Di-(2-ethylhexyl) phthalate induced an increase in blood pressure via activation of ACE and inhibition of the bradykinin-NO pathway

Environ Pollut. 2019 Apr;247:927-934. doi: 10.1016/j.envpol.2019.01.099. Epub 2019 Jan 31.


Epidemiological studies and animal experiments have suggested that exposure to Di-(2-ethylhexyl) phthalate (DEHP) is strongly associated with an increase in blood pressure. However, the mechanisms that result in the detrimental effects of DEHP exposure on blood pressure are unclear. In our study, mice were orally exposed to DEHP dosages of 0.1, 1, 10 mg/kg/day for 6 weeks. The results showed that DEHP could induce a significant increase in systolic blood pressure (SBP) and heart rate, and a significant thickening of the ventricular wall. To explore the underlying mechanism, we measured the level of: angiotensin converting enzyme (ACE); bradykinin B2 receptor (BK2R); endothelial nitric oxide synthase (eNOS); bradykinin and Ca2+ in cardiac cytoplasm as well as in serum nitric oxide (NO). The results suggested that DEHP could induce an increase in ACE levels, and a decrease in bradykinin levels. Moreover, BK2R, Ca2+, eNOS and NO decreased when mice were exposed to 10 mg/kg/day DEHP. Interestingly, 5 mg/kg/day angiotensin converting enzyme inhibitor (ACEI) treatment inhibited the increase in blood pressure, and inhibited the decrease in the levels of BK2R, Ca2+, eNOS, and NO, that were induced by DEHP exposure. Our results suggest that DEHP might increase blood pressure by activating ACE expression, and inhibiting the bradykinin-NO pathway.

Keywords: ACE; Blood pressure; Bradykinin-NO pathway; Di-(2-ethylhexyl) phthalate.

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Bradykinin / metabolism*
  • Diethylhexyl Phthalate / toxicity*
  • Male
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Peptidyl-Dipeptidase A / metabolism*
  • Receptor, Bradykinin B2 / metabolism
  • Signal Transduction / drug effects


  • Receptor, Bradykinin B2
  • Nitric Oxide
  • Diethylhexyl Phthalate
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Peptidyl-Dipeptidase A
  • Bradykinin