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Exposure to phthalates and bisphenol A is associated with higher risk of cardiometabolic impairment in normal weight children

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Some obese individuals have normal metabolic profile, and some normal-weight persons have impaired metabolic status. Our hypothesis was that one of the potential underlying factors for such differences in cardiometabolic profiles might be the exposure to some environmental chemicals. This study aimed to investigate the association of serum bisphenol A (BPA) and phthalate metabolites with cardiometabolic risk factors in children and adolescents independent of their weight status. This case–control study was conducted on a subsample of 320 participants of a national school-based surveillance program in Iran. We measured serum BPA and phthalate metabolites by gas chromatography mass spectrophotometry. We compared them in children and adolescents with and without excess weight and those with and without cardiometabolic risk factors (80 in each group). We categorized the concentrations of chemicals to tertiles and then we applied logistic regression models after adjustment for potential confounding factors. The concentrations of BPA and some metabolites of phthalates were significantly different in the four groups studied. MEHP concentration was associated with higher odds ratio of cardiometabolic risk factors in participants with normal weight (OR, 95% CI 2.82, 1.001–7.91) and those with excess weight (OR, 95% CI 3.15, 1.27–7.83). MBP concentration increased the odds ratio of cardiometabolic risk factors only in normal weight children and adolescents (OR, 95% CI 6.59, 2.33–18.59, P < 0.001). In participants without cardiometabolic risk factor, MMP and MEHHP were significantly associated with increased risk of excess weight (OR, 95% CI 5.90, 1.21–28.75 and 7.82, 1.5–41.8, respectively). This study showed that the association of BPA and phthalate with cardiometabolic risk factors is independent of the weight status. Our findings suggest that the metabolic impairment in some normal weight children and normal metabolic profile of some obese children can be, in part, related to exposure to these environmental chemicals.

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  1. Amin MM, Ebrahim K, Poursafa P (2017) Development of a dispersive liquid–liquid microextraction (DLLME) method coupled with GC/MS as a simple and valid method for simultaneous determination of phthalate metabolites in plasma. Int J Environ Anal Chem 97:1362–1377

  2. Amin MM, Parastar S, Ebrahimpour K, Shoshtari-Yeganeh B, Hashemi M, Mansourian M, Poursafa P, Fallah Z, Rafiei N, Kelishadi R (2018a) Association of urinary concentrations of phthalate metabolites with cardiometabolic risk factors and obesity in children and adolescents. Chemosphere 211:547–556

  3. Amin MM, Parastar S, Ebrahimpour K, Shoshtari-Yeganeh B, Hashemi M, Mansourian M, Kelishadi R (2018b) Association of urinary phthalate metabolites concentrations with body mass index and waist circumference. Environ Sci Pollut Res Int 25:11143–11151

  4. Barr DB, Silva MJ, Kato K, Reidy JA, Malek NA, Hurtz D, Sadowski M, Needham LL, Calafat AM (2003) Assessing human exposure to phthalates using monoesters and their oxidized metabolites as biomarkers. Environ Health Perspect 111:1148–1151

  5. Bhandari R, Xiao J, Shankar A (2013) Urinary bisphenol A and obesity in US children. Am J Epidemiol 177:1263–1270

  6. Boas M, Frederiksen H, Feldt-Rasmussen U, Skakkebæk NE, Hegedüs L, Hilsted L, Juul A, Main KM (2010) Childhood exposure to phthalates: associations with thyroid function, insulin-like growth factor I, and growth. Environ Health Perspect 118:1458–1464

  7. Bodin J, Bølling AK, Samuelsen M, Becher R, Løvik M, Nygaard UC (2013) Long-term bisphenol A exposure accelerates insulitis development in diabetes-prone NOD mice. Immunopharmacol Immunotoxicol 35:349–358

  8. Carwile JL, Michels KB (2011) Urinary bisphenol A and obesity: NHANES 2003–2006. Environ Res 111:825–830

  9. Casey MF, Neidell M (2013) Disconcordance in statistical models of bisphenol A and chronic disease outcomes in NHANES 2003-08. PLoS One 8:e79944

  10. Durmaz E, Özmert EN, Erkekoğlu P, Giray B, Derman O, Hıncal F, Yurdakök K (2010) Plasma phthalate levels in pubertal gynecomastia. Pediatrics 125:e122–e129

  11. Eng DS, Lee JM, Gebremariam A, Meeker JD, Peterson K, Padmanabhan V (2013) Bisphenol A and chronic disease risk factors in US children. Pediatrics peds.2013-0106 132:e637–e645

  12. Eveillard A, Mselli-Lakhal L, Mogha A, Lasserre F, Polizzi A, Pascussi J-M, Guillou H, Martin PG, Pineau T (2009) Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): a novel signalling pathway sensitive to phthalates. Biochem Pharmacol 77:1735–1746

