Influence Of Non-toxic Chemicals On Mode Of Action Of As Toxicity And Underlying Mechanisms

Arsenic(As)represents a typical environmental pollutant which receives extensive attention.Epidemiological studies and clinical observations indicate that long-term exposure of As is associated with cancer and diabetes.Since environment is characterized by complicated components,it becomes urgent to evaluate the combined toxicity of As with other contaminants at the same time.However,existing research about combined toxicity of As mainly concentrated on the influence of toxic and harnful substances,for some chemicals which are abundant in the environment,such as High-fat feeding,the role they played in the toxicity of As has not been well studied.Based on above backgrounds,we chose several non-toxic chemicals as combined factors from the perspective of As toxication and effect,and three parts of research were studied with the techniques of multipal omics and technology platforms of in vivo and in vitro assays.(D Since the main toxic mechanism of As is associated with the generation of ROS,Fe was chosen for both participation of ROS generation process and ubiquity in drinking water,and Fe was rarely considered because of its low toxicity;?Since membrane transport is an important way for As detoxification,we analysed the effect of nanomaterials at non-toxic concentration on membrane ABC transporter and As toxicity;? Based on the similar adverse health effects on liver and diabetes caused by HFD and As,influence by consumption of HFD on As was studiedThe results are summrized as follows:(1)Influence of Fe on As toxicity:Fe could further decrease cell viability caused by As exposure,increase apoptosis?oxidative stress and DNA breaks.The results provide evidence that co-exposure of As and Fe on HepG2 cells can lead to a synergy effect.Animal experiment showed that Fe could reduce the As toxicity,indicating an antagonistic effect.The result of transcriptomic profiles revealed that the number of DEGs in As+Fe group was significantly lower than that in As group.Co-exposure of As and Fe lowered the influence caused by As on MAPK and JAK-STAT pathways;The changes of metabolites indicated that co-exposure of As and Fe reduced the adverse effects caused by As on gut microbial community and function at metabolic levels,resulting in fewer influence on metabolites in serum and urine;The chemical analysis results indicated that As bioavailability in intestinal system was reduced under co-exposure of As and Fe,since more As was eliminated through feces and urine,which could be the major reason for the contrary conclusions in vivo and vitro assays.Our results support the viewpoint that when evaluating the safety of As in drinking water,it is necessary to fully consider the influence of Fe and other chemicals which may affect the ROS generation process.(2)Influence of low concentration/non-toxic nanomaterials on As toxicity:For the first time,we found that extracellular graphene and GO at relatively low concentrations,which were 100-times and 400-times lower than their lowest toxic concentration,could alter plasma membrane efflux transporter function by damaging the integrity and fluidity of membrane.However,ABC transporters play a key role in transportation and detoxification of As at a cell level.Thus graphene and GO can make cells more susceptible to As,by suppressing activities of ABC transporters.Different strategies of chemical addition resulted in different toxic effect.When graphene or GO was added after As exposure,they significantly increased the cytotoxicity of As by decreasing activities of ABC transporters.However,when graphene or GO was added first,they did not significantly increase the cytotoxicity of As,since As bioavailability was reduced by the interaction between nanomaterials and cell membrane.Our results support the viewpoint that when evaluating the safety of As in drinking water,it is necessary to fully consider the influence of low concentration nanomaterials and other chemicals which may affect the detoxification of As.(3)Influence of HFD on As toxicity:The HFD increased the intake of As through drinking water and lowered the excretion of As;The hepatic damage and metabolic disorder(especially diabetogenic effects)caused by As were enhanced by the HFD,showing a synergy effect.Insulin signaling pathway might play an important role in the combined effects of As and HFD.Diabetic model mice were adopted to further investigate the pre-diabetic effects caused by co-exposure of HFD and As.Results showed that As exposure could cause pre-diabetic effects by altering the lipid metabolism,gluconeogenesis and insulin secretion in normal individuals,and could worsen diabetic effects in diabetes individuals through these processes.We also found that the As exposure improved the insulin sensitivity by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals,indicating the mechanism of diabetogenic effects of As exposure is different from the mechanism associated with traditional risk factors(such as obesity).Our results support the viewpoint that health characteristics of the target population should be taken into considertation when evaluating the safety of As.In summary,this study analysed influences of typical chemicals on As toxicity which were chosen from the point of As toxication and effect.The results revealed that the chemicals,which were seldomly considered during the toxicity evaluation of As,had great impacts on As toxicity.This study indicates that chemicals involving in the toxication and detoxification process of As deserve fully consideration as well as the hazardous contaminants when they exist toghther with As.This study provides new insight and essential data for health risk assessment of As.