Comparing the effects of diethylhexyl phthalate and dibutyl phthalate exposure on hypertension in mice

Abstract

Epidemiological studies have shown that high molecular weight phthalates (HMW) such as diethylhexyl phthalate (DEHP), are associated with hypertension in humans, while low molecular weight phthalates (LMW) such as dibutyl phthalate (DBP), have hardly any impact on the elevation of blood pressure. However, the molecular mechanisms responsible for this difference are not completely understood. In this experiment, mice were exposed to 0.1/1/10 mg/kg/day DEHP and 0.1/1/10 mg/kg/day DBP for 6 weeks, and their blood pressure was monitored using the tail pressure method. The results showed that exposure to DEHP dosages of 1 or 10 mg/kg/day resulted in a sharp increase in blood pressure, while exposure to DBP did not induce any significant changes in blood pressure. Investigating the renin-angiotensin-aldosterone system (RAAS) and NO pathway in mice exposed to DEHP, we found that levels of angiotensin-converting enzyme (ACE) and angiotensin II (AngII) increased with increasing exposure to DEHP, and the expression of nitric oxide synthase (eNOS) and the level of NO decreased. Treatment with ACE inhibitor (ACEI) to block the ACE pathway inhibited the enhancement of RAAS expression, inhibited the increase in blood pressure, and inhibited the decrease in NO levels induced by DEHP. However, the expression of ACE, AngII, AT1R, and eNOS in the DBP treatment groups showed no significant changes. When examining estradiol in vivo, we found that exposure to DBP resulted in a significant increase in the level of estradiol, while exposure to DEHP did not lead to a significant change. When ICI182780 was used to block the estradiol receptors, any increase in the level of NO induced by DBP exposure, was inhibited. These results indicate that exposure to DEHP induces an increase in mouse blood pressure through RAAS, and the different effects of DEHP and DBP on blood pressure are partly due to the different estradiol levels induced by DEHP and DBP.