Objective To observe the effects of chronic exposure to low-dose di (2-ethylhexyl) phthalate (DEHP) on glucose metabolism in female rats.
Methods Twenty-four female SPF SD rats were randomly divided into four groups0, 3, 30, and 300 mg/kg (in terms of body weight) DEHP groups, respectively, with six rats in each group, and exposed to DEHP by gavage for continuous 46 weeks. Fasting blood glucose of rats and body weight change were measured regularly. Twenty-four hours after the last exposure, rats' body weight was measured, and oral glucose tolerance test (OGTT) was conducted to estimate area under curve (AUC) of blood glucose over time. Insulin tolerance test (ITT) was also carried out. Then the rats were given chloral hydrate anesthesia and sacrificed to collect samples of heart apex, weigh liver, pancreas, gastrocnemius muscle, and white fat around genital organs, and to observe histopathological changes of the tissues after fixed in 10% neutral formalin (except muscle sample).
Results During the DEHP exposure, no obvious toxic effect was observed in any groups. Compared with the 0 mg/kg group, there was no significant difference in the body weight of the experimental groups (P > 0.05). The liver organ coefficients of the 300 mg/kg group was elevated (P < 0.05) and the other experimental groups showed no differences (P > 0.05) compared with the 0 mg/kg group. There were no significant differences in the organ coefficients of pancreas, white fat around genital, and gastrocnemius muscle among the experimental groups (P > 0.05). Compared with the 0 mg/kg group, elevated fasting blood glucose was observed in the 300 mg/kg group treated with DEHP for 18 weeks (P < 0.05), while there was no significant difference in the fasting blood glucose at different exposure time (P>0.05). The homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI), and serum insulin levels showed no differences among all groups (P > 0.05). The OGTT results showed that, for the 300 mg/kg group, blood glucose reached peak value at 15 min after administration with glucose (P=0.004) then was significantly decreased at 60 min and 120 min after the administration (P=0.038, P=0.039), and the value at 120 min was lower than the fasting level; in addition, the blood glucose AUC was decreased (P=0.040). The ITT results showed that the blood glucose of the 30 mg/kg group at 15 min was significantly lower than that of the 0 mg/kg group (P=0.029); the blood glucose of the 300 mg/kg group was decreased more obviously with a reduction more than 50% at 60 min and 120 min (P=0.017, P=0.038), and returned to the fasting blood glucose value slowly; the blood glucose AUC of the 300 mg/kg group was also decreased (P=0.028). The liver cells of each DEHP exposure group showed edema, interstitial loose, and varied degrees of bile duct inflammation. Shrinkages in area of pancreatic islets and count of islet cells were observed in each DEHP group. The changes of white fat around genitalia of each DEHP group included shrunk cell morphology, different cell sizes, and irregular cell arrangement.
Conclusion Chronic exposure to low-dose DEHP can lead to insulin resistance in female rats.
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