title: Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways.
abstract: The aims of this study were to clarify the metabonome alteration in fetal rats after prenatal caffeine ingestion and to explore the underlying mechanism pertaining to the increased fetal circulatory glucocorticoid (GC). Pregnant Wistar rats were daily intragastrically administered with different doses of caffeine (0, 20, 60 and 180 mg/kg) from gestational days (GD) 11 to 20. Metabonome of fetal plasma and amniotic fluid on GD20 were analyzed by ¹H nuclear magnetic resonance-based metabonomics. Gene and protein expressions involved in the GC metabolism, glucose and lipid metabolic pathways in fetal liver and gastrocnemius were measured by real-time RT-PCR and immunohistochemistry. Fetal plasma metabonome were significantly altered by caffeine, which presents as the elevated α- and β-glucose, reduced multiple lipid contents, varied apolipoprotein contents and increased levels of a number of amino acids. The metabonome of amniotic fluids showed a similar change as that in fetal plasma. Furthermore, the expressions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) were decreased, while the level of blood GC and the expressions of 11β-HSD-1 and glucocorticoid receptor (GR) were increased in fetal liver and gastrocnemius. Meanwhile, the expressions of insulin-like growth factor 1 (IGF-1), IGF-1 receptor and insulin receptor were decreased, while the expressions of adiponectin receptor 2, leptin receptors and AMP-activated protein kinase α2 were increased after caffeine treatment. Prenatal caffeine ingestion characteristically change the fetal metabonome, which is probably attributed to the alterations of glucose and lipid metabolic pathways induced by increased circulatory GC, activated GC metabolism and enhanced GR expression in peripheral metabolic tissues.
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan University, Wuhan 430071, China.
authors.forename: Yansong
authors.initials: Y
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Jianghua
authors.initials: J
authors.lastname: Feng
authors.forename: Hao
authors.initials: H
authors.lastname: Kou
authors.forename: Gai
authors.initials: G
authors.lastname: Liang
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: He
authors.forename: Baifang
authors.initials: B
authors.lastname: Zhang
authors.forename: Liaobin
authors.initials: L
authors.lastname: Chen
authors.forename: Jacques
authors.initials: J
authors.lastname: Magdalou
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002110:Caffeine / Q000633:toxicity*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D005260:Female; D005333:Fetus; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods; D018482:Muscle, Skeletal / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018812:Paternal Exposure; D011247:Pregnancy; D025341:Principal Component Analysis; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
chemical_list: D000697:Central Nervous System Stimulants; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D002110:Caffeine; D005947:Glucose