Archives of Toxicology

, Volume 90, Issue 1, pp 181–190 | Cite as

Di-(2-ethylhexyl) phthalate accelerates atherosclerosis in apolipoprotein E-deficient mice

  • Jin-Feng Zhao
  • Sheng-Huang Hsiao
  • Ming-Hua Hsu
  • Kuan-Chuan Pao
  • Yu Ru Kou
  • Song-Kun Shyue
  • Tzong-Shyuan LeeEmail author
Organ Toxicity and Mechanisms


Di-(2-ethylhexyl) phthalate (DEHP) is associated with atherosclerosis-related cardiovascular disease complications, but we lack direct evidence of its unfavorable effect on atherogenesis. In this study, we aimed to clarify in vivo and in vitro the contribution of DEHP to the development of atherosclerosis and its underlying mechanisms. Apolipoprotein E-deficient (apoE−/−) mice chronically treated with DEHP for 4 weeks showed exacerbated hyperlipidemia, systemic inflammation, and atherosclerosis. In addition, DEHP promoted low-density lipoprotein (LDL) oxidation, which led to inflammation in endothelial cells as evidenced by increased protein expression of pro-inflammatory mediators. Furthermore, chronic DEHP treatment increased hepatic cholesterol accumulation by downregulating the protein expression of key regulators in cholesterol clearance including LDL receptor, cholesterol 7α-hydrolase, ATP-binding cassette transporter G5 and G8, and liver X receptor α. Moreover, the adiposity and inflammation of white adipose tissues were promoted in DEHP-treated apoE−/− mice. In conclusion, DEHP may disturb cholesterol homeostasis and deregulate the inflammatory response, thus leading to accelerated atherosclerosis.


DEHP Atherosclerosis Cholesterol metabolism Inflammation Obesity 



The authors thank Laura Smales (BioMedEditing) for help in language editing.

Conflict of interest

The authors have declared no conflicts of interest.

Supplementary material

204_2014_1377_MOESM1_ESM.doc (1.8 mb)
Supplementary material 1 (DOC 1792 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jin-Feng Zhao
    • 1
  • Sheng-Huang Hsiao
    • 2
  • Ming-Hua Hsu
    • 3
  • Kuan-Chuan Pao
    • 3
  • Yu Ru Kou
    • 1
  • Song-Kun Shyue
    • 4
  • Tzong-Shyuan Lee
    • 1
    Email author
  1. 1.Department of Physiology, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Department of SurgeryRen-Ai Taipei City HospitalTaipeiTaiwan
  3. 3.Nuclear Science and Technology Development CenterNational Tsing Hua UniversityHsinchuTaiwan
  4. 4.Cardiovascular Division, Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan

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