Associations of Phthalate Metabolites and Obesity-Related Metabolic Factors

Lu Wang, MD, PhD, Xi Zhang, PhD, Yiqing Song, MD, ScD


Diabetes and obesity have reached epidemic rates in most developed and developing countries. Over-nutrition and physical inactivity are established risk factors with key roles in the etiology of type 2 diabetes. However, these factors alone cannot fully account for either the rate or the magnitude with which diabetes has increased worldwide. Research on whether exposure to environmental endocrine disrupting chemicals (EDCs) may be a preventable risk factor for diabetes development has attracted considerable attention since the 1990s. Phthalates are a group of EDCs characterized by widespread human exposure; concerns about the adverse effects of exposure to phthalates on human health are increasing. Early studies regarding the toxicity of phthalates largely focused on reproductive health and development effects. More recent research has shifted towards possible metabolic effects that may increase the risk for obesity, insulin resistance, diabetes, and other related adverse health outcomes.  Considering the ubiquity of phthalates in the environment, it is important to understand the potential hazards of these chemicals even at very low exposure levels; if those are confirmed, strategies must be developed to remove them from the environment or at least preclude widespread contamination. This review aimed to summarize current evidence on the potential hazards of phthalates with regard to metabolic disease and highlighted the importance of further investigation that will have high public health significance for both developed as well as developing countries, where the exposure may continue to be high for decades to come.

 [N A J Med Sci. 2017;10(2):88-93.   DOI:  10.7156/najms.2017.1002088]



endocrine disrupting chemicals, phthalates, obesity, diabetes

Full Text:



Lakind JS, Goodman M, Mattison DR. Bisphenol A and indicators of obesity, glucose metabolism/type 2 diabetes and cardiovascular disease: a systematic review of epidemiologic research. Criti Rev Toxicol. 2014;44:121-150.

Kabir ER, Rahman MS, Rahman I. A review on endocrine disruptors and their possible impacts on human health. Environ Toxicol Pharmacol. 2015;40:241-258.

International Programme on Chemical Safety. Global assessment of the state-of-the science of endocrine disruptors. World Health Organization. Accessed August 25, 2015.

Kavlock RJ, Ankley GT. A perspective on the risk assessment process for endocrine-disruptive effects on wildlife and human health. Risk Anal. 1996;16:731-739.

Toxicological Profile for Di(2-ethylhexyl)phthalate (DEHP) Atlanta, GA: Agency for Toxic Substances & Disease Registry. Accessed September 3, 2015.

Koniecki D, Wang R, Moody RP, et al. Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ Res. 2011;111:329-336.

Schettler T. Human exposure to phthalates via consumer products. Int J Androl. 2006;29:134-139; discussion 81-85.

Meeker JD, Calafat AM, Hauser R. Urinary phthalate metabolites and their biotransformation products: predictors and temporal variability among men and women. J Exp Sci Environ Epidemiol. 2012;22:376-385.

Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res. 2007;51:899-911.

Kato K, Silva MJ, Reidy JA, et al. Mono(2-ethyl-5-hydroxyhexyl) phthalate and mono-(2-ethyl-5-oxohexyl) phthalate as biomarkers for human exposure assessment to di-(2-ethylhexyl) phthalate. Environ Health Perspec. 2004;112:327-330.

Silva MJ, Barr DB, Reidy JA, et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ Health Perspec. 2004;112:331-338.

Wittassek M, Wiesmuller GA, Koch HM, et al. Internal phthalate exposure over the last two decades--a retrospective human biomonitoring study. Int J Hyg Environ Health. 2007;210:319-333.

Di(2-ethylhexyl phthalate. IARC monographs on the evaluation of carcionogenic risks to humans. World Health Organization, International Agency for Research on Cancer. Vol. 77, 2000. Accessed September 3, 2015.

Bay K, Asklund C, Skakkebaek NE, et al. Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab. 2006;20:77-90.

Caserta D, Mantovani A, Marci R, et al. Environment and women's reproductive health. Hum Reprod Update. 2011;17:418-433.

Andra SS, Makris KC. Thyroid disrupting chemicals in plastic additives and thyroid health. Journal of environmental science and health Part C, Environ Carcinog Ecotoxicol Rev. 2012;30:107-151.

Hauser R, Sokol R. Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult male. Fertil Steril. 2008;89:e59-65.

Feige JN, Gelman L, Rossi D, et al. The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis. J Biol Chem. 2007;282:19152-19166.

Grun F. Obesogens. Curr Opin Endocrinol Diabetes Obes. 2010;17:453-459.

Lind PM, Roos V, Ronn M, et al. Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Environ Health. 2012;11:21.

Lind PM, Zethelius B, Lind L. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes care. 2012;35:1519-1524.

Olsen L, Lampa E, Birkholz DA, et al. Circulating levels of bisphenol A (BPA) and phthalates in an elderly population in Sweden, based on the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). Ecotoxicol Environ Safety. 2012;75:242-248.

Martinelli MI, Mocchiutti NO, Bernal CA. Dietary di(2-ethylhexyl)phthalate-impaired glucose metabolism in experimental animals. Hum Exp Toxicol. 2006;25:531-538.

Rengarajan S, Parthasarathy C, Anitha M, et al. Diethylhexyl phthalate impairs insulin binding and glucose oxidation in Chang liver cells. Toxicol In Vitro. 2007;21:99-102.

Rajesh P, Balasubramanian K. Di(2-ethylhexyl)phthalate exposure impairs insulin receptor and glucose transporter 4 gene expression in L6 myotubes. Hum Exp Toxicol. 2014;33:685-700.

Rajesh P, Sathish S, Srinivasan C, et al. Phthalate is associated with insulin resistance in adipose tissue of male rat: role of antioxidant vitamins. J Cell Biochem. 2013;114:558-569.

