title: Metyrapone alleviates deleterious effects of maternal food restriction on lung development and growth of rat offspring.
abstract: Maternal food restriction (MFR) causes intrauterine growth restriction, a known risk factor for developing chronic lung disease. However, it is unknown whether this negative outcome is gender specific or preventable by blocking the MFR-induced hyperglucocorticoidism. Using a well-established rat model, we used metyrapone (MTP), an inhibitor of glucocorticoid synthesis, to study the MFR-induced lung changes on postnatal day (p) 21 in a gender-specific manner. From embryonic day 10 until delivery, pregnant dams were fed either an ad libitum diet or a 50% caloric restricted diet with or without MTP supplementation. Postnatally, the offspring were fed ad libitum from healthy dams until p21. Morphometric, Western blot, and immunohistochemical analysis of the lungs demonstrated that MTP mitigated the MFR-mediated decrease in alveolar count, decrease in adipogenic protein peroxisome proliferator-activated receptor γ, increase in myogenic proteins (fibronectin, α-smooth muscle actin, and calponin), increase in Wnt signaling intermediates (lymphoid enhancer-binding factor 1 and β-catenin), and increase in glucocorticoid receptor (GR) levels. The MFR-induced lung phenotype and the effects of MTP were similar in both genders. To elucidate the mechanism of MFR-induced shift of the adipogenic-to-myogenic phenotype, lung fibroblasts were used to independently study the effects of (1) nutrient restriction and (2) excess steroid exposure. Nutrient deprivation increased myogenic proteins, Wnt signaling intermediates, and GR, all changes blocked by protein supplementation. MTP also blocked, likely by normalizing nicotinamide adenine dinucleotide phosphate levels, the corticosterone-induced increase in myogenic proteins, but had no effect on GR levels. In summary, protein restriction and increased glucocorticoid levels appear to be the key players in MFR-induced lung disease, affecting both genders.
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Paek
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakurai
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Saraswat
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: Yishi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Khorram
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Torday
authors.affiliation: Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California, Torrance, Los Angeles, CA, USA vrehan@labiomed.org.
authors.forename: Virender K
authors.initials: VK
authors.lastname: Rehan
mesh_terms: D000367:Age Factors; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D031204:Caloric Restriction; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008297:Male; D044342:Malnutrition / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D039382:Maternal Nutritional Physiological Phenomena; D008797:Metyrapone / Q000494:pharmacology*; D009752:Nutritional Status; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D008797:Metyrapone
keywords: bronchopulmonary dysplasia; glucocorticoid; intrauterine growth restriction; lung development; maternal food restriction; metyrapone