. Scholar
  37. Ibhazehiebo, K., & Koibuchi, N. (2006). Thyroid hormone receptor-mediated transcription is suppressed by low dose phthalate. Nigerian Journal of Physiological Sciences: Official Publication of the Physiological Society of Nigeria, 26, 143–149.Google Scholar
  38. James-Todd, T., Stahlhut, R., Meeker, J. D., Powell, S. G., Hauser, R., Huang, T., & Rich-Edwards, J. (2012). Urinary phthalate metabolite concentrations and diabetes among women in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. Environmental Health Perspectives, 120(9), 1307–1313. Scholar
  39. James-Todd, T. M., Huang, T., Seely, E. W., & Saxena, A. R. (2016). The association between phthalates and metabolic syndrome: the National Health and Nutrition Examination Survey 2001-2010. Environmental Health, 15(1), 52. Scholar
  40. Jay, D., Hitomi, H., & Griendling, K. K. (2006). Oxidative stress and diabetic cardiovascular complications. Free Radical Biology & Medicine, 40(2), 183–192. Scholar
  41. Kahn, H. S. (2005). The “lipid accumulation product” performs better than the body mass index for recognizing cardiovascular risk: a population-based comparison. BMC Cardiovascular Disorders, 5(1), 26. Scholar
  42. Kato, K., Silva, M. J., Needham, L. L., & Calafat, A. M. (2006). Quantifying phthalate metabolites in human meconium and semen using automated off-line solid-phase extraction coupled with on-line SPE and isotope-dilution high-performance liquid chromatography—tandem mass spectrometry. Analytical Chemistry, 78(18), 6651–6655. Scholar
  43. Katsikantami, I., Sifakis, S., Tzatzarakis, M. N., Vakonaki, E., Kalantzi, O. I., Tsatsakis, A. M. et al. (2016). A global assessment of phthalates burden and related links to health effects. Environment International.Google Scholar
  44. Keith, S. W., Redden, D. T., Katzmarzyk, P. T., Boggiano, M. M., Hanlon, E. C., Benca, R. M., Ruden, D., Pietrobelli, A., Barger, J. L., Fontaine, K. R., Wang, C., Aronne, L. J., Wright, S. M., Baskin, M., Dhurandhar, N. V., Lijoi, M. C., Grilo, C. M., DeLuca, M., Westfall, A. O., & Allison, D. B. (2006). Putative contributors to the secular increase in obesity: exploring the roads less traveled. International Journal of Obesity: Journal of the International Association for the Study of Obesity, 30(11), 1585–1594. Scholar
  45. Kim, S. M., Yoo, J. A., Baek, J. M., & Cho, K. H. (2015). Diethyl phthalate exposure is associated with embryonic toxicity, fatty liver changes, and hypolipidemia via impairment of lipoprotein functions. Toxicology In Vitro: an International Journal Published in Association with BIBRA, 30(1), 383–393. Scholar
  46. Kuo, C. C., Moon, K., Thayer, K. A., & Navas-Acien, A. (2013). Environmental chemicals and type 2 diabetes: an updated systematic review of the epidemiologic evidence. Current Diabetes Reports, 13(6), 831–849. Scholar
  47. Kwack, S. J., Han, E. Y., Park, J. S., Bae, J. Y., Ahn, I. Y., Lim, S. K., Kim, D. H., Jang, D. E., Choi, L., Lim, H. J., Kim, T. H., Patra, N., Park, K. L., Kim, H. S., & Lee, B. M. (2010). Comparison of the short term toxicity of phthalate diesters and monoesters in sprague-dawley male rats. Toxicological Research, 26(1), 75–82. Scholar
  48. Lapinskas, P. J., Brown, S., Leesnitzer, L. M., Blanchard, S., Swanson, C., Cattley, R. C., & Corton, J. C. (2005). Role of PPARalpha in mediating the effects of phthalates and metabolites in the liver. Toxicology, 207(1), 149–163. Scholar
  49. Larsen, T. M., Toubro, S., & Astrup, A. (2003). PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity, 27(2), 147–161. Scholar