Mushtaq M, Srivastava SP, Seth PK. Effect of di-2-ethylhexyl phthalate (DEHP) on glycogen metabolism in rat liver. Toxicology. 1980;16:153-161.

Gayathri NS, Dhanya CR, Indu AR, et al. Changes in some hormones by low doses of di (2-ethyl hexyl) phthalate (DEHP), a commonly used plasticizer in PVC blood storage bags & medical tubing. Indian J Med Res. 2004;119:139-144.

Lin Y, Wei J, Li Y, et al. Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat. American journal of physiology Endocrinol Metab. 2011;301:E527-538.

Bility MT, Thompson JT, McKee RH, et al. Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol Sci. 2004;82:170-182.

Hurst CH, Waxman DJ. Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci. 2003;74:297-308.

Ahmadian M, Suh JM, Hah N, et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557-566.

Casals-Casas C, Feige JN, Desvergne B. Interference of pollutants with PPARs: endocrine disruption meets metabolism. Int J Obes. 2008;32(Suppl 6):S53-61.

Desvergne B, Feige JN, Casals-Casas C. PPAR-mediated activity of phthalates: A link to the obesity epidemic? Mol Cell Endocrinol. 2009;304:43-48.

Grun F, Blumberg B. Endocrine disrupters as obesogens. Mol Cell Endocrinol. 2009;304:19-29.

Sargis RM, Johnson DN, Choudhury RA, et al. Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity. 2010;18:1283-1288.

Janesick A, Blumberg B. Minireview: PPARgamma as the target of obesogens. J Steroid Biochem Mol Biol. 2011;127:4-8.

Stahlhut RW, van Wijngaarden E, Dye TD, et al. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 2007;115:876-882.

Svensson K, Hernandez-Ramirez RU, Burguete-Garcia A, et al. Phthalate exposure associated with self-reported diabetes among Mexican women. Environ Res. 2011;111:792-796.

James-Todd T, Stahlhut R, Meeker JD, et al. Urinary phthalate metabolite concentrations and diabetes among women in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. Environ Health Perspect. 2012;120:1307-1313.

Olsen L, Lind L, Lind PM. Associations between circulating levels of bisphenol A and phthalate metabolites and coronary risk in the elderly. Ecotoxicol Environ Safety. 2012;80:179-183.

Huang T, Saxena AR, Isganaitis E, et al. 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. Environ Health. 2014;13:6.

Sun Q, Cornelis MC, Townsend MK, et al. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses' Health Study (NHS) and NHSII cohorts. Environ Health Perspect. 2014;122:616-623.

Hatch EE, Nelson JW, Qureshi MM, et al. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999-2002. Environ Health. 2008;7:27.

Kasper-Sonnenberg M, Koch HM, Wittsiepe J, et al. Levels of phthalate metabolites in urine among mother-child-pairs - results from the Duisburg birth cohort study, Germany. Int J Hyg Environ Health. 2012;215:373-382.

Wirth JJ, Rossano MG, Potter R, et al. A pilot study associating urinary concentrations of phthalate metabolites and semen quality. Syst Biol Reprod Med. 2008;54:143-154.

Duty SM, Calafat AM, Silva MJ, et al. Phthalate exposure and reproductive hormones in adult men. Hum Reprod. 2005;20:604-610.

Wolff MS, Engel SM, Berkowitz GS, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect. 2008;116:1092-1097.

Whyatt RM, Adibi JJ, Calafat AM, et al. Prenatal di(2-ethylhexyl)phthalate exposure and length of gestation among an inner-city cohort. Pediatrics. 2009;124:e1213-1220.

Casas L, Fernandez MF, Llop S, et al. Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children. Environ Int. 2011;37:858-866.

Huang PC, Kuo PL, Guo YL, et al. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod. 2007;22:2715-2722.

Song Y, Hauser R, Hu FB, et al. Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women. Int J Obes. 2014;38:1532-1537.

Frederiksen H, Skakkebaek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res. 2007;51:899-911.

Koch HM, Calafat AM. Human body burdens of chemicals used in plastic manufacture. Philos Trans R Soc Lond B Biol Sci. 2009;364:2063-2078.

Committee on the Health Risks of Phthalates. Phthalates and Cumulative Risk Assessment: The Task Ahead. Washington D.C.: National Academies Press; 2008.

Braun JM, Smith KW, Williams PL, et al. Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect. 2012;120:739-745.

Fromme H, Bolte G, Koch HM, et al. Occurrence and daily variation of phthalate metabolites in the urine of an adult population. Int J Hyg Environ Health. 2007;210:21-33.

Hoppin JA, Brock JW, Davis BJ, et al. Reproducibility of urinary phthalate metabolites in first morning urine samples. Environ Health Perspect. 2002;110:515-518.

Peck JD, Sweeney AM, Symanski E, et al. Intra- and inter-individual variability of urinary phthalate metabolite concentrations in Hmong women of reproductive age. J Expos Sci Environ Epidemiol. 2010;20:90-100.

Teitelbaum SL, Britton JA, Calafat AM, et al. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environ Res. 2008;106:257-269.

Townsend MK, Franke AA, Li X, Hu FB, Eliassen AH. Within-person reproducibility of urinary bisphenol A and phthalate metabolites over a 1 to 3 year period among women in the Nurses' Health Studies: a prospective cohort study. Environ Health. 2013;12:80.

Barr DB, Wilder LC, Caudill SP, et al. Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements. Environ Health Perspect. 2005;113:192-200.

Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782-787.

Diamond J. The double puzzle of diabetes. Nature. 2003;423:599-602.

Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378:31-40.


  • There are currently no refbacks.