| With the development of nanotechnology,large amounts of products containing nanosized materials are widely used in our daily life.The number of nanomaterials(NMs)-based consumer products on the market has reached 1827 by March of 2017.Besides,the unique physical/chemical properties of NMs lead to their extensively applications in energy,chemical engineering,electronics,as well as biomedicine.The production,usage,and disposal of NMs-based products have inevitably increased the environmental accumulation and human exposures to NMs.NMs exhibit toxicity in cells and animal models through various mechanisms including induction of oxidative stress and inflammation.Vulnerable populations such as pregrant,lactating or aged populations,as well as populations with various diseases,are more susceptible to adverse factors.Therefore,it is necessary and urgent to evaluate the potential toxicity of nanomaterials in susceptible populations.Overweight and obesity refer to abnormal or excessive fat accumulation that may impair health.Being overweight and obesity significantly increases the risk of human death as well as many serious diseases such as fatty liver,diabetes,high blood pressure,insulin resistance syndrome,and a variety of cancers.Besides,overweight and obesity populations have been reported to be more susceptible to environmental pollutants.Recently,changes in diet and lifestyle have led to rising rates of overweight and obesity all over the world.According to WHO,more than 1.9 billion adults were overweight or obesity in 2014,among which 69%(1.3 billion)were overweight(25 kg/m2<body mass index(BM1)<30 kg/m2).Besides,the overweight rate among children and adolescents have reached 10%.As a result,toxicity assessment of nanoparticles to overweight population is undoubtedly of considerable realistic significance.Silver nanoparticles(Ag NPs)are one of the most widely commercialized NMs.This increases the risk of human exposure to Ag NPs.Previous studies have shown that Ag NPs are harmful to various cells and animal models,leading to cytotoxicity and target organ injuries.Oxidative stress,inflammation and mitochondrial damage have been reported as major mechanisms.Besides,released Ag+ ions are considered as a possible source of Ag NPs-induced toxicity.Although it is necessary to elucidate the toxicity of Ag NPs to healthy populations,it is more urgent to determine the adverse effects of these nanoparticles on vulnerable populations,such as overweight individuals.In this study,we firstly evaluated the toxicity of Ag NPs to high fat diet-induced overweight mice and the underlying mechanisms.Results showed that the liver is the major organ for both Ag NPs and Ag+ accumulation after their absorption from the gastrointestinal tract.By quantitatively and qualitatively analyzing the Ag status in the liver,we found that Ag+ reduction occurred only in the liver of overweight mice after exposed to Ag+,with the reduction rate of about 5%.The amounts of Ag NPs in both groups were comparable(0.60 ?g/g vs 0.74 ?g/g)after about 5%of Ag+ ions in fatty liver were reduced to Ag NPs.Oral administration of Ag NPs(300 mg/kg)or Ag+(18 mg/kg)caused no toxicity in noraml mice,but accelerated the disease progression from steatosis to steatohepatitis by similar degrees in overweight mice,as evidenced by focal inflammation,hydropic degeneration and enhanced steatosis in the liver,as well as increased hepatic levels of tumor necrosis factor-?(TNF-?),interleukin-6(IL-6)and total cholesterol(TC).This finding underscored an enhanced health risk in the overweight population compared with the healthy adult population.Given that the amounts of Ag NPs in both Ag NPs and Ag+ administrated groups were comparable after a 5%reduction of deposited Ag+in fatty liver,we concluded that that it was Ag NPs deposited or formed in situ in the liver of overweight mice,not Ag+ ions or the combination of the two,which caused the disease progression.To explore the molecular mechanisms underlying the Ag NP-induced acceleration of fatty liver disease in overweight mice,we first analyzed the treatment-induced expressions of 84 genes related to fatty liver disease in liver tissues of overweight mice using a fatty liver-specific RT2 ProfilerTM PCR Array.Results showed that several inflammation-related genes(such as Il10,Tnfa and 116)were upregulated,and genes involved in fatty acid oxidation(Ppard,Pdk4)were downregulated in the livers of overweight mice after treatments with Ag NPs or Ag+.Further exploration on the inflammatory changes in the livers showed that,in accompany with the activation of NF?B,JNK and p38 MAPK signaling pathways,Ag NPs deposited or formed in the livers of overweight mice induced pro-inflammatory activation of Kupffer cells,resulting in an increased level of hepatic inflammation.Additionally,Ag NPs administration downregulated fatty acid oxidation-related genes,leading to increased fat accumulation in the livers of overweight mice.The combined effects of Ag NPs-induced hepatic inflammation and inhibition of fatty acid oxidation aggravated high fat diet-induced hepatic steatosis to steatohepatitis.Meanwhile,the increased production and usage of nanomaterials increase the likelihood of their release into environment and their co-existence with various pollutants.Besides,enhanced environmental applications of nanomaterials because of their superior performance in pollutant absorption,catalysis,and sensing further increases the chance of human exposure to both nanoparticles and pollutants such as heavy metals.Previous studies have shown that nanopaticles affected the bioaccumulation of heavy metals in cells,aquatic organisms and healthy adult mammals,leading to increased toxicity of the heavy metals.However,the toxicity that may result from co-exposure to nanoparticles and heavy metals in susceptible populations is still not well understood.To evaluate the impact of such co-exposures in susceptible populations such as overweight subjects,we orally administered zinc oxide nanoparticles(ZNPs,58 nm)and/or Pb(Ac)2 at tolerable doses to both overweight and normal mice.Results showed that co-xeposure with ZNPs enhanced the deposition of Pb2+ in various organs of both normal and overweight mice.On the one hand,ZNPs might act as carriers to assist Pb2+deposition in organs.On the other hand,the ZNP/Pb2+ nanoadducts deposited in the organs should have a lower clearance rate compared with free Pb21 ions.These may be responsible for the elhanced Pb2+ deposition and accumulation in organs under the co-administration conditions.Furthermore,high fat diet feeding increased the intestinal permeability,resulting in an enhanced Pb deposition in organs of overweight mice,compared with the Pb levels in the normal mice under the same conditions.Noticeable body weight loss was only detected in overweight mice co-exposed to ZNPs and Pb2+,suggesting that the overweight mice were more susceptible to the toxic effects caused by the ZNP/Pb2+ complex than the normal mice.Even though ZNPs and Pb2+ co-administration exhibited a minor toxic effect in the spleen and the kidneys of both normal and overweight mice under our experimental conditions,ZNPs-enhanced liver deposition of Pb2+ increased the levels of hepatic ROS and inflammation,induced severe vacuolar degeneration in the liver,and increased the plasma levels of ALT and AST only in overweight mice.The findings that the overweight mice are more susceptible to nanoparticle/Pb(Ac)2-induced toxicity argue that more caution is needed regarding exposure to nanoparticle/heavy metal adducts in overweight populations.Although potential toxicity from nanoparticles and nanoparticle/pollutant complex,and their potential threats to human health have been frequently suggested,this pilot study emphasizes that such threats are increased to the susceptible overweight population.One needs to be cautious about translating mouse studies to humans and the different exposures between laboratory studies and in real environment.The findings from this study should raise concerns for the applications or accidental exposures of nanoparticles as well as nanoparticle/pollutant complex to the overweight population. |
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