Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites

PLoS One. 2015 Dec 2;10(12):e0143190. doi: 10.1371/journal.pone.0143190. eCollection 2015.

Abstract

Di-(2-ethylhexyl)-phthalate (DEHP), an ubiquitous environmental contaminant, has been shown to cause adverse effects on glucose homeostasis and insulin sensitivity in epidemiological studies, but the underlying mechanisms are still unknown. We therefore tested the hypothesis that chronic DEHP exposure causes impaired insulin sensitivity, affects body weight, adipose tissue (AT) function and circulating metabolic parameters of obesity resistant 129S6 mice in vivo. An obesity-resistant mouse model was chosen to reduce a potential obesity bias of DEHP effects on metabolic parameters and AT function. The metabolic effects of 10-weeks exposure to DEHP were tested by insulin tolerance tests and quantitative assessment of 183 metabolites in mice. Furthermore, 3T3-L1 cells were cultured with DEHP for two days, differentiated into mature adipocytes in which the effects on insulin stimulated glucose and palmitate uptake, lipid content as well as on mRNA/protein expression of key adipocyte genes were investigated. We observed in female mice that DEHP treatment causes enhanced weight gain, fat mass, impaired insulin tolerance, changes in circulating adiponectin and adipose tissue Pparg, adiponectin and estrogen expression. Serum metabolomics indicated a general increase in phospholipid and carnitine concentrations. In vitro, DEHP treatment increases the proliferation rate and alters glucose uptake in adipocytes. Taken together, DEHP has significant effects on adipose tissue (AT) function and alters specific serum metabolites. Although, DEHP treatment led to significantly impaired insulin tolerance, it did not affect glucose tolerance, HOMA-IR, fasting glucose, insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does not cause impaired glucose metabolism at the whole body level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / cytology*
  • Adipose Tissue / drug effects*
  • Adipose Tissue / metabolism
  • Animals
  • Biological Transport / drug effects
  • Blood / drug effects*
  • Blood / metabolism*
  • Body Weight / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Diethylhexyl Phthalate / metabolism
  • Diethylhexyl Phthalate / toxicity*
  • Environmental Pollutants / metabolism
  • Environmental Pollutants / toxicity*
  • Female
  • Gene Expression Regulation / drug effects
  • Glucose / metabolism
  • Insulin Resistance
  • Lipid Metabolism / drug effects
  • Male
  • Mice
  • Oxidation-Reduction

Substances

  • Environmental Pollutants
  • Diethylhexyl Phthalate
  • Glucose

Grant support

This work was supported by the German United Association for Clinical Chemistry and Laboratory Medicine (DGKL), by Deutsche Forschungsgemeinschaft SFB1052: projects B1 (to MB) and B4 (to NK), by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (N. Klöting) and by the Helmholtz Alliance ICEMED – Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association. We acknowledge support from the German Research Foundation (DFG) and the Universität Leipzig within the program Open Access Publishing.