title: Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep.
abstract: OBJECTIVE
  Preterm infants exhibit chronic deficits in white matter (WM) and cortical maturation. Although fetal infection/inflammation may contribute to WM pathology, the factors contributing to cortical changes are largely unknown. We examined the effect of fetal lipopolysaccharide (LPS) exposure on WM and cortical development as assessed by magnetic resonance imaging (MRI), electroencephalography (EEG), and histopathology in fetal sheep at preterm human equivalent age.
  
  
  METHODS
  LPS was administered to fetal sheep at 102.5 ± 0.5 days of gestation. Continuous biophysical recordings were analyzed for 10 days after LPS. At postmortem, measurement of cerebral WM and cortical tissue volumes was achieved by stereological techniques. Specific effects of LPS on MRI-assessed T(1)-weighted and T(2)-weighted images, and immunohistochemical expression of oligodendrocytes, proliferating cells, cortical NeuN-positive and Nurr1-positive neurons (subplate marker), and cell death mechanisms were examined.
  
  
  RESULTS
  We observed reductions in WM (~21%; LPS, 1.19 ± 0.04 vs control, 1.51 ± 0.07 cm(3); p < 0.001) and cortical (~18%; LPS, 2.34 ± 0.10 vs control, 2.85 ± 0.07 cm(3); p < 0.001) volumes, associated with overt and diffuse WM injury, T(1)-/T(2) -weighted signal alterations, and reduced numbers of WM oligodendrocytes (LPS, 485 ± 31 vs control, 699 ± 69 cells/mm(2); p = 0.0189) and NeuN-positive (LPS, 421 ± 71 vs control 718 ± 92 cells/mm(2); p = 0.04) and Nurr1-positive (control, 2.5 ± 0.6 vs LPS, 0.6 ± 0.1 cells/mm(2); p = 0.007) cortical neurons after LPS. Moreover, there was loss of the normal maturational increase in cortical EEG amplitude, which correlated with reduced cortical volumes.
  
  
  CONCLUSIONS
  Fetal exposure to LPS prior to myelination onset can impair both white matter and cortical development in a preclinical large animal model, supporting a role for maternal/fetal infection in the pathogenesis of preterm brain injury.
authors: Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Justin M
authors: JM
authors: Dean
authors: Yohan
authors: Y
authors: van de Looij
authors: Stephane V
authors: SV
authors: Sizonenko
authors: Gregory A
authors: GA
authors: Lodygensky
authors: Francois
authors: F
authors: Lazeyras
authors: Hayde
authors: H
authors: Bolouri
authors: Ingemar
authors: I
authors: Kjellmer
authors: Petra S
authors: PS
authors: Huppi
authors: Henrik
authors: H
authors: Hagberg
authors: Carina
authors: C
authors: Mallard
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D004569:Electroencephalography; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008279:Magnetic Resonance Imaging; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology* / Q000503:physiopathology; D012756:Sheep
chemical_list: D008070:Lipopolysaccharides