Effects Of Triphenyl Phosphate Sub-chronic Exposure On Hepatic And Renal Lipid Metabolism In Mice Under Different Diets

Triphenyl phosphate(TPP),as one of the most extensively used organophosphorus flame retardant(OPFRs),is considered to be the most effective flame retardant in many polymers.With the mass production and use of TPP,the residues can be detected in all kinds of environmental samples.The necessity of TPP environmental and health risk assessment has gradually attracted attention.However,most TPP health impact studies are based on in vitro models or zebrafish,and are not suitable as supporting data for health risk assessment.Studies have shown that TPP has potential fattening properties.The limited studies on mice and TPP’s health effects mainly focus on reproductive toxicity,neurotoxicity,and endocrine disruption effects and so on.Few studies investigated the effects of TPP on lipid metabolism associated with obesityLipid metabolism,as one of the metabolism activities of the body,is of great significance for life activities.It has been proposed that regulating lipid metabolism might be the starting point to improve or even cure lipid metabolism related diseases,which is of great significance to deal with the obesity problem.Therefore,it is urgent to study and evaluate the interference effect of TPP to lipid metabolism.It is reported that liver and kidney are prone to fatty degeneration and fat deposition,which can be important organs to study lipid metabolism.Moreover,the gut microbiome is closely related to lipid metabolism,and the imbalance of gut microbiome may lead to the lipid metabolic abnormality.Based on the above background and considering the actual exposure of TPP,this study explored the effects of sub-chronic exposure of environmental related doses of TPP on hepatic and renal lipid metabolism in mice under different diets,and tried to analyze the potential mechanism.The main results and conclusions are listed as follows(1)After 12 weeks of TPP exposure,the food intake of C57 mice were affected,glucose tolerance and insulin tolerance were abnormal,and the content of triglyceride and total cholesterol in serum increased.The effect was dose-dependent and the effect of low dose exposure is more significant.When high fructose and high fat diets(HFF)and TPP were exposed together,TPP could promote serum lipid content increase and abnormal glucose tolerance and insulin tolerance caused by HFF exposure,indicating that TPP could promote HFF induced lipid metabolism disorder and enhance HFF health risk(2)The sub-chronic exposure of TPP at environmentally relevant level could cause ultrastructure such as cell nucleus,endoplasmic reticulum and mitochondria of mouse hepatocytes to be damaged,lead to the edema degeneration and steatosis of mouse hepatocytes,induce liver injury and inflammation,and result in the abnormal lipid metabolism.In the presence of HFF,the damage caused by TPP exposure was more serious.Proteomics and Western blot were applied to explore the mechanism of TPP-induced lipid metabolism disorder in mouse liver.The results showed that TPP exposure could affect peroxisome proliferator-activated receptor(PPAR)signaling pathway by causing significant differential expression of fatty acid binding protein 5(FABP5),malic enzyme 1(ME1)and other related genes,which might lead to the hepatic lipid accumulation,hepatocyte and hepatocyte organelle damage.Meanwhile,in the presence of HFF,TPP exposure could cause significant down-regulation of FABP5,which is slightly higher than that in HFF group,indicating that TPP might affect the mechanism of HFF-induced hepatic lipid metabolism disorder in mice(3)Although TPP exposure of 0.01 mg/kg/d did not result in significant renal structural damage and triglyceride accumulation,it led to significant inflammatory reaction in renal tissue under different dietary conditions as well,which means it may also have potential health risks and can increase the risk of occurrence and development of chronic renal disease and other related cardiovascular and metabolic diseases.However,sub-chronic exposure of 1 mg/kg/d TPP for 12 weeks significantly affected the expression level of nuclear factor kappa B/Nod-like receptor protein 3(NF-κB p65/NLRP3),caused renal inflammatory response and renal cell apoptosis,led to renal structural damage and lipid accumulation,and further affected the renal function of mice.Under the condition of HFF,TPP aggravated the renal dysfunction and renal inflammation induced by HFF sub-chronic exposure,and worsened the lipid metabolism disturbance in mice,which means the combined exposure of HFF and TPP have the highest health riskIn summary,this study provided direct evidence that TPP sub-chronic exposure in environment-related doses could influence hepatic and renal lipid metabolism of mice.Meanwhile,the present study revealed the role of TPP on the effects of HFF exposure,and the effects of dietary factors on health risk assessment of environmental pollution.This study provides theoretical basis for TPP environmental and human health risk assessment,as well as the prevention and treatment of obesity and its related syndromes.