| Per-and polyfluoroalkyl substances(PFASs)are a class of manmade organic chemicals.The legacy PFAS such as PFOS and PFOA were banned or severely restricted due to their environmental persistence,bioaccumulation and multiple potential toxicity,which has led to the development and production of a range of PFAS alternatives.Recently,perfluoroalkyl ether carboxylic acids(PFECAs),a substitute for PFOA or a by-product of the synthesis process,has been frequently detected in environmental media and human serum,and its potential health hazards have become an urgent concern.In the current study,we explored the potential bioaccumulation and elimination ability of PFO4 DA and PFO5 DoDA,and their chronic effects and mechanisms on liver after prolonged treatment in male mice.The main results are as follows:1.The male BALB/c mice were administered in a single intravenous injection of 10 μg/kg body weight of PFO4 DA or PFO5 DoDA via the caudal vein,serum samples were then repeatedly collected for PFO4 DA and PFO5 DoDA detection during the following times,respectively.The serum half-life of compound were calculated using the single compartment model with first-order elimination: the serum clearance half-life of PFO4 DA was 24 h,whereas the half-life of PFO5 DoDA was up to 43 d.After 6 months,PFO5 DoDA was still detectable in serum at 2-3 ng/m L after 6 months.2.The compound concentrations in liver was much higher than that in serum in both 2 and10 μg/kg/d of PFO4 DA and PFO5 DoDA exposure groups after 140 d exposure,indicating that both compounds were more inclined to accumulate in the liver..There was no significant changes in their liver histopathological sections and the serum biochemical indicators such as ALT and AST,suggesting that exposure did not lead to significant damage or necrosis in hepatocytes.However,hepatomegaly was identified after 140 d exposure with relative liver weight increasing by 7.25% and 21.81% in the 10 μg/kg/d PFO4 DA and PFO5 DoDA groups,respectively,compared to control group.3.Transcriptome analysis showed chronic treatment of PFO4 DA and PFO5 DoDA changed the hepatic transcriptomic profile.In total DGEs,126 genes were shared in both exposure groups,accounting for 57.0% and 17.8% of DGEs in PFO4 DA and PFO5 DoDA groups,respectively.A stronger changes of most DEGs were observed in PFO5 DoDA group.In addition,KEGG enrichment analysis revealed three shared pathways by both PFO4 DA and PFO5 DoDA groups,i.e.,mitogen-activated protein kinase(MAPK)signaling,which responds to cellular stress,peroxisome proliferators-activated receptor(PPAR)and insulin resistance signaling,which are involved in glucose and lipid metabolism.4.The levels of glucose in liver and serum were significantly increased after 10 μg/kg/d PFO4 DA and PFO5 DoDA exposure,while the intrahepatic pyruvate levels decreased,compared to control groups.In addition,the intrahepatic lactate levels decreased in the 10μg/kg/d PFO5 DoDA-treated group,compared to the control group.The expression level of Pfkfb3,the rate-limiting enzyme of glycolysis,was significantly lower than that of the control group.The suppression on Pfkfb3 may have contributed to the observed increase in glucose and decrease in pyruvate and lactate levels in the liver.The levels of serum triglycerides were significantly increased in 10 μg/kg/d PFO4 DA and PFO5 DoDA groups,while the total serum cholesterol was no changed.The levels of total cholesterol and triglycerides in the liver were significantly lower in the 10 μg/kg/d PFO5 DoDA group compared to the control group,while only triglycerides were lower in the 10 μg/kg/d PFO4 DA treatment.The endocrine factor Fgf21,which plays an important regulatory role in glycolipid catabolism,was significantly decreased in the livers of both the PFO4 DA and PFO5 DoDA-treated groups.In summary,the chronic low-dose exposure to PFO4 DA and PFO5 DoDA inhibited hepatic stress response molecules and disrupted glucolipid metabolism,leading to the elevated metabolites such as glucose and triglycerides in the serum. |
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