title: Late gestational intermittent hypoxia induces metabolic and epigenetic changes in male adult offspring mice.
abstract: Late gestation during pregnancy has been associated with a relatively high prevalence of obstructive sleep apnoea (OSA). Intermittent hypoxia, a hallmark of OSA, could impose significant long-term effects on somatic growth, energy homeostasis and metabolic function in offspring. Here we show that late gestation intermittent hypoxia induces metabolic dysfunction as reflected by increased body weight and adiposity index in adult male offspring that is paralleled by epigenomic alterations and inflammation in visceral white adipose tissue. Fetal perturbations by OSA during pregnancy impose long-term detrimental effects manifesting as metabolic dysfunction in adult male offspring.
  
  
  
  Pregnancy, particularly late gestation (LG), has been associated with a relatively high prevalence of obstructive sleep apnoea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, could impose significant long-term effects on somatic growth, energy homeostasis, and metabolic function in offspring. We hypothesized that IH during late pregnancy (LG-IH) may increase the propensity for metabolic dysregulation and obesity in adult offspring via epigenetic modifications. Time-pregnant female C57BL/6 mice were exposed to LG-IH or room air (LG-RA) during days 13-18 of gestation. At 24 weeks, blood samples were collected from offspring mice for lipid profiles and insulin resistance, indirect calorimetry was performed and visceral white adipose tissues (VWAT) were assessed for inflammatory cells as well as for differentially methylated gene regions (DMRs) using a methylated DNA immunoprecipitation on chip (MeDIP-chip). Body weight, food intake, adiposity index, fasting insulin, triglycerides and cholesterol levels were all significantly higher in LG-IH male but not female offspring. LG-IH also altered metabolic expenditure and locomotor activities in male offspring, and increased number of pro-inflammatory macrophages emerged in VWAT along with 1520 DMRs (P < 0.0001), associated with 693 genes. Pathway analyses showed that genes affected by LG-IH were mainly associated with molecular processes related to metabolic regulation and inflammation. LG-IH induces metabolic dysfunction as reflected by increased body weight and adiposity index in adult male offspring that is paralleled by epigenomic alterations and inflammation in VWAT. Thus, perturbations to fetal environment by OSA during pregnancy can have long-term detrimental effects on the fetus, and lead to persistent metabolic dysfunction in adulthood.
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Cortese
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Zhuanhong
authors.initials: Z
authors.lastname: Qiao
authors.affiliation: Section of Endocrinology and Metabolism, Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Honggang
authors.initials: H
authors.lastname: Ye
authors.affiliation: Center for Research Informatics, Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, USA.
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.affiliation: Center for Research Informatics, Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: David
authors.identifier: 0000-0001-8195-6036
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D053263:Gene Regulatory Networks / Q000502:physiology; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000378:metabolism*; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000235:genetics / Q000378:metabolism*
keywords: epigenetics; gestation; intermittent hypoxia; metabolic syndrome; methylation; sleep apnea