  13. Fang C, Ning B, Waqar AB, Niimi M, Li S, Satoh K, Shiomi M, Ye T, Dong S, Fan J (2014) Bisphenol A exposure enhances atherosclerosis in WHHL rabbits. PLoS One 9:e110977

  14. Feige JN, Gelman L, Rossi D, Zoete V, MÉtivier R, Tudor C, Anghel SI, Grosdidier A, Lathion C, Engelborghs Y (2007) The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor γ modulator that promotes adipogenesis. J Biol Chem 282:19152–19166

  15. Fenichel P, Chevalier N, Brucker-Davis F (2013) Bisphenol A: an endocrine and metabolic disruptor. Ann Endocrinol (Paris) 74:211–220

  16. Frederiksen H, Nielsen JKS, MØrck TA, Hansen PW, Jensen JF, Nielsen O, Andersson A-M, Knudsen LE (2013) Urinary excretion of phthalate metabolites, phenols and parabens in rural and urban Danish mother–child pairs. Int J Hyg Environ Health 216:772–783

  17. Galloway T, Cipelli R, Guralnik J, Ferrucci L, Bandinelli S, Corsi AM, Money C, McCormack P, Melzer D (2010) Daily bisphenol A excretion and associations with sex hormone concentrations: results from the InCHIANTI adult population study. Environ Health Perspect 118:1603–1608

  18. Gao X, Wang HS (2014) Impact of bisphenol a on the cardiovascular system - epidemiological and experimental evidence and molecular mechanisms. Int J Environ Res Public Health 11:8399–8413

  19. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J, Zoeller RT (2015) Executive summary to EDC-2: the endocrine society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev 36:593–602

  20. Group WMGRS, De Onis M (2006) WHO child growth standards based on length/height, weight and age. Acta Paediatr 95:76–85

  21. Grün F (2010) Obesogens. Curr Opin Endocrinol Diabetes Obes 17:453–459

  22. Harley KG, Schall RA, Chevrier J, Tyler K, Aguirre H, Bradman A, Holland NT, Lustig RH, Calafat AM, Eskenazi B (2013) Prenatal and postnatal bisphenol A exposure and body mass index in childhood in the CHAMACOS cohort. Environ Health Perspect 121:514–520

  23. Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, Webster TF (2008) Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002. Environ Health 7:27

  24. Hong Y-C, Park E-Y, Park M-S, Ko JA, Oh S-Y, Kim H, Lee K-H, Leem J-H, HA E-H (2009) Community level exposure to chemicals and oxidative stress in adult population. Toxicol Lett 184:139–144

  25. Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW, Ben-Jonathan N (2008) Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ Health Perspect 116:1642–1647

  26. Johns LE, Cooper GS, Galizia A, Meeker JD (2015) Exposure assessment issues in epidemiology studies of phthalates. Environ Int 85:27–39

  27. Kelishadi R, Poursafa P (2014) A review on the genetic, environmental, and lifestyle aspects of the early-life origins of cardiovascular disease. Curr Probl Pediatr Adolesc Health Care 44:54–72

  28. Kelishadi R, Poursafa P, Jamshidi F (2013) Role of environmental chemicals in obesity: a systematic review on the current evidence. J Environ Public Health 2013:896789

  29. Khalil N, Ebert JR, Wang L, Belcher S, Lee M, Czerwinski SA, Kannan K (2014) Bisphenol A and cardiometabolic risk factors in obese children. Sci Total Environ 470-471:726–732

  30. Kim K, Park H, Yang W, Lee JH (2011) Urinary concentrations of bisphenol A and triclosan and associations with demographic factors in the Korean population. Environ Res 111:1280–1285

  31. Kim MJ, Moon MK, Kang GH, Lee KJ, Choi SH, Lim S, Oh BC, Park DJ, Park KS, Jang HC, Park YJ (2014) Chronic exposure to bisphenol A can accelerate atherosclerosis in high-fat-fed apolipoprotein E knockout mice. Cardiovasc Toxicol 14:120–128

  32. Lang IA, Galloway TS, Scarlett A, Henley WE, Depledge M, Wallace RB, Melzer D (2008) Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300:1303–1310

  33. Li D-K, Miao M, Zhou Z, Wu C, Shi H, Liu X, Wang S, Yuan W (2013) Urine bisphenol-A level in relation to obesity and overweight in school-age children. PLoS One 8:e65399

  34. Lind L, Lind PM (2012) Can persistent organic pollutants and plastic-associated chemicals cause cardiovascular disease? J Intern Med 271:537–553

