title: Placental oxidative stress and decreased global DNA methylation are corrected by copper in the Cohen diabetic rat.
abstract: Fetal Growth Restriction (FGR) is a leading cause for long term morbidity. The Cohen diabetic sensitive rats (CDs), originating from Wistar, develop overt diabetes when fed high sucrose low copper diet (HSD) while the original outbred Sabra strain do not. HSD induced FGR and fetal oxidative stress, more prominent in the CDs, that was alleviated more effectively by copper than by the anti-oxidant vitamins C and E. Our aim was to evaluate the impact of copper or the anti-oxidant Tempol on placental size, protein content, oxidative stress, apoptosis and total DNA methylation. Animals were mated following one month of HSD or regular chow diet and supplemented throughout pregnancy with either 0, 1 or 2 ppm of copper sulfate or Tempol in their drinking water. Placental weight on the 21st day of pregnancy decreased in dams fed HSD and improved upon copper supplementation. Placental/fetal weight ratio increased among the CDs. Protein content decreased in Sabra but increased in CDs fed HSD. Oxidative stress biochemical markers improved upon copper supplementation; immunohistochemistry for oxidative stress markers was similar between strains and diets. Caspase 3 was positive in more placentae of dams fed HSD than those fed RD. Placental global DNA methylation was decreased only among the CDs dams fed HSD. We conclude that FGR in this model is associated with smaller placentae, reduced DNA placental methylation, and increased oxidative stress that normalized with copper supplementation. DNA hypomethylation makes our model a unique method for investigating genes associated with growth, oxidative stress, hypoxia and copper.
authors.affiliation: Hebrew University Hadassah Medical School, Jerusalem, Israel. Electronic address: zivanit@hadassah.org.il.
authors.forename: Zivanit
authors.initials: Z
authors.lastname: Ergaz
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Guillemin
authors.affiliation: Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Meytal
authors.initials: M
authors.lastname: Neeman-Azulay
authors.affiliation: Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Liza
authors.initials: L
authors.lastname: Weinstein-Fudim
authors.affiliation: Department of Obstetrics and Gynecology, University of Rochester, Rochester, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Stodgell
authors.affiliation: Department of Obstetrics and Gynecology, University of Rochester, Rochester, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Miller
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Asher
authors.initials: A
authors.lastname: Ornoy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003300:Copper / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D007150:Immunohistochemistry; D008098:Litter Size / Q000187:drug effects; D018384:Oxidative Stress; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013113:Spin Labels
chemical_list: D003497:Cyclic N-Oxides; D013113:Spin Labels; D003300:Copper; C001803:tempol
keywords: Copper; DNA methylation; Diabetes; Oxidative stress; Placenta; Tempol