  50. Legler, J., Fletcher, T., Govarts, E., Porta, M., Blumberg, B., Heindel, J. J., & Trasande, L. (2015). Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. The Journal of Clinical Endocrinology and Metabolism, 100(4), 1278–1288. Scholar
  51. Lottrup, G., Andersson, A. M., Leffers, H., Mortensen, G. K., Toppari, J., Skakkebaek, N. E., & Main, K. M. (2006). Possible impact of phthalates on infant reproductive health. International Journal of Andrology, 29(1), 172–180; discussion 181-185. Scholar
  52. Medic Stojanoska, M., Milankov, A., Vukovic, B., Vukcevic, D., Sudji, J., Bajkin, I., Curic, N., Icin, T., Kovacev Zavisic, B., & Milic, N. (2015). Do diethyl phthalate (DEP) and di-2-ethylhexyl phthalate (DEHP) influence the metabolic syndrome parameters? Pilot study. Environmental Monitoring and Assessment, 187(8), 526. Scholar
  53. Medic Stojanoska, M., Milosevic, N., Milic, N., & Abenavoli, L. (2017). The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders. Endocrine, 55(3), 666–681. Scholar
  54. Meeker, J. D., & Ferguson, K. K. (2011). Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Environmental Health Perspectives, 119(10), 1396–1402. Scholar
  55. Meeker, J. D., Calafat, A. M., & Hauser, R. (2007). Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environmental Health Perspectives, 115(7), 1029–1034. Scholar
  56. Milošević, N., Jakšić, V., Sudji, J., Vuković, B., Ičin, T., Milić, N., & Medić Stojanoska, M. (2017). Possible influence of the environmental pollutant bisphenol A on the cardiometabolic risk factors. International Journal of Environmental Health Research, 27(1), 11–26. Scholar
  57. Mortensen, G. K., Main, K. M., Andersson, A.-M., Leffers, H., & Skakkebæk, N. E. (2005). Determination of phthalate monoesters in human breast milk, consumer milk and infant formula by tandem mass spectrometry (LC/MC/MS). Analytical and Bioanalytical Chemistry, 382(4), 1084–1092. Scholar
  58. Navarro-González, D., Sánchez-Íñigo, L., Pastrana-Delgado, J., Fernández-Montero, A., & Martinez, J. A. (2016). Triglyceride-glucose index (TyG index) in comparison with fasting plasma glucose improved diabetes prediction in patients with normal fasting glucose: the vascular-metabolic CUN cohort. Preventive Medicine, 86, 99–105. Scholar
  59. OECD. (2012). Health at a Glance: Europe 2012. OECD Publishing. Accessed 21 Nov 2016.
  60. Ogden, C. L., Carroll, M. D., Fryar, C. D., & Flegal, K. M. (2015). Prevalence of obesity among adults and youth: United States, 2011-2014. NCHS Data Brief, 219, 1–8.Google Scholar
  61. Oh, J. Y., Sung, Y. A., & Lee, H. J. (2013). The visceral adiposity index as a predictor of insulin resistance in young women with polycystic ovary syndrome. Obesity (Silver Spring), 21(8), 1690–1694. Scholar
  62. Parajapati, H., & Verma, R. J. (2014). Diethyl phthalate causes oxidative stress: An in vitro study. Iranian Journal of Toxicology, 8(24), 1011–1016.Google Scholar
  63. Penza, M., Montani, C., Romani, A., Vignolini, P., Pampaloni, B., Tanini, A., Brandi, M. L., Alonso-Magdalena, P., Nadal, A., Ottobrini, L., Parolini, O., Bignotti, E., Calza, S., Maggi, A., Grigolato, P. G., & di Lorenzo, D. (2006). Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. Endocrinology, 147(12), 5740–5751. Scholar
  64. Pereira, C., & Rao, C. V. (2006). Combined and individual administration of diethyl phthalate and polychlorinated biphenyls and its toxicity in female Wistar rats. Environmental Toxicology and Pharmacology, 21(1), 93–102. Scholar
  65. Pereira, C., Mapuskar, K., & Rao, C. V. (2006). Chronic toxicity of diethyl phthalate in male Wistar rats--a dose-response study. Regulatory Toxicology and Pharmacology: RTP, 45(2), 169–177. Scholar
  66. Peters, J. M., Cattley, R. C., & Gonzalez, F. J. (1997). Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis, 18(11), 2029–2033. Scholar
