title: Oxidative stress and the induction of cyclooxygenase enzymes and apoptosis in the murine placenta.
abstract: Placental oxidative stress has been implicated in many complications of human pregnancy, including preterm delivery and preeclampsia. It is now appreciated that reactive oxygen species can induce a spectrum of changes, ranging from homeostatic induction of enzymes to apoptotic cell death. Little is known regarding the occurrence of placental oxidative stress in other species. We investigated markers of oxidative stress in the labyrinthine (LZ) and junctional (JZ) zones of the murine placenta across gestational age, and correlated these with expression of the cyclooxygenase enzymes COX-1 and COX-2, and apoptosis. We tested a causal link between the two by subjecting placental explants to hypoxia-reoxygenation (H/R) in vitro, a known stimulus for generation of oxidative stress. Western blotting demonstrated significant increases in the concentrations of hydroxynonenal (HNE), COX-1 and COX-2 with gestational age. Dual-labelling demonstrated co-localisation of HNE, and COX-1 and COX-2 within the trophoblast of the LZ, and glycogen cells of the JZ. An apoptotic index based on TUNEL-positivity demonstrated an increase with gestational age, and dual-labelling showed co-localisation of TUNEL labelling with HNE and active caspase-3 within the trophoblast of the LZ. H/R significantly increased oxidative stress, induction of COX-1 and COX-2, and the apoptotic index. Co-localisation demonstrated the increases in COX to be within the trophoblast of the LZ, and in particular the glycogen cells of the JZ. Apoptosis was restricted to the LZ. We speculate that the induction of COX enzymes is a physiological response to oxidative stress, and may play a role in initiating or augmenting parturition. Generation of oxidative stress may also play a role in influencing the growth trajectory of the placenta, and its component cell types. The mouse may provide an experimental genetic model in which to investigate these phenomena.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors.forename: C
authors.initials: C
authors.lastname: Burdon
authors.forename: C
authors.initials: C
authors.lastname: Mann
authors.forename: T
authors.initials: T
authors.lastname: Cindrova-Davies
authors.forename: A C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.forename: G J
authors.initials: GJ
authors.lastname: Burton
mesh_terms: D000447:Aldehydes / Q000032:analysis; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D053148:Caspase 3 / Q000032:analysis; D051545:Cyclooxygenase 1 / Q000032:analysis / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010920:Placenta / Q000166:cytology / Q000201:enzymology*; D011247:Pregnancy; D015854:Up-Regulation
chemical_list: D000447:Aldehydes; D015415:Biomarkers; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal