8-hydroxy-2--deoxyguanosine and Biliary-Atresia

Alu and LINE-1 elements are retrotransposons with a ubiquitous presence in the human genome that can cause genomic instability, specifically relating to telomere length. Genotoxic agents may induce methylation of retrotransposons, in addition to oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methylation of retrotransposons induced by these agents may contribute to biliary atresia (BA) etiology. Here, we investigated correlations between global methylation, 8-OHdG, and relative telomere length, as well as reporting on Alu and LINE-1 hypomethylation in BA patients. Alu and LINE-1 hypomethylation were found to be associated with elevated risk of BA (OR = 4.07; 95% CI: 2.27-7.32; P < 0.0001 and OR = 3.51; 95% CI: 1.87-6.59; P < 0.0001, respectively). Furthermore, LINE-1 methylation was associated with liver stiffness in BA patients (β coefficient = -0.17; 95% CI: -0.24 to -0.10; P < 0.0001). Stratified analysis revealed negative correlations between Alu and LINE-1 methylation and 8-OHdG in BA patients (P < 0.0001). In contrast, positive relationships were identified between Alu and LINE-1 methylation and relative telomere length in BA patients (P < 0.0001). These findings suggest that retrotransposon hypomethylation is associated with plasma 8-OHdG and telomere length in BA patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Alu Elements; Bile Ducts, Extrahepatic; Biliary Atresia; Case-Control Studies; Child; Deoxyguanosine; DNA Damage; DNA Methylation; Epigenesis, Genetic; Female; Genome-Wide Association Study; Humans; Liver; Long Interspersed Nucleotide Elements; Male; Oxidative Stress; Risk; Telomere; Telomere Homeostasis; Twins, Monozygotic

Many post-operative patients with biliary atresia (BA) suffer from liver dysfunction, such as chronic inflammation even without jaundice after a Kasai's hepatic portoenterostomy.. The presence and degree of oxidative stress were evaluated in the post-operative patients with BA. Twelve outpatients who underwent a Kasai's hepatic portoenterostomy were evaluated. The active oxygen products, the rate of bioantioxidant, the markers of oxidative stress, and the degree of hepatic oxidative stress were examined by immunohistochemical staining of biopsied specimens.. All of the oxidative stress markers in the post-operative patients with BA increased in comparison to those in the controls. Moreover, 8-OHdG immunohistochemical staining was positive in 84+/-4.8% in hepatic cells in the portal area in the post-operative patients with BA.. The post-operative patients with BA were under increased oxidative stress, even if their liver dysfunction was mild without jaundice. Antioxidant therapy might be necessary to decrease of oxidative stress in the post-operative patients with BA.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alanine Transaminase; Biliary Atresia; Biomarkers; Case-Control Studies; Child; Child, Preschool; Collagen Type IV; Deoxyguanosine; Dinoprost; Female; gamma-Glutamyltransferase; Humans; Immunohistochemistry; Infant; Insulin-Like Growth Factor I; Liver Diseases; Male; Oxidative Stress; Portoenterostomy, Hepatic; Postoperative Period; Superoxide Dismutase

Oxidative stress is known to be involved in the pathogenesis of biliary atresia (BA), but the mechanism has yet to be elucidated. We studied 8-hydroxydeoxyguanosine (8-OHdG) and mitochondrial copy number as potential markers for oxidative stress in BA.. Hepatic immunoreactive 8-OHdG expression was investigated during the early stage of BA when the patients received Kasai portoenterostomy (KP), during the late stage when the patients received liver transplantation (LT), in patients with choledochal cyst as disease control, and in patients with histologically normal liver as normal control. Apoptosis of liver cells was examined by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeling stain. The mitochondrial DNA copy number was measured by real-time polymerase chain reaction.. The number of hepatocytes positive for immunoreactive 8-OHdG was significantly increased in KP (65% +/- 18%) compared with LT (30% +/- 32%; P = 0.029) and choledochal cyst (25% +/- 20%; P = 0.037). The 8-OHdG labeling index was significantly correlated with the grade of chronic hepatitis activity (Spearman r = 0.495; P = 0.037). The hepatocyte terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end-labeling index in KP (15% +/- 4%) was significantly higher than that in LT (5% +/- 2%; P = 0.018) and in choledochal cyst (3% +/- 2%; P = 0.010). Mitochondrial copy number was significantly less in KP than in LT (7.33 +/- 0.75 vs 8.91 +/- 1.32; P = 0.045) and in normal control (7.33 +/- 0.75 vs 9.20 +/- 1.20; P = 0.021).. The early stage of BA is associated with stronger inflammatory reaction, augmented oxidative DNA, and mitochondrial DNA damage as manifested by higher immunoreactive 8-OHdG and apoptotic activities and by a decrease in mitochondrial copy number.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Apoptosis; Biliary Atresia; Biomarkers; Child; Child, Preschool; Deoxyguanosine; DNA Damage; DNA, Mitochondrial; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Infant; Liver; Liver Diseases; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Polymerase Chain Reaction; Severity of Illness Index; Statistics, Nonparametric