  67. Reilly, J. J., Armstrong, J., Dorosty, A. R., Emmett, P. M., Ness, A., Rogers, I., Steer, C., Sherriff, A., & Avon Longitudinal Study of Parents and Children Study Team. (2005). Early life risk factors for obesity in childhood: cohort study. BMJ: British Medical Journal, 330(7504), 1357–1350. Scholar
  68. Rosen, E. D., & Spiegelman, B. M. (2001). PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. The Journal of Biological Chemistry, 276(41), 37731–37734. Scholar
  69. Rudel, R. A., Gray, J. M., Engel, C. L., Rawsthorne, T. W., Dodson, R. E., Ackerman, J. M., Rizzo, J., Nudelman, J. L., & Brody, J. G. (2011). Food packaging and bisphenol A and bis(2-ethyhexyl) phthalate exposure: findings from a dietary intervention. Environmental Health Perspectives, 119(7), 914–920. Scholar
  70. Salgado, A. L., Carvalho, L., Oliveira, A. C., Santos, V. N., Vieira, J. G., & Parise, E. R. (2010). Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals. Arquivos de Gastroenterologia, 47(2), 165–169. Scholar
  71. Sánchez-Íñigo, L., Navarro-González, D., Fernández-Montero, A., Pastrana-Delgado, J., & Martínez, J. A. (2016). The TyG index may predict the development of cardiovascular events. European Journal of Clinical Investigation, 46(2), 189–197. Scholar
  72. Sattar, N., Scherbakova, O., Ford, I., O'Reilly, D. S., Stanley, A., Forrest, E., Macfarlane, P. W., Packard, C. J., Cobbe, S. M., Shepherd, J., & west of Scotland coronary prevention study. (2004). Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes, 53(11), 2855–2860. Scholar
  73. Schettler, T. (2006). Human exposure to phthalates via consumer products. International Journal of Andrology, 29(1), 134–139; discussion 181-185. Scholar
  74. Silva, M. J., Reidy, J. A., Herbert, A. R., Preau Jr., J. L., Needham, L. L., & Calafat, A. M. (2004). Detection of phthalate metabolites in human amniotic fluid. Bulletin of Environmental Contamination and Toxicology, 72(6), 1226–1231.CrossRefGoogle Scholar
  75. Silva, M. J., Reidy, J. A., Samandar, E., Herbert, A. R., Needham, L. L., & Calafat, A. M. (2005). Detection of phthalate metabolites in human saliva. Archives of Toxicology, 79(11), 647–652. Scholar
  76. Stahlhut, R. W., van Wijngaarden, E., Dye, T. D., Cook, S., & Swan, S. H. (2007). Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environmental Health Perspectives, 115(6), 876–882. Scholar
  77. Stepien, M., Stepien, A., Wlazel, R. N., Paradowski, M., Rizzo, M., Banach, M., et al. (2014). Predictors of insulin resistance in patients with obesity: a pilot study. Angiology, 65(1), 22–30. Scholar
  78. Stocker, R., & Keaney Jr., J. F. (2004). Role of oxidative modifications in atherosclerosis. Physiological Reviews, 84(4), 1381–1478. Scholar
  79. Swan, S. H. (2008). Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environmental Research. Section A, 108(2), 177–184. Scholar
  80. Teitelbaum, S. L., Britton, J. A., Calafat, A. M., Ye, X., Silva, M. J., Reidy, J. A., Galvez, M. P., Brenner, B. L., & Wolff, M. S. (2008). Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environmental Research, 106(2), 257–269. Scholar
  81. Teitelbaum, S. L., Mervish, N., Moshier, E. L., Vangeepuram, N., Galvez, M. P., Calafat, A. M., et al. (2012). Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environmental Research, 112, 186–193. Scholar
  82. Trasande, L., Cronk, C., Durkin, M., Weiss, M., Schoeller, D. A., Gall, E. A., Hewitt, J. B., Carrel, A. L., Landrigan, P. J., & Gillman, M. W. (2009). Environment and obesity in the National Children’s study. Environmental Health Perspectives, 117(2), 159–166. Scholar
