| Cadmium is a toxic heavy metal, ranked the eighth environmental pollutant in the ATSDR 20 kinds of dangerous substances. Toxic emission, sewage disposal, waste residue and agricultural uses of phosphate fertilizers have been identified as major causes of widespread dispersion of the metal at trace levels into the general environment and human foodstuffs. Human may be exposed to cadmium through inhalation of particulate containing cadmium, ingestion contaminated food and occupational exposure in nickel-cadmium batteries and electroplating industry. After entering blood circulation, cadmium is mainly accumulate in liver, kidney and bone, followed by their injury and a risk of cancer.Due to its a unique surface properties, TiO2 nanoparticles(TNP) have been widely used in paints, photocell, cosmetics and biomedicine areas. TNP may be release into the environment during their production, usage and dispose. Due to their large surface area, TNP inevitably adsorb the co-existent environmental pollutants, which greatly increases the chances of coexposure to TNP and pollutants and pose potential health risks to humans. So it’s necessary to consider the evaluation of coexposure toxicity as an important part of safety evaluation of nanomaterials. Study on aquatic organisms showed the interaction of TNP and pollutants may not only affect TNP migration and settlement, but also change the pollutants bioavailability and toxicity. However, few studies reported toxicity of coexposure of nanoparticles and heavy metals in rodent, and toxicity in disease models has not been reported..It is reported that TNP were mainly accumulated in liver and induced oxidative stress-mediated liver injury, as indicated by elevated transaminase in serum, release of pro-inflammatory cytokines and hepatocyte injury. As a representative heavy metal in water and soil, cadmium could induce hepatotoxicity after acute exposure. Cadmium may bind to proteins containing sulphur and induced oxidative stress; in addition, cadmium induced release of pro-inflammatory cytokines by activation of Kupffer cells. Then what toxicitywould be induced when coexposure of both of them in mammals? Would there are some difference between the health mice and hepatitise mice?In this study, TNP or and cadmium were exposured to mice through tail intravenous injection with 100% bioavailability. Then we can compare toxicity of coexposure of TNP and cadmium with TNP or cadmium and explore the possible mechanisms of involved in aggravated liver damage induced by coexposure of them.The experiment section of this text can be divided into three parts for illustration. The first part, the optimal ConA induced acute liver injury conditions were explored. Serum biochemistry index, pro-inflammatory cytokines and liver pathology were checked for system evaluation of liver injury at different time(3,6,8,12,24 h) after intravenous injection of 15 mg/kg or 20 mg/kg B.W. ConA. The result showed the above indexes were consistent with epidemiological feature of hepatitis at 6 h after ConA administration, so hepatitis model could be established in these conditions..In the second part part, we studied toxicity of coexposure of TNP and cadmium. We firstly evaluated liver function of each exposure group under in healthy mice by setting the vehicle control group (saline), cadmium exposure (1.0mg/kg B.W.) group, TNP (15mg/kg B.W.) and coexposure of cadmium and TNP (TNP:15 mg/kg B.W, cadmium:1.0 mg/kg B.W.) group. There was no significant difference in organ coefficient, serum biochemistry index, liver pathology and pro-inflammatory cytokines release between the administrated groups and the control group. So coexposure of cadmium and TNP at low doses would not cause significant liver injury in healthy mice. However it was different in hepatitis mice after the same administration. After pre-exposure of the four materials 48 h, it arrived the endpoint detection at 6 h postinjection of 20 mg/kgB.W. ConA. Due to hepatic sinus congestion, a significant increase in organ coefficient of hepatitis mice liver compare with the normal liver, but not between the hepatitis groups. Coexposure of cadmium and TNP induced more significant increase of serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST) compare with exposure of TNP or cadmium. So coexposure of the two induce more severe liver injury. Liver pathological examination consistented with the above results, indicated by more inflammatory cells immersed in liver after coexposure and semi-quantitative pathology results of liver damage.The third part, we investigated the possible mechanism of aggravated liver injury induced by coexpoure of TNP and cadmium in hepatitis mice. Study on TNP and cadmium distribution in multiple organs of all the hepatitis groups showed 1) TNP was mainly accumulated in liver, spleen and lungs, and TNP accumulation in liver was not changed by addition of cadmium; 2) Cadmium was mainly accumulated in liver and kidney and coexposure of TNP and cadmium significantly increased cadmium accumulation in the liver of hepatitis mice. Study on the progress of TNP and cadmium accumulation in liver showed that Ti content in liver after coexpoure of the two showed the similar tendency with the TNP group, but cadmium cotent significantly incresed compared with the cadmium group. Meanwhile, cadmium increased 30% accumulation by calculate the area of time-concentration curve. Then evaluation of oxidative stress showed a significantly decrease of GSH and increase of MDA in coexposure group. And coexposure increased the release pro-inflammatory cytokines and induced a higher level of autophagy protein LC3 and apoptosis protein PARP.In summary, coexposure of TNP and cadmium facilitated cadmium accumulation in liver and TNP may serve as important carrier. Due to its sensitivity to the inflammation, the hepatitis mice suffer greater liver injury after exposure to TNP or cadmium, but the coexposure to the two aggravated liver injury compared with TNP or cadmium. The mechanism may coexpoure induced more severe oxidative damage, more pro-inflammatory cytokines release after activation of kupffer cells and hepatocyte damage. So exposure to low dose of TNP or cadmium may induce severe liver injury in hepatitis people than normal people and coexposure of them had a combined effect. This study provide an important basis for toxicity assessment for coexposure of nanoparticles and cadmium in hepatitis people. |
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