  35. Marmugi A, Ducheix S, Lasserre F, Polizzi A, Paris A, Priymenko N, Bertrand-Michel J, Pineau T, Guillou H, Martin PG (2012) Low doses of bisphenol A induce gene expression related to lipid synthesis and trigger triglyceride accumulation in adult mouse liver. Hepatology 55:395–407

  36. Maserejian NN, Trachtenberg FL, Hauser R, Mckinlay S, Shrader P, Bellinger DC (2012) Dental composite restorations and neuropsychological development in children: treatment level analysis from a randomized clinical trial. Neurotoxicology 33:1291–1297

  37. Melzer D, Rice NE, Lewis C, Henley WE, Galloway TS (2010) Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06. PLoS One 5:e8673

  38. Melzer D, Osborne NJ, Henley WE, Cipelli R, Young A, Money C, McCormack P, Luben R, Khaw K-T, Wareham NJ (2012) Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women clinical perspective. Circulation 125:1482–1490

  39. MichaŁowicz J (2014) Bisphenol A–sources, toxicity and biotransformation. Environ Toxicol Pharmacol 37:738–758

  40. Mielke H, Gundert-Remy U (2009) Bisphenol A levels in blood depend on age and exposure. Toxicol Lett 190:32–40

  41. Mok-Lin E, Ehrlich S, Williams P, Petrozza J, Wright D, Calafat A, Ye X, Hauser R (2010) Urinary bisphenol A concentrations and ovarian response among women undergoing IVF. Int J Androl 33:385–393

  42. Motlagh ME, Ziaodini H, Qorbani M, Taheri M, Aminaei T, Goodarzi A, Ataie-Jafari A, Rezaei F, Ahadi Z, Shafiee G (2017a) Methodology and early findings of the fifth survey of childhood and adolescence surveillance and prevention of adult noncommunicable disease: the CASPIAN-V study. Int J Prev Med 8:4. https://doi.org/10.4103/2008-7802.198915

  43. Motlagh ME, Ziaodini H, Qorbani M, Taheri M, Aminaei T, Goodarzi A, Ataie-Jafari A, Rezaei F, Ahadi Z, Shafiee G, Shahsavari A, Heshmat R, Kelishadi R (2017b) Methodology and early findings of the fifth survey of childhood and adolescence surveillance and prevention of adult noncommunicable disease: the CASPIAN-V study. Int J Prev Med 8:4

  44. Olsen L, Lind L, Lind PM (2012) Associations between circulating levels of bisphenol A and phthalate metabolites and coronary risk in the elderly. Ecotoxicol Environ Saf 80:179–183

  45. Oppeneer SJ, Robien K (2015) Bisphenol A exposure and associations with obesity among adults: a critical review. Public Health Nutr 18:1847–1863

  46. Pediatrics AAO (2004) National high blood pressure education program working group on high blood pressure in children and adolescents. Pediatrics 114:iv–iv

  47. Peretz J, Vrooman L, Ricke WA, Hunt PA, Ehrlich S, Hauser R, Padmanabhan V, Taylor HS, Swan SH, Vandevoort CA, Flaws JA (2014) Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect 122:775–786

  48. Philips EM, Jaddoe VWV, Trasande L (2017) Effects of early exposure to phthalates and bisphenols on cardiometabolic outcomes in pregnancy and childhood. Reprod Toxicol 68:105–118

  49. Posnack NG (2014) The adverse cardiac effects of Di(2-ethylhexyl)phthalate and bisphenol A. Cardiovasc Toxicol 14:339–357

  50. Poursafa P, Dadvand P, Amin MM, Hajizadeh Y, Ebrahimpour K, Mansourian M, Pourzamani H, Sunyer J, Kelishadi R (2018) Association of polycyclic aromatic hydrocarbons with cardiometabolic risk factors and obesity in children. Environ Int 118:203–210

  51. Ranciere F, Lyons JG, Loh VH, Botton J, Galloway T, Wang T, Shaw JE, Magliano DJ (2015) Bisphenol A and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence. Environ Health 14:46

  52. Richter CA, Birnbaum LS, Farabollini F, Newbold RR, Rubin BS, Talsness CE, Vandenbergh JG, Walser-Kuntz DR, Vom Saal FS (2007) In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 24:199–224

  53. Savastano S, Tarantino G, D'esposito V, Passaretti F, Cabaro S, Liotti A, Liguoro D, Perruolo G, Ariemma F, Finelli C, Beguinot F, Formisano P, Valentino R (2015) Bisphenol-A plasma levels are related to inflammatory markers, visceral obesity and insulin-resistance: a cross-sectional study on adult male population. J Transl Med 13:169

