Effects of Oxygen on Cell Turnover and Expression of Regulators of Apoptosis in Human Placental Trophoblast

• Published in: Placenta (Eastbourne) Vol. 29; no. 2; pp. 175 - 186
• Main Authors: Heazell, A.E.P, Lacey, H.A, Jones, C.J.P, Huppertz, B, Baker, P.N, Crocker, I.P
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2008; Elsevier
• Subjects: Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biological and medical sciences; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Dose-Response Relationship, Drug; Embryology: invertebrates and vertebrates. Teratology; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Genes, p53; Humans; Internal Medicine; Necrosis; Obstetrics and Gynecology; Organ Culture Techniques; Oxygen; Oxygen - pharmacology; p53; Placental villous explants; Pregnancy; Proto-Oncogene Proteins c-mdm2 - genetics; Trophoblast; Trophoblasts - cytology; Trophoblasts - drug effects; Trophoblasts - metabolism; Trophoblasts - pathology; Oxygen; Trophoblast; Placental villous explants; Apoptosis; p53; Human; Trophoblaste; Vertebrata; Mammalia; Placenta; Fetal membrane; Turnover; Regulator; Cell
• ISSN: 0143-4004; 1532-3102
• DOI: 10.1016/j.placenta.2007.11.002

Abstract Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with aberrant cell turnover, including increased apoptosis, in placental villous trophoblast. The increased apoptosis is associated with exaggerated expression of p53, which promotes cell cycle arrest or apoptosis via downstream proteins such as p21 or Bax. These changes in apoptosis and p53 expression are purported to result from exposure to altered oxygen tension. Using a model of villous trophoblast turnover, we examined the effect of 20%, 6% and 1% ambient oxygen (O2 ) on apoptosis, necrosis, proliferation and expression of p53 and related regulators of cell turnover, compared to both fresh tissue. Altered O2 tension exerted an effect on cell turnover in cultured term villous tissue: cytotrophoblast proliferation was increased by culture in 20% O2 and reduced in 1% O2 (median proliferative index: fresh tissue = 0.32%, 20% O2 = 0.9%, 6% O2 = 0.28%, 1% O2 = 0.07%). Apoptosis was increased in all culture environments, but was significantly enhanced by culture in 1% O2 (median apoptotic index: fresh tissue = 0.64%, 20% O2 = 2.96%, 6% O2 = 3.81%, 1% O2 = 9.2%). Necrotic cell death was also increased by culture in 1% O2 compared to 6% and 20% O2 . The expression of p53, p21 and Mdm2 in both cytotrophoblast and stromal cells was increased following culture in 1% O2 . There was no alteration in the expression of Bax or Bcl-2. This study provides evidence that p53 is elevated in trophoblast following exposure to hypoxia. The potential role of the p53-pathway in the control of cell turnover in villous trophoblast and the regulation of p53 by altered O2 tension merits further investigation.