Dynamic Effects And Mechanisms Of Aroclor 1254 On Glucose Homeostasis In Male Mice

As a member of persistent organic pollutants,polychlorinated biphenyls(PCBs)have multiple toxic effects on organisms.Although a lot of researches have demonstrated that PCBs exposure can induce type 2 diabetes mellitus(T2DM),there are few studies on the dynamic effects and mechanisms of PCBs on T2DM,and the related epigenetic mechanisms are largely unknown.In order to reveal the exact dynamic process and underlying epigenetic mechanisms,3 weeks old C57BL/6 male mice were treated with Aroclor 1254 once every three days with a dosage of 0.5,5,50 and 500?g/kg.The present study consisted of three stages:first,male mice had been exposed to Aroclor 1254 until they had appeared an impaired glucose homeostasis.Then the exposure was stopped and the exposed mice were recovered to a normal glucose homeostasis.And finally,mice were re-exposed to Aroclor 1254 to have shown an impaired glucose homeostasis again.Results were shown as follows:1.After exposed to Aroclor 1254 for 66 day,the mice showed an impaired glucose tolerance,and the impaired glucose tolerance could be recovered normal after stopping the exposure for 90 days.After re-exposure to Aroclor 1254 for 30 days,fasting blood glucose was significantly increased in the 5,50 and 500 ?g/kg groups compared to the control.2.Re-exposure to Aroclor 1254 resulted in a significant increase of GSK3?expression in the 500 ?g/kg group.Re-exposure to Aroclor 1254 caused no significant effects on the protein expressions of the insulin receptor pathway in the liver.3.Treatment with 50 and 500 ?g/kg Aroclor 1254 for 66 days increased significantly the serum insulin level in mice.The increased serum insulin was recovered to normal levels after stopping the exposure for 90 days.After 30 days exposed to Aroclor 1254 again,serum insulin levels were significantly decreased compared to the control.Serum glucagon levels were significantly decreased in the 50?g/kg group after re-exposed to Aroclor 1254 for 30 days.4.After exposure to Aroclor 1254 for 66 days,pancreatic ? cell mass was significantly increased in the 500 ?g/kg group.After recovery for 90 days,? cell mass in all the treatments had no significant change compared to the control.Although ?cell mass was increased after re-exposed for 30 days,it did not show a significant different with the control.Pancreatic a cell mass was significantly reduced in the 5?g/kg group after the first exposure and in the 500 ?g/kg group after the re-exposure.5.Insulin gene 2(INS2)mRNA levels in the 50 and 500 ?g/kg were all significantly reduced after exposure to Aroclor 1254 for 66 days,recovery for 90 days and re-exposure for 30 days.It might be a main reason why serum insulin levels were apparently decreased after exposure to Aroclor 1254 for 30 days.Exposure to Aroclor 1254 for 66 days significantly reduced glucagon gene(GCG)mRNA levels in the 5 and 500 ?g/kg groups.And GCG mRNA level showed a reduction after recovery for 90 days.After re-exposure to Aroclor 1254 again,GCG mRNA levels in all the treatments were significantly reduced compared to the control.6.Exposure to Aroclor 1254 for 66 days resulted in an elevation in the INS2 promoter methylation level,and this elevation appeared a significant different between all the treatments and the control after recovery for 90 days.INS2 promoter methylation levels were significantly increased in the 50 and 500 ?g/kg after re-exposure to Aroclor 1254 for 30 days.Increased INS2 promoter methylation might cause the low levels of INS2 mRNA.GCG promoter methylation levels were significantly increased in the 500 ?g/kg group after first exposure and in the 5 ?g/kg group after re-exposure.In summary,the present study uncovered that impaired glucose homeostasis caused by the first exposure to Aroclor 1254 was recoverable.Aroclor 1254 could inhibit the mRNA expression of pancreatic INS2 via elevating promoter methylation levels of this gene,which resulted in the reduction of serum insulin levels.This persistent effect caused that the glucose homeostasis of the mice was more vulnerable to re-exposure of Aroclor 1254.