title: Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity.
abstract: BACKGROUND
  Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal-fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called 'hypoxamir' regulated by HIF-1α, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity.
  
  
  METHODS
  Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25-24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription-PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation.
  
  
  RESULTS
  Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1α in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFα) were increased in OW and OB placentas of females but not males, and in silico analysis suggested that activation of miR-210 expression in these placentas might be activated by NFκB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFα showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFα-mediated inhibition of mitochondrial respiration.
  
  
  CONCLUSIONS
  Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFκB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses.
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Muralimanoharan
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Myatt
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Maloyan
mesh_terms: D000328:Adult; D015153:Blotting, Western; D015687:Cell Hypoxia; D005260:Female; D047109:Fetal Development; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D010920:Placenta / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism* / Q000503:physiopathology; D037841:Pregnant People; D021381:Protein Transport; D012727:Sex Characteristics; D047929:Term Birth
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B
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