title: Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude.
abstract: Pregnancy at high altitude is associated with a reduction in birth weight of ∼100 g/1000 m of ascent. The underlying mechanisms are unclear but may involve alteration in energy-demanding activities, such as protein synthesis. To test this hypothