Oxidative Damage And Potential Carcinogenicity Induced By Acrylamide And Its Metabolite On Mice

Acrylamide(AA) as a potential carcinogen, is widely used in various industrialfield and even produced in food, which does harm to human health. At present, thetoxic, carcinogenic and mutagenic mechanism of AA is unclear, but it may has closerelationship to its oxidative metabolites in vivo–glycidamide(GA), and GA may bethe main factor of AA caused the toxic damage to the organ. However, the role andmechanism on oxidative damage of GA is unclear, which hinders the process to clearthe toxicity mechanism of AA, and prevents from establishing the protection methodagainst toxicity induced by AA. The purpose of this work is to study the possiblemechanism of the lipid peroxidation and cancer induced by AA and GA.First of all, effects of AA and GA on oxidative damage were studied. It wastreated70male Balb/c mice with AA and GA at the dosages of0mg/kg b.w./day,25mg/kg b.w./day,50mg/kg b.w./day and75mg/kg b.w./day for30days, respectivelyto clear the oxidative damage effects of AA and GA, and the effects on inflammatoryinjury induced by oxidative stress. The animal behavior, animal body weight, the levelof ROS in serum, the damage index of DNA and the levels of inflammatory cytokines(IL-1, IL-6, IL-10, TNF-α,NF-κB) in serum were determined. Biochemical oxidationindexes of SOD, GSH-Px, GST, MDA, MPO in liver, kidney, brain and lung, theinflammation injury by HE staining and the influence on function of liver and kidneythrough the indexes of AST、ALT、BUN、Cr and LDH were investigated. Resultsshowed that, AA and GA had obvious effect of oxidative damage in mice. On the onehand, AA and GA increased the levels of ROS and8-OHdG in serum of micesignificantly. AA and GA also enhanced the levels of pro-inflammatory cytokines IL-1,IL-6, TNF-α, NF-κB, and decreased the content of anti-inflammatory factor IL-10. Onthe other hand, AA and GA inhabited the activity of antioxidants that of SOD, GSH-Px, GST and enhanced the activity of MPO and the level of MDA in liver,kidney,brain and brain. They increased the levels of AST, ALT, BUN, Cr, LDH inserum, and caused damage on the function of liver and kidney. HE revealedinflammatory cell infiltration in liver. Liver is also the most obvious oxidative damageobserved, and it may be the main target organs of oxidative damage induced by AAand GA. GA plays a significant role on the inhibition of activity of anti-oxidativeenzymes, which is more obvious than that of AA.Secondly, expression of protein and the regulation of gene in liver related tooxidative damage and cancer induced by AA and GA were studied. Liver wasselected as the target organ, which was damaged most by oxidative stress. It wasfocused on the regulation of gene and the expression of typical protein induced by AAand GA.100male Balb/c mice were intragastric administration with AA and GA atthe doses of0mg/kg b.w./day,25mg/kg b.w./day,50mg/kg b.w./day,75mg/kgb.w./day for30days. The liver tissue was used for affymetrix microarray detection.Foldchange of gene expression were analyzed to clear the impact of AA and GA ongene regulation. Western bolt was used to study the expression change of typicalprotein: Bcl2, Rad51, P21, and Egfr. It showed that: AA and GA (50mg/kg b.w./day)significantly up-regulated genes that related to oxidative stress, cancer, tumor andinflammation and down-regulated the genes related to anti-apoptosis, tumorsuppressor and the synthesis of fatty acid. At the same time,(50~75mg/kgb.w./day)AA and GA significantly down-regulated the protein expression oftumor suppressor gene Bcl2in liver, and up-regulated the protein expression of Rad51and Egfr related to cancer. Therefore, AA and GA have strong ability to induceoxidative damage and the potential carcinogenic effects on the liver of mice. AA(50~75mg/kg b.w./day) was significantly down-regulated the protein expression oftumor suppressor gene P21, but GA had no significant effect.In summary, AA and GA have obvious oxidative damage on mice, and the liver isthe most significant damaged tissue, which is a target organ of oxidative stress injuryinduced by AA and GA. AA and GA also have potential carcinogenicity in mice liver, and it is closely related to the ability of GA that could attack DNA and regulate therelated gene to inhibit the repair of DNA. The oxidative damage and carcinogenesison mice induced by AA have closely relationships to the generation process of GAand its strong oxidation ability. Therefore, we should inhibit the transformation fromAA to GA in vivo to establish the protection mechanism against the toxicity of AA.