title: A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver.
abstract: Prenatal undernutrition affects offspring phenotype via changes in the epigenetic regulation of specific genes. We hypothesized that pregnant females that were fed a calcium (Ca)-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and altered epigenetic gene regulation. Female Wistar rats ate either a Ca-deficient or control diet from 3 weeks before conception to 21 days after parturition. Pups were allowed to nurse from their original mothers and then euthanized on day 21. Methylation of individual cytosine-guanine dinucleotides in the phosphoenolpyruvate carboxykinase (Pck1), peroxisome proliferator-activated receptor α (Ppara), glucocorticoid receptor (Nr3c1), 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1), and 11β-hydroxysteroid dehydrogenase-2 (Hsd11b2) promoters was measured in liver tissue using pyrosequencing. For each gene, quantitative real-time polymerase chain reaction was used to assess mRNA levels in liver tissue. Overall Hsd11b1 methylation was lower in the Ca-deficient group than in the control group; however, overall methylation of each other gene did not differ between groups. Serum corticosterone levels in male pups from Ca-deficient dams were higher than those in control pups. Expression of Pck1 and Nr3c1 was lower in the Ca-deficient group than in the control group. A Ca-deficient diet for a dam during gestation and early nursing may alter glucocorticoid metabolism and lead to higher intracellular glucocorticoid concentrations in the hepatic cells of her offspring; moreover, this abnormal glucocorticoid metabolism may induce the metabolic complications that are associated with Ca deficiency. These findings indicated that prenatal nutrition affected glucocorticoid metabolism in offspring in part by affecting the epigenome of offspring.
authors.affiliation: Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan. Electronic address: takaya@takii.kmu.ac.jp.
authors.forename: Junji
authors.initials: J
authors.lastname: Takaya
authors.forename: Anna
authors.initials: A
authors.lastname: Iharada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okihana
authors.forename: Kazunari
authors.initials: K
authors.lastname: Kaneko
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000172:deficiency*; D003345:Corticosterone / Q000097:blood; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation; D003677:Deficiency Diseases / Q000150:complications / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D005938:Glucocorticoids / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications; D039401:Prenatal Nutritional Physiological Phenomena / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003596:Cytosine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C582554:Pck1 protein, rat; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D002118:Calcium; D003345:Corticosterone
keywords: 11β-HSD1; 11β-hydroxysteroid dehydrogenase-1; 11β-hydroxysteroid dehydrogenase-1 gene; 11β-hydroxysteroid dehydrogenase-2 gene; Calcium; CpG; Epigenetics; Gapdh; Glyceraldehyde-3-phosphate dehydrogenase gene; Hsd11b1; Hsd11b2; Nr3c1; PCR; Pck1; Ppara; Pyrosequence; Rat; cytosine-guanine; glucocorticoid receptor gene; in vivo; phosphoenolpyruvate carboxykinase gene; polymerase chain reaction; rat peroxisome proliferator-activated receptor α gene