Effects Of Cadmium On Oxidative Stress And Lipid Metabolism Disorder In Mice

Health concerns regarding the environmental heavy metals in wildlife and humans have increased in recent years.Cadmium(Cd)is an environmental pollutant known to cause liver damage;however,the mechanisms of its hepatotoxicity remain poorly understood.Firstly,we evaluated the effects of exposure of mice to low doses of cadmium(Cd)on oxidative-and ER-stress.Male adult mice were orally exposed to Cd(0.5 and 2 mg /kg)daily for 36 days.It was observed that the bioaccumulation of Cd in the liver in a dose-dependent manner,and the Cd contents in the 2 mg/kg Cd treated groups reached 2.43 liver weights.In addition,treatments with 2 mg/kg Cd,significantly decreased body and liver weights,increased the levels of reactive oxygen species(ROS),malondialdehyde(MDA)and activities of catalase(CAT)and glutathione peroxidase(GPX)in the liver.Moreover,Cd exposures also elevated the transcription of the oxidative-and endoplasmic reticulum(ER)-stress related genes including Cat,Gpx,heme oxygenase 1(Ho-1),regulated protein 78(Grp78),activating transcription factor 6(Atf6)and proaoptotic CCAAT/-enhancer-binding protein homologous protein(Chop)in a dose dependent manner in the liver.And hepatic cytochrome c levels increased in all Cd treated groups.Furthermore,the transcriptional status and the activities of Caspase 9 and Caspase 3 were increased significantly in the liver when exposed to high doses of Cd.These results suggested that a long period exposure of mice to Cd has the potential to elicit oxidative-and ER-stress mediated apoptosis in their livers.Secondly,effects of subchronic exposure in mice to low doses of Cd on energy metabolism and the gut microbiome were also evaluated.The exposure of mice to 10 mg/L Cd supplied in drinking water for 10 weeks increased hepatic triacylglycerol(TG),serum free fatty acid(FFA),and TG levels.The mRNA levels of several key genes involved in both de novo FFA synthesis and transport pathways and in TG synthesis in the liver also increased significantly in the Cd-treated mice,indicating that alterations of these genes may be a possible mechanism to explain subchronic Cd exposure induced hepatic toxicity at a molecular level.As for the gut microbiome,at the phylum level,the amounts of Firmicutes and ?-proteobacteria decreased significantly in the feces after 4 weeks of Cd exposure,and the quantity of Firmicutes decreased significantly in the cecum contents after 10 weeks of Cd exposure.In addition,16 S rRNA gene sequencing further revealed that Cd exposure significantly perturbed the gut microflora structure and richness at family and genus levels.The alteration of gut microbiome composition might result in an increase in serum lipopolysaccharide(LPS)and induce hepatic inflammation,which may indirectly cause perturbations of energy homeostasis after Cd exposure.Taken together,the present study indicated that subchronic Cd exposure caused the dysregulation of energy metabolism and changed the gut microbiome composition in mice.These data were useful to understand the hepatic toxicity of heavy metal on mammals.