Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites
December
Di-(2-Ethylhexyl)-Phthalate (DEHP) Causes Impaired Adipocyte Function and Alters Serum Metabolites
0 Funding: 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
1 Editor: Jonathan Peterson, East Tennessee State University , UNITED STATES
2 1 IFB AdiposityDiseases, University of Leipzig , Leipzig, Germany , 2 Department of Medicine, University of Leipzig , Leipzig, Germany , 3 Institute of Anatomy, University of Leipzig , Leipzig, Germany , 4 German Center for Diabetes Research (DZD) , Leipzig, Germany , 5 Institute for Clinical Chemistry, Otto-von- Guericke-University Magdeburg , Magdeburg, Germany , 6 Department of Anatomy and Cell Biology, Martin Luther University Halle , Halle (Saale), Germany , 7 Department of Metabolomics, Helmholtz Centre for Environmental Research Leipzig , Leipzig, Germany , 8 Department of Proteomics, Helmholtz Centre for Environmental Research Leipzig , Leipzig, Germany , 9 Department of Biotechnology and Environmental Engineering, University of Aalborg , Aalborg , Denmark
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,
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OPEN ACCESS
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
insulin or triglyceride serum concentrations. This may suggest that DEHP treatment does
not cause impaired glucose metabolism at the whole body level.
acknowledge support from the German Research
Foundation (DFG) and the Universität Leipzig within
the program Open Access Publishing.
Introduction
Obesity is the fastest growing health problem in Europe and worldwide. Overweight affects
between 30% and 80% of adults in the WHO European Region and up to one third of children
[
1
]. In addition to genetic factors, life style factors such as excessive caloric intake, high fat
diets, and low physical activity contribute to obesity. However, there is also increasing evidence
that environmental pollutants including endocrine-disrupting chemicals may contribute to the
development of obesity and metabolic disorders [
2
]. Chronic exposure to endocrine-disrupting
chemicals such as dioxins [
3
] bisphenol A [
4
] or phthalates [
5,6
] has been linked to an
increased risk of developing insulin resistance or diabetes. Importantly, in the Prospective
Investigation of the Vasculature in Uppsala Seniors Study of 1,016 elderly (age>70 years), Lind
and coworkers demonstrated that several phthalate metabolites are related to diabetes
prevalence, as well as to markers of insulin secretion and resistance [7].
Among those environmental factors, the plasticizer di(2-ethylhexyl)phthalate (DEHP), has
been reported to induce glucose intolerance and alterations in hepatic glycogen content in rats.
DEHP improves flexibility of polyvinyl chloride [
8
]. Humans are widely exposed to DEHP,
because it is used in many daily products, including vinyl flooring, wall covering, plastic bags
and covers, food containers, cosmetics, and toys [
9
]. Humans are expo (...truncated)