Exposure to diisononyl phthalate induced an increase in blood pressure through activation of the ACE/ AT1R axis and inhibition of NO production

• Published in: Toxicology letters 2019-07, Vol.309, p.42-50
• Main Authors: Deng, Ting, Xie, Xiaoman, Duan, Jiufei, Chen, Mingqing
• Format: Article
• Language: English
• Subjects: Angiotensin converting enzyme; Angiotensin-II- type 1 receptor; Blood pressure; Diisononyl phthalate; Endothelial nitric oxide synthase
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2019.03.011

[Display omitted] •DINP exposure could induce marked increase in blood pressure.•DINP exposure resulted in the increase of ACE and AT1R expression.•DINP exposure inhibit the eNOS expression and NO production.•ACEI treatment effectively alleviated the increase in blood pressure level. Recent epidemiological studies have found that diisononyl phthalate (DINP) is associated with an increase in blood pressure. However, this correlation had not been clarified, nor has the underlying mechanism been characterized. In this study, C57/BL6 mice were exposed to DINP doses of 0.15 mg/kg/day, 1.5 mg/kg/day or 15 mg/kg/day for 6 weeks. Dexamethasone (DEXA) was used to build the hypertension model. After DINP exposure and 1 mg/kg/day DEXA treatment, the levels of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) were determined, and any histopathological changes in hypertension targeted organs of the mice were investigated. The results suggest that DINP exposure and DEXA treatment induced marked increases in SBP, DBP, and MBP, and that 15 mg/kg/day DINP exposure could also increase the HR level. Along with the blood pressure increase, DINP exposure induced pathological changes to the heart, aorta, and kidney. To explore the underlying mechanism, we measured the expression of angiotensin converting enzyme (ACE), angiotensin-II type 1 receptor (AT1R) and endothelial nitric oxide synthase (eNOS) in the aorta, as well as the nitric oxide (NO) concentration in serum. The data suggest that DINP exposure and DEXA treatment enhance the expression of ACE and AT1R, and inhibit eNOS expression and NO production. Interestingly, treatment with 5 mg/kg/day ACE inhibitor (ACEI) alleviated the increase in blood pressure induced by DINP exposure and DEXA treatment. These findings expand our understanding of how DINP exposure impacts the development of hypertension, and elucidates the underlying mechanisms.