Chronotoxicology Of Bisphenol A On Liver Lipid Metabolism In Mice

BackgroundCharacterized by abdominal obesity,insulin resistance,hypertension,and hyperlipidemia,metabolic syndrome(MS)is a complex of endocrine and metabolic disorders,including non-alcoholic fatty liver disease(NAFLD).Bisphenol A(BPA),as an environmental endocrine-disrupting chemical,can cause metabolic syndrome.Chronotoxicology describes the time-specific toxicity of exogenous compounds.The relationships between BPA exposure and liver lipid metabolism are inconclusive.There are few studies on the effects of BPA exposure at different times on hepatic lipid metabolism.Therefore,this study aims to explore the time-specific toxic effect of BPA exposure on liver lipid metabolism in mice.ObjectiveTo study the time-specific effects of BPA exposure on lipid metabolism a in mice,and explore the possible potential mechanisms related to circadian rhythm.Objective and Methods60 female C57BL/6J mice were selected and divided into 6 groups according body weight:ZT3 gavage control group,ZT3 gavage 50 μg/kg·bw/day BPA,ZT3 gavage 500 μg/kg·bw/day BPA,ZT15 gavage control group,ZT15 gavage 50 μg/kg·bw/day BPA,as well as ZT15 gavage 500 μg/kg·bw BPA.BPA gavage contamination was conducted for mice daily at ZT3 or ZT15.(ZT is the Zeitgeber time,ZT0 represents the light-on time,ZT12 represents the light-off time,ZT0 is 7:00am,ZT12 is 7:00pm in this study).BPA-treated group mice was conducted with BPA gavage by 50 and 500 μg/kg bw/day diluted by corn oil.Same volume of corn oil gavage was for mice in control group.The experiment lasted 4 weeks,during which mouse weight,food intake,and glucose tolerance were detected.After 4 weeks,mice of each group died after anesthesia at ZT3 and ZT15.Blood and organs were taken for determining plasma biochemical indicators,mRNA expression levels of liver TG and related genes.Results1.Effects of BPA exposure on liver lipid metabolism in miceCompared with the control group,liver triglyceride content in mice of BPA treatment group increased(P=0.001).According to results of liver HE and Oil Red O staining,compared with the control group,lipid small empty follicles and fat red dye degree in the 50 and 500 μg/kg·bw/day BPA groups had significantly increased.In the ZT15 sacrifice group,compared with the control group,plasma glucose content in 50μg/kg·bw/day BPA group increased(P=0.001).Compared with the control group,plasma insulin level in 500 μg/kg·bw/day BPA group increased(P=0.008).2.Chronotoxicology effect of BPA on liver lipid metabolism in miceAccording to the results of the Oil Red O staining sections,compared to the ZT15 gavage control group,there was significant increase lipid deposition lesions rate of moderate or severe of mice liver in ZT15 gavage 50 and 500 μg/kg·bw/day BPA treatment group(P=0.032).Compared to the ZT3 gavage control group,there was no statistical significance for the difference in the lesion rate of ZT 13 gavage 50 and 500μg/kg·bw/day BPA treatment group(P=0.562).3.Regulation of mice liver related genes in the chronotoxicology effect of BPA on liver lipid metabolismAt ZT3,the mRNA expression levels of liver lipid synthesis gene sterol regulatory element-binding transcription factor 1(Srebplc)was lower in 50 and 500μg/kg·bw/day BPA group(P=0.028).At ZT15,the mRNA expression levels of liver lipid synthesis gene Srebplc was higher in ZT15 50 and 500 μg/kg·bw/day BPA group(P=0.015).Compared with ZT15 control group,the mRNA expression levels of liver lipid synthesis genes acetyl coA carboxylase(Acc1)(P=0.035)and hydroxymethyl glutarate monoacyl coenzyme A reductase(Hmgcr)(P=0.001)was higher in ZT15 500 μg/kg·bw/day BPA group.There was no significant difference in the mRNA expression levels of liver lipid synthesis genes Accl(P=0.819)and Hmgcr(P=0.639)between ZT3 control group and ZT3 500 μg/kg·bw/day BPA group.Compared with ZT15 control group,the mRNA expression levels of liver lipid synthesis gene carbohydrate response element binding protein(Chrebp)was higher in ZT15 50 and 500 μg/kg·bw/day BPA group(P=0.022).There was no significant difference in the mRNA expression levels of liver lipid synthesis gene Chrebp between ZT3 control group and ZT3 50 and 500 μg/kg·bw/day BPA group.Conclusions1.Bisphenol A may increase plasma glucose and insulin levels,and also hepatic lipid deposition in mice;2.The effects of bisphenol A on hepatic lipid deposition in mice show time dependent manner,and are stronger at resting stage exposure(ZT15);3.Bisphenol A may increase the hepatic mRNA expression levels of lipid synthesis factors Accl,Srebp1c,Hmgcr and Chrebp in mice in a time-dependent manner,and also are stronger at resting stage exposure(ZT15)when observed at activity stage(ZT3).