Effects of typical phthalate esters on lipid metabolism in rats and its potential mechanism / 环境与职业医学

ABSTRACT

Background Di(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) are representative environmental endocrine disruptors of phthalate esters (PAEs). Some studies have shown that PAEs exposure may have an impact on lipid metabolism. Objective To investigate the effects of DEHP and/or DBP on lipid metabolism in rats and their possible mechanisms of action. Methods Thirty-six weaned healthy SD male rats, 3 weeks old, weighing 50-70 g, were divided into four groups, i.e., a corn oil control group, a DEHP (750 mg·kg−1) group, a DBP (500 mg·kg−1) group, and a DEHP+DBP (750 mg·kg−1+500 mg·kg−1) group. The rats were exposed to DEHP and/or DBP by oral gavage for 8 weeks, and weighed once a week. The rats were anesthetized 24 h after the last dose, and blood was taken from the apical part of the heart. Serum high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) were detected. Liver tissues and perigenital adipose tissues were collected, weighed, and one portion of the tissues was fixed in 10% neutral formalin for pathomorphological observation, and another portion was used for mRNA detection of lipid metabolism-related genes such as Janus kinase 3 (JAK3), signal transducer and activator of transcription 5b (STAT5b), and peroxisome proliferator-activated receptor γ (PPARγ). Results During the DEHP and/or DBP exposure period, the rats in all groups were free to eat and drink without death or injury observed. Compared with the control group The body weight gain in the DEHP+DBP group was lower at all time points from the 2nd week onwards (P<0.05); the liver organ coefficients of the DEHP and the DEHP+DBP groups were higher (P<0.05); the serum LDL-C levels in the DEHP and the DBP groups were higher (P<0.05). Compared with the DEHP+DBP group The body weight gains in the DEHP group at the 2nd, 4th, 5th, and 8th weeks were higher (P<0.05), and the body weight gains in the DBP group were higher at all time points except the 1st week (P<0.05); the liver organ coefficients in the DEHP group and the DBP group were lower (P<0.05); the serum TG level in the DEHP group was higher(P<0.05), and the serum LDL-C levels in the DEHP and the DBP groups were higher (P<0.05). The pathomorphological results of liver tissues showed that the hepatocytes in the DEHP, DBP, and DEHP+DBP groups were disordered with loss of cord-like arrangement, swelling (suggesting change of cell proliferation), and presented bilirubin pigmentation. The pathomorphological results of rat perigenital adipose tissues showed had irregular alignment, sizes, and arrangement of adipocyte in the DEHP, DBP, and DEHP+DBP groups. The results of rat liver lipid metabolism-related gene mRNA levels showed that the liver JAK3, STAT5b, and PPARγ mRNA levels in the DEHP, DBP, and DEHP+DBP groups were lower than those in the control group (P<0.05); the rat liver PPARγ mRNA levels in the DEHP and DBP groups were lower than those in the DEHP+DBP group (P<0.05). Conclusion DEHP and/or DBP can inhibit the increase of body weight to varying degrees, induce inflammatory damage to liver tissues, and cause abnormal lipid metabolism in rats, and the associated mechanism may be related to inhibiting the activation of JAK3/STAT5b/PPARγ signaling pathway in rat liver tissues.