title: Global "omics" evaluation of human placental responses to preeclamptic conditions.
abstract: Preeclampsia (PE) is a leading cause of maternal death. Its cause is still debated but there is general agreement that the placenta plays a central role. Perhaps the most commonly proposed contributors to PE include placental hypoxia, oxidative stress, and increased proinflammatory cytokines. How the placenta responds to these abnormalities has been considered but not as part of a comprehensive analysis of low-molecular-weight biomolecules and their responses to these accepted PE conditions.
  
  
  
  Using a peptidomic approach, we sought to identify a set of molecules exhibiting differential expression in consequence of provocative agents/chemical mediators of PE applied to healthy human placental tissue.
  
  
  
  Known PE conditions were imposed on normal placental tissue from 13 uncomplicated pregnancies and changes in the low-molecular-weight peptidome were evaluated. A t test was used to identify potential markers for each imposed stress. These markers were then submitted to a least absolute shrinkage and selection operator multinomial logistic regression model to identify signatures specific to each stressor. Estimates of model performance on external data were obtained through internal validation.
  
  
  
  A total of 146 markers were increased/decreased as a consequence of exposure to proposed mediators of PE. Of these 75 changed with hypoxia; 23 with hypoxia-reoxygenation/oxidative stress and 48 from exposure to tumor necrosis factor-α. These markers were chemically characterized using tandem mass spectrometry. Identification rates were: hypoxia, 34%; hypoxia-reoxygenation, 60%; and tumor necrosis factor-α, 50%. Least absolute shrinkage and selection operator modeling specified 16 markers that effectively distinguished all groups, ie, the 3 abnormal conditions and control. Bootstrap estimates of misclassification rates, multiclass area under the curve, and Brier score were 0.108, 0.944, and 0.160, respectively.
  
  
  
  Using this approach we found previously unknown molecular changes in response to individual PE conditions that allowed development biomolecular signatures for exposure to each accepted pathogenic condition.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT.
authors.forename: Komal
authors.initials: K
authors.lastname: Kedia
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Wright
authors.affiliation: Department of Statistics, Brigham Young University, Provo, UT.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Barnes
authors.affiliation: Department of Statistics, Brigham Young University, Provo, UT.
authors.forename: H Dennis
authors.initials: HD
authors.lastname: Tolley
authors.affiliation: Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Intermountain Health Care, Murray, UT.
authors.forename: M Sean
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT. Electronic address: swgraves@chem.byu.edu.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Graves
mesh_terms: D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D040901:Proteomics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014409:Tumor Necrosis Factor-alpha
keywords: hypoxia; lipidomics; oxidative stress; peptidomics; placenta; preeclampsia; tissue culture; tumor necrosis factor-α