Effects Of Chronic Exposure To Phenanthrene On Glucose Homeostasis In Mice And Mechanisms Involved

Polycyclic aromatic hydrocarbons(PAHs)are a type of ubiquitous organic pollutants.The pollution degree of PAHs is increasing rapidly,which has aroused widespread concern.Epidemiological investigations show that the content of PAHs in human body is connected with the destruction of glucose homeostasis,but it has not been confirmed in animal experiments.Therefore,the effect of PAHs on glucose homeostasis and underlying mechanism are still puzzling.1.Exposure to phenanthrene(Phe)disturbed glucose homeostasis in male mice.In our experiment,Phe was selected as a typical of PAHs,and adolescent male KM mice were chosen as the research objects to study the toxic mechanism of glucose metabolism disorder caused by chronic exposure to Phe at environmental levels.Mice were exposed to Phe at concentrations of 5,50 and 500 ng/kg via gavage once every two days.The glucose homeostasis was monitored every 30 days until changed.The levels of serum insulin and glucagon of males were significantly increased after Phe exposure for 210 days,and their counterregulation action resulted in an inverted-U shape changes in the fasting blood glucose levels and the area under the GTT curve(OGTT AUC).Homeostasis model of HOMA-IR and HOMA-β cell were significantly elevated,along with hyperinsulinemia,suggested the occurrence of insulin resistance in mice.The relative area and mass of α-and β-cells were increased and showed significant differences,which corresponded to the increase of serum insulin and glucagon levels.It showed that during the period of insulin resistance,the compensatory hyperplasia of β-cells could relieve the pressure of insulin sensitivity decline,and increased α-cell mass and hyperglucagon might promote the development of type 2 diabetes.The inhibition of the insulin receptor signaling pathway in skeletal muscle might contribute to glucose intolerance.Under the nonobese state,the adiponectin levels were decreased,while the serum levels of tumor necrosis factor-α,interleukin-6 and resistin were increased.The changes in serum levels of these adipokines were in keeping with their mRNA levels in white adipose tissue.The promoter methylation levels of Retn and Adipoq were negatively correlated to their transcription levels,suggesting that Phe treatment might induce disorders of adipocytokine secretion through epigenetic modification.Ⅱ.Exposure to Phe disturbed glucose homeostasis in female mice.In the current work,adolescent female KM mice were chosen as the research objects to study the toxic mechanism of glucose metabolism caused by chronic exposure to Phe at environmental level.Mice were treatment with Phe at concentrations of 0.05,0.5 and 5 ng/mL though their drinking water.The drinking water was changed every two days and the glucose homeostasis was monitored every 30 days until changed.After 270 days of Phe exposure,female mice demonstrated disorder of glucose metabolism and showed an inverted U-shaped dose effect.The significant elevation of fasting blood glucose level and OGTT AUC in the 0.05 ng/mL group,indicating that glucose intolerance occurred which might be caused by the inhibition of the insulin receptor signaling pathway in skeletal muscle.The significant elevation in HOMA-IR,accompanied by insulinemia,suggested the occurrence of insulin resistance in mice.The adiponectin levels were decreased,while the serum levels of tumor necrosis factor-α,interleukin-6 and resistin were increased,which were in keeping with the mRNA levels of genes in white adipose tissue.These changes were related to the variation of DNA methylation level in the genes.After 90 days of exposure,Phe began to induce dose-dependent decrease in body weight and continued to the end of treatment in female mice.Further observation revealed that the reduced white adipose tissue mass was positively correlated with that of body weight.The expression of peroxisome proliferator-activated receptor y(PPARy)and CCAAT/enhancer binding protein(C/EBPa)shown no significant differences,while the expression of hormone-sensitive lipase(HSL)was significantly increased in white adipose tissue.Furthermore,the transcriptional levels of key genes for fatty acid oxidation,for instance peroxisome proliferator-activated receptor y costimulatory factor 1α(Pgc1α),pyruvate dehydrogenase kinase 4(Pdk4),and ester acyl-CoA oxidase 1(Acox1),were also significantly upregulated,indicated Phe had no effect on adipogenesis,whereas promoted the lipolysis,strengthened theβ-oxidation of of fatty acids,resulted in adipose tissue loss and weight loss.Further study found that Phe accumulation in the brain caused a damage to hypothalamic neuronal cells,and led to a significant decrease in the expression of hypothalamic intermediate degeneration lymphoma kinase(ALK),activated the sympathetic nervous system,increased the level of norepinephrine in white adipose tissue.Thus,Phe promotes the lipolysis of white adipose tissue.In addition,Phe exposure induced dose-dependent increment of drinking water uptake in female mice,and combined with weight loss and glucose metabolism disorders,showed a symptom similar to emaciation-thirst(Xiaoke).The levels of arginine vasopressin in the serum were reduced significantly,and the expression of arginine vasopressin protein in the hypothalamic was significantly down-regulated,which was responsible for the increase in drinking water volume.In summary,chronic exposure to Phe at environmental level can disrupt glucose and lipids homeostasis in both male and female mice,however the exposure time and adverse effects are different.