  54. Schuhmacher M, Nadal M, Domingo JL (2009) Environmental monitoring of PCDD/Fs and metals in the vicinity of a cement plant after using sewage sludge as a secondary fuel. Chemosphere 74:1502–1508

  55. Shankar A, Teppala S (2011) Relationship between urinary bisphenol A levels and diabetes mellitus. J Clin Endocrinol Metab 96:3822–3826

  56. Shankar A, Teppala S (2012) Urinary bisphenol A and hypertension in a multiethnic sample of US adults. J Environ Public Health 2012:1–5

  57. Shankar A, Teppala S, Sabanayagam C (2012) Urinary bisphenol a levels and measures of obesity: results from the national health and nutrition examination survey 2003–2008. ISRN Endocrinol 2012:1–6

  58. Shiue I (2014) Higher urinary heavy metal, phthalate, and arsenic but not parabens concentrations in people with high blood pressure, US NHANES, 2011–2012. Int J Environ Res Public Health 11:5989–5999

  59. Stahlhut RW, Van Wijngaarden E, Dye TD, Cook S, Swan SH (2007) Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult US males. Environ Health Perspect 115:876–882

  60. Teitelbaum SL, Mervish N, Moshier EL, Vangeepuram N, Galvez MP, Calafat AM, Silva MJ, Brenner BL, Wolff MS (2012) Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environ Res 112:186–193

  61. Thayer KA, Heindel JJ, Bucher JR, Gallo MA (2012) Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review. Environ Health Perspect 120:779–789

  62. Trasande L, Cronk C, Durkin M, Weiss M, Schoeller DA, Gall EA, Hewitt JB, Carrel AL, Landrigan PJ, Gillman MW (2009) Environment and obesity in the National Children’s study. Environ Health Perspect 117:159–166

  63. Trasande L, Attina TM, Blustein J (2012) Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. Jama 308:1113–1121

  64. Trasande L, Attina TM, Trachtman H (2013a) Bisphenol A exposure is associated with low-grade urinary albumin excretion in children of the United States. Kidney Int 83:741–748

  65. Trasande L, Sathyanarayana S, Spanier AJ, Trachtman H, Attina TM, Urbina EM (2013b) Urinary phthalates are associated with higher blood pressure in childhood. J Pediatr 163:747–53 e1

  66. Trasande L, Spanier AJ, Sathyanarayana S, Attina TM, Blustein J (2013c) Urinary phthalates and increased insulin resistance in adolescents. Pediatrics 132:e646–e655

  67. Trasande L, Sathyanarayana S, Trachtman H (2014) Dietary phthalates and low-grade albuminuria in US children and adolescents. Clin J Am Soc Nephrol 9:100–109

  68. Vafeiadi M, Roumeliotaki T, Myridakis A, Chalkiadaki G, Fthenou E, Dermitzaki E, Karachaliou M, Sarri K, Vassilaki M, Stephanou EG, Kogevinas M, Chatzi L (2016) Association of early life exposure to bisphenol A with obesity and cardiometabolic traits in childhood. Environ Res 146:379–387

  69. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV (2007) Human exposure to bisphenol A (BPA). Reprod Toxicol 24:139–177

  70. Vandenberg LN, Chahoud I, Padmanabhan V, Paumgartten FJ, Schoenfelder G (2010) Biomonitoring studies should be used by regulatory agencies to assess human exposure levels and safety of bisphenol A. Environ Health Perspect 118:1051–1054

  71. Wang T, Li M, Chen B, Xu M, Xu Y, Huang Y, Lu J, Chen Y, Wang W, Li X (2012) Urinary bisphenol A (BPA) concentration associates with obesity and insulin resistance. J Clin Endocrinol Metab 97:E223–E227

  72. 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:e56800

  73. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS (2012) Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology 153:4097–4110

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This study was conducted as the Elite grant of the National Institute for Medical Research Development, assigned to the corresponding author.


The National Institute for Medical Research Development in Iran funded this study (Project number: 958289).

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Correspondence to Roya Kelishadi.

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The study protocols of the main survey were reviewed and approved by ethical committees and other relevant national regulatory organizations. The Research and Ethics Committee of Isfahan University of Medical Sciences approved the main study (Project number: 194049). The current study was approved by the National Institute for Medical Research Development (Project number: 958289). After complete explanation of the study objectives and protocols, written informed and verbal consents were obtained from the parents and students, respectively.

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Mansouri, V., Ebrahimpour, K., Poursafa, P. et al. Exposure to phthalates and bisphenol A is associated with higher risk of cardiometabolic impairment in normal weight children. Environ Sci Pollut Res 26, 18604–18614 (2019). https://doi.org/10.1007/s11356-019-05123-z

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  • Children and adolescents
  • Obesity
  • Weight
  • Endocrine disruptor chemicals