Research Regarding The Mechanism Of Tributyltin-induced Metabolism Disturbance

Tributyltin（TBT）is a common organotin compound mainly used in marine antifouling coatings.Although the use of TBT containing coatings has been banned since 2003,due to its long half-life,the risk of its exposure to human and environmental organisms is still very high.It has been reported that TBT not only has neurotoxicity and immunotoxicity,but also may have obesity-inducing effect.It is possible that TBT might belong to one of the environmental obesogens,which can interfere lipid metabolism and lead to obesity.However,the underlying mechanism is not completely clear.Previous studies have found that TBT can activate peroxisome proliferator activated receptor gamma（PPARγ）,which is an important nuclear transcription factor regulating lipid metabolism and the expression of target genes related to lipid synthesis and lipid metabolism.Previous studies mainly found that TBT regulates PPARγin 3T3-L1 adipocytes,however,PPARγis widely expressed not only in adipose tissue,but also in liver tissue and macrophages.Therefore,to elucidate the molecular mechanism by which TBT interferes with metabolism,this paper studies the regulatory effect of TBT on PPARγand lipid metabolism in macrophages,hepatocytes as well as in vivo mouse studies.In this paper,we first determined the nonlethal concentration of TBT in macrophages.Through luciferase reporter gene experiments,it was found that TBT significantly activated PPARγin macrophages,and q RT-PCR experiments revealed that TBT induced the expression of PPARγtarget genes（CD36、FABP4、NR₁H₃）.In addition,TBT can induce the increase of lipid droplets in macrophages and hepatocytes through oil red O staining experiments,suggesting that TBT indeed interfered with lipid metabolism in macrophages and hepatocytes.By using PPARγknockout cells or PPARγinhibitors,lipid droplet formation and the expression of lipid metabolism related genes induced by TBT were significantly inhibited,suggesting that PPARγpathway is involved in regulating the lipid metabolism disturbed by TBT.We further conducted animal experiments to prove that TBT exposure resulted in body weight gain,glucose intolerance,and increased the mRNA expression of PPARγand genes related to lipid metabolism,lipid synthesis（Srebp1-c、Lxrβ、Scd1、Fas）,lipid lysis（Pparα、Aco、Cyp4a10、Cyp4a14、Lcad）and endoplasmic reticulum stress-related genes（Grp78、Xbp1）in the liver.In conclusion,TBT can significantly activate PPARγin macrophages and hepatocytes,thus disturbing lipid metabolism both in vitro and in vivo.Our results indicate that TBT does have obesity-inducing effect and therefore its metabolic toxicity should not be ignored.