Percentage fractions of urinary di(2-ethylhexyl) phthalate metabolites: Association with obesity and insulin resistance in Korean girls.

Shin-Hye Kim,Jiyeon Yang,Jong Chul Won,Kyung Soo Ko,Heesoo Pyo,Mi Jung Park,Ji-Won On,Elena Baixeras

doi:10.1371/journal.pone.0208081

Abstract

ObjectiveWe assessed the associations of percentage fractions of urinary di(2-ethylhexyl) phthalate (DEHP) metabolites with obesity and insulin resistance in Korean girls.MethodsIn total, 137 girls, aged 6 to 13 years (65 overweight cases and 72 controls), were recruited. Anthropometric indices and the homeostatic model assessment of insulin resistance (HOMA-IR) index were determined. Four major urinary DEHP metabolites were analyzed in spot urine samples by gas chromatography-tandem mass spectrometry, including mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate.ResultsThere were no significant differences in the urinary concentrations of the DEHP metabolites between the overweight and control groups. The percentage fraction of MEHHP (MEHHP%) among all DEHP metabolites was significantly higher in the overweight prepubertal girls than in the controls (P = 0.035). MEHHP% was positively associated with the body mass index percentile, waist circumference, body fat percentage, and HOMA-IR index in the prepubertal girls. After adjusting for covariates, the prepubertal girls in a higher MEHHP% quartile were found to have a higher odds ratio for central obesity than those in a lower quartile (odds ratios: 5.05 for quartile 3; 7.30 for quartile 4). The relative rate of MEHHP oxidation to MEOHP was negatively associated with the body mass index percentile and waist circumference in the prepubertal girls. However, no such association was observed in the pubertal girls.ConclusionsMEHHP% was positively associated with obesity and insulin resistance in prepubertal girls. Further studies are necessary to elucidate the causal links between altered phthalate metabolism and increased susceptibility to insulin resistance in children.

Highlights

Phthalates are 1,2-benzenedicarboxylic acid esters used as plasticizers to make plastics more flexible and soft and as vehicles in cosmetics [1]
There were no significant differences in the urinary concentrations of the di(2-ethylhexyl) phthalate (DEHP) metabolites between the overweight and control groups
The percentage fraction of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (MEHHP %) among all DEHP metabolites was significantly higher in the overweight prepubertal girls than in the controls (P = 0.035)

Summary

Introduction

Phthalates are 1,2-benzenedicarboxylic acid esters used as plasticizers to make plastics more flexible and soft and as vehicles in cosmetics [1] They are found in various consumer products, including food packaging, toys, medical devices, building materials, and cosmetics [1]. DEHP is rapidly hydrolyzed by esterases in the gut, liver, and blood into mono(2-ethylhexyl) phthalate (MEHP), which is subsequently metabolized by hepatic and intestinal cytochrome P450 (CYP) enzymes into various secondary oxidative metabolites. Those secondary oxidative metabolites include mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) (Fig 1). The measured urinary concentrations of the oxidative DEHP metabolites are commonly used as biomarkers of exposure to DEHP [1, 3]

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