  83. Trevino, L. S., Coarfa, C., Dong, J., Foulds, C. E., Gallo, M., & Walker, C. L. (2017). Early Life Environmental Exposure Creates “Super-Promoters” By Developmentally Reprogramming the Epigenome of Genes Associated with NAFLD. Endocrine society,
  84. Unger, G., Benozzi, S. F., Perruzza, F., & Pennacchiotti, G. L. (2014). Triglycerides and glucose index: A useful indicator of insulin resistance. Endocrinología y nutrición: órgano de la Sociedad Española de Endocrinología y Nutrición, 61(10), 533–540. Scholar
  85. Vozarova, B., Stefan, N., Lindsay, R. S., Saremi, A., Pratley, R. E., Bogardus, C., & Tataranni, P. A. (2002). High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes, 51(6), 1889–1895. Scholar
  86. Wang, H., Zhou, Y., Tang, C., He, Y., Wu, J., Chen, Y., & Jiang, Q. (2013). Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. PLoS One, 8(2), e56800. Scholar
  87. Wannamethee, S. G., Shaper, A. G., Lennon, L., & Whincup, P. H. (2005). Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care, 28(12), 2913–2918. Scholar
  88. Wellen, K. E., & Hotamisligil, G. S. (2005). Inflammation, stress, and diabetes. The Journal of Clinical Investigation, 115(5), 1111–1119. Scholar
  89. Welsh, M., Saunders, P. T., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., et al. (2008). Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. The Journal of Clinical Investigation, 118(4), 1479–1490. Scholar
  90. Wenzel, A., Franz, C., Breous, E., & Loos, U. (2005). Modulation of iodide uptake by dialkyl phthalate plasticisers in FRTL-5 rat thyroid follicular cells. Molecular and Cellular Endocrinology, 244(1-2), 63–71. Scholar
  91. Wolff, M. S., Teitelbaum, S. L., Windham, G., Pinney, S. M., Britton, J. A., Chelimo, C., Godbold, J., Biro, F., Kushi, L. H., Pfeiffer, C. M., & Calafat, A. M. (2007). Pilot study of urinary biomarkers of phytoestrogens, phthalates, and phenols in girls. Environmental Health Perspectives, 115(1), 116–121.CrossRefGoogle Scholar
  92. Wormuth, M., Scheringer, M., Vollenweider, M., & Hungerbühler, K. (2006). What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Analysis: an Official Publication of the Society for Risk Analysis, 26(3), 803–824. Scholar
  93. Yaghjyan, L., Sites, S., Ruan, Y., & Chang, S. H. (2015). Associations of urinary phthalates with body mass index, waist circumference and serum lipids among females: National Health and Nutrition Examination Survey 1999-2004. International Journal of Obesity: Journal of the International Association for the Study of Obesity, 39(6), 994–1000. Scholar
  94. Yavaşoğlu, N. Ü., Köksal, C., Dağdeviren, M., Aktuğ, H., & Yavaşoğlu, A. (2014). Induction of oxidative stress and histological changes in liver by subacute doses of butyl cyclohexyl phthalate. Environmental Toxicology, 29(3), 345–353. Scholar
  95. Zota, A. R., Calafat, A. M., & Woodruff, T. J. (2014). Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001-2010. Environmental Health Perspectives, 122(3), 235–241. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Nataša Milošević
    • 1
  • Nataša Milić
    • 1
    Email author
  • Dragana Živanović Bosić
    • 2
  • Ivana Bajkin
    • 3
  • Ivanka Perčić
    • 4
  • Ludovico Abenavoli
    • 5
  • Milica Medić Stojanoska
    • 3
  1. 1.Department of Pharmacy, Faculty of MedicineUniversity of Novi SadNovi SadSerbia
  2. 2.Health Center RumaRumaSerbia
  3. 3.Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of VojvodinaUniversity of Novi SadNovi SadSerbia
  4. 4.Faculty of Medicine, Clinic for Haematology, Clinical Center of VojvodinaUniversity of Novi SadNovi SadSerbia
  5. 5.Department of Health SciencesUniversity Magna GraeciaCatanzaroItaly

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