title: Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner.
abstract: Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
authors.affiliation: a Department of Basic Medicine , Medical College of Hunan Normal University , Changsha , China.|b Institute of Nutritional Science, University of Potsdam , Nuthetal , Germany.|c IFLb, Laboratoriumsmedizin Berlin GmbH , Berlin , Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.affiliation: d Department of Internal Medicine IV/Nephrology (UKBF) , Charité Campus Benjamin Franklin , Berlin , Germany.|e Center for Cardiovascular Research, Charité Campus Mitte , Berlin , Germany.
authors.forename: Hannah
authors.initials: H
authors.lastname: Haumann
authors.affiliation: b Institute of Nutritional Science, University of Potsdam , Nuthetal , Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: b Institute of Nutritional Science, University of Potsdam , Nuthetal , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Reichetzeder
authors.affiliation: d Department of Internal Medicine IV/Nephrology (UKBF) , Charité Campus Benjamin Franklin , Berlin , Germany.|e Center for Cardiovascular Research, Charité Campus Mitte , Berlin , Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kalk
authors.affiliation: d Department of Internal Medicine IV/Nephrology (UKBF) , Charité Campus Benjamin Franklin , Berlin , Germany.|f Diaverum Deutschland , Potsdam , Germany.
authors.forename: Thiemo
authors.initials: T
authors.lastname: Pfab
authors.affiliation: b Institute of Nutritional Science, University of Potsdam , Nuthetal , Germany.|e Center for Cardiovascular Research, Charité Campus Mitte , Berlin , Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Tsuprykov
authors.affiliation: g Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology , Stuttgart , Germany.|h University of Tübingen , Tübingen , Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: g Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology , Stuttgart , Germany.|h University of Tübingen , Tübingen , Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: a Department of Basic Medicine , Medical College of Hunan Normal University , Changsha , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: b Institute of Nutritional Science, University of Potsdam , Nuthetal , Germany.
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
authors.affiliation: i Institute of Physiology, University of Tübingen , Tübingen , Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: j Institute of Translational Immunology, University Medical Center of the Johannes Gutenberg University Mainz , Mainz , Germany.|k Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston , MA , USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: g Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology , Stuttgart , Germany.|l Department of Clinical Pharmacology , University Hospital Tübingen , Tübingen , Germany.|m Department of Pharmacy and Biochemistry , University Tübingen , Tübingen , Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: g Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology , Stuttgart , Germany.|h University of Tübingen , Tübingen , Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D019175:DNA Methylation; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D018392:Genomic Imprinting; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D012737:Sex Factors
chemical_list: D052250:Nitric Oxide Synthase Type III
keywords: Epigenetics; Fetal programming; eNOS; fatty liver; metabolism