Effects Of Environmental Factors In Utero On The Glucose And Lipid Metabolism In F1 Adult Mice And Mechanisms Involved

Fetus are undergoing vigorous development and are susceptible during pregnancy.Many environmental factors affect the development of the fetus by affecting the structure and function of the placenta,directly penetrating the placental barrier and entering the fetus,and altering epigenetic modification,and further influence their metabolic homeostasis in the later life.I.Prenatal supplementation with β-carotene(BC)disorders lipids metabolism and glucose homeostasis in female F1.BC is a substitute for vitamin A and has no teratogenicity,mutagenicity,and embryotoxicity.Therefor,BC is abused in clinical,health care,and food supplementation.However,the effect of supplementation with BC during pregnancy on the health of offspring has not been reported.In this study,C57BL6 mice were used as animal models to study the effect of prenatal supplementation with BC on the metabolism of glucose and lipids in the offspring.The mice on the 0.5th day of pregnancy were intragastrically administered with 1 mg/kg body weight of BC once every 3 days,and a total of 6 doses during pregnancy.The F1 adult female mice prenatally supplemented with BC showed a significantly increased abdominal fat accumulation,reduced glucose tolerance,while males did not have these symptoms compared to the control group.The reduced serum estradiol levels in F1 female mice and no significant altered serum testosterone levels in F1 male mice by the prenatal BC supplementation may account for this gender-dependent difference.This study showed that prenatal supplementation with BC upregulated the mRNA expression of the rxrβ via reducing the DNA methylation status of its promoter region,and then upregulate its protein level in the liver of F1 female mice.Meanwhile,the protein expression of PPARy in liver and white adipose tissue were also upregulated,accompanied by adipogenesis and a significant accumulation of fat.Obesity is a major risk factor for diabetes,the accumulation of abdominal fat in F1 female mice caused by BC led an increase in the levels of serum resistin,leptin and interleukin-6,and a decrease in serum adiponectin levels,which in turn affected the body’s glucose homeostasis.There was no significant change in the accumulation of abdominal fat and expression level of PPARy in the liver and white adipose tissue of F1 adult male mice,which might be one of the reasons why the F1 male mice did not exhibit symptoms of glucose metabolism disorder such as abnormal blood glucose or impaired glucose tolerance.However,glucose intolerance in F1 female mice may result from the insulin resistance in skeletal muscle caused by downregulation of the insulin receptor signaling,and insufficient insulin secretion caused by the damage of the structure and function of β-cell maybe another reason.The increase of a-cell mass and the upregulation of proglucagon gene gcg by prenatal supplementation with BC may further result in overt diabetes in the F1 female mice.Ⅱ.Prenatal exposure to Phenanthrene(Phe)disturbs the glucose and lipids metabolism homeostasis in F1 offspringPolycyclic aromatic hydrocarbons(PAHs)are a kind of pollutants existing anywhere,and epidemiological surveys show that the risk of developing diabetes is closely related to the amount of polycyclic aromatic hydrocarbons in human.However,the effect of intrauterine exposure of PAHs on glucose metabolism in adult mice has not been reported.In this study,phenanthrene(Phe)was used as a representative of PAHs,to study the effects of prenatal exposure to Phe on glucose and lipid metabolism in F1 adult offspring in C57BL6 mice.The mice on the 0.5th day of pregnancy were intragastrically administered with 60,600,6000 μg/kg body weight of Phe,once every 3 days,and given a total of 6 doses during pregnancy.The levels of serum estradiol and testosterone of F1 females after prenatal exposure to Phe was decreased compared to the control.However,in the F1 male mice,the serum estradiol levels did not show significant changes by prenatal exposure to Phe,and the serum testosterone levels was increased significantly in the 600 μg/kg group.In addition,the expression of estrogen receptor alpha(ERa)in the pancreas of F1 females after prenatal exposure to Phe was decreased compared to the control,and the expression of androgen receptor(AR)was increased.However,the expression of ERa in the pancreas of male mice did not exhibit significant changes,and the expression level of the AR was increased.These different alterations of the serum levels of estradiol and testosterone between the F1 females and males by prenatal exposure to Phe maybe account for the sexual dimorphism in the effects of in-utero Phe on metabolic homeostasis in the F1 mice.In F1 female mice,prenatal exposure to Phe at 60 and 600μg/kg reduced the mass and relative area of islet a cells,and Phe at 6000 μg//kg increased the mass and the relative area of islet a cells,while exposure to Phe at all levels in these research decreased the expression of ARX,the marker protein of pancreatic islet a cells,significantly reduced the transcription of the pancreatic proglucagon gene(gcg)and the level of serum glucagon,and upregulated the expression of the insulin receptor signaling in livers.These changes collectively led to a decrease in fasting blood glucose levels after prenatal exposure to Phe.In addition,exposure to Phe at 60 μg/kg reduced the mass and the relative area of islet β cells,and exposure to Phe at 600 and 6000 μg/kg resulted in a compensatory increase in the mass and relative area of islet βcells,while the expression levels of PAX4(marker of islet β cells undergoing differentiation)and PDX1(marker of mature islet β cells)was reduced after prenatal exposure to Phe at all the levels used in this research compared to the control,the transcription of the pancreatic proinsulin gene(ins2)and the serum insulin levels were decreased as well.Meanwhile,the expression of insulin receptor signalings was decreased.These alterations finally induced insulin resistance and glucose intolerance in the F1 females prenatally exposed to Phe.The serum levels of free fatty acid,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol and total cholesterol were decreased,while the serum triglyceride levels were increased.In F1 female mice,prenatal exposure to Phe downregulated the insulin receptor signaling in liver and skeletal muscle,futher inducing compensatory secretion of insulin and finally causing fasting hyperglycemia and hyperinsulinemia.In addition,prenatal exposure to Phe at 600 and 6000 μg/kg significantly reduced the mass and relative area of islet β and a cells,and decreased the expression of PAX4,while PDX1 and ARX was not significantly affected.The mRNA levels of the pancreatic ins2 and gcg of the F1 males prenatally exposed to Phe at 600 μg/kg were significantly increased,which may be related to the increase of serum testosterone levels.The levels of triglyceride,free fatty acid,high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in serum were reduced,while the total cholesterol levels in serum were elevated.In summary,the disturbance of in-utero environment may disturb the homeostasis of glucose and lipid metabolism in F1 offspring,and further increase the risk of developing diabetes,suggesting that micronutrients should be used cautiously,and attention should be paid to avoid exposure to environmental pollution during pregnancy.