title: Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease.
abstract: BACKGROUND
  Wilson disease (WD) is characterized by hepatic copper accumulation with progressive liver damage to cirrhosis. This study aimed to characterize the toxic milk mouse from The Jackson Laboratory (Bar Harbor, ME, USA) (tx-j) mouse model of WD according to changes over time in hepatic copper concentrations, methionine metabolism, global DNA methylation, and gene expression from gestational day 17 (fetal) to adulthood (28 weeks).
  
  
  METHODS
  Included liver histology and relevant biochemical analyses including hepatic copper quantification, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) liver levels, qPCR for transcript levels of genes relevant to methionine metabolism and liver damage, and DNA dot blot for global DNA methylation.
  
  
  RESULTS
  Hepatic copper was lower in tx-j fetuses but higher in weanling (three weeks) and adult tx-j mice compared to controls. S-adenosylhomocysteinase transcript levels were significantly lower at all time points, except at three weeks, correlating negatively with copper levels and with consequent changes in the SAM:SAH methylation ratio and global DNA methylation.
  
  
  CONCLUSIONS
  Compared to controls, methionine metabolism including S-adenosylhomocysteinase gene expression is persistently different in the tx-j mice with consequent alterations in global DNA methylation in more advanced stages of liver disease. The inhibitory effect of copper accumulation on S-adenosylhomocysteinase expression is associated with progressively abnormal methionine metabolism and decreased methylation capacity and DNA global methylation.
authors.affiliation: Department of Nutrition, University of California Davis, 3135 Meyer Hall, One Shields Avenue, Davis, CA 95616, USA. bichanhle@gmail.com.
authors.forename: Anh
authors.initials: A
authors.lastname: Le
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA. nshibata@ucdavis.edu.
authors.forename: Noreene M
authors.initials: NM
authors.lastname: Shibata
authors.affiliation: Department of Pathology, UCLA/Harbor Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA. sfrench@labiomed.ord.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.affiliation: Department of Public Health Sciences, Division of Biostatistics, University of California Davis, One Shields Avenue, Med-Sci 1C, Davis, CA 95616, USA. kmkim@ucdavis.edu.
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Kim
authors.affiliation: Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, VA Medical Center R-151, 4101 Woolworth Avenue, Omaha, NE 68105, USA. kkharbanda@unmc.edu.
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.affiliation: Department of Medical Microbiology and Immunology, University of California Davis, One Shields Avenue, Tupper Hall, Davis, CA 95616, USA. saharul123@yahoo.com.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Islam
authors.affiliation: Department of Medical Microbiology and Immunology Genome Center, and MIND Institute, University of California Davis, One Shields Avenue, Tupper Hall, Davis, CA 95616, USA. jmlasalle@ucdavis.edu.
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA. chhalsted@ucdavis.edu.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Halsted
authors.affiliation: Department of Nutrition, University of California Davis, 3135 Meyer Hall, One Shields Avenue, Davis, CA 95616, USA. clkeen@ucdavis.edu.
authors.forename: Carl L
authors.initials: CL
authors.lastname: Keen
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street, Suite 3500, Sacramento, CA 95817, USA. valentina.medici@ucdmc.ucdavis.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Medici
mesh_terms: D000818:Animals; D001835:Body Weight; D003300:Copper / Q000032:analysis / Q000378:metabolism*; D019175:DNA Methylation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008715:Methionine / Q000235:genetics / Q000378:metabolism*; D051379:Mice / Q000235:genetics / Q000378:metabolism
chemical_list: D003300:Copper; D008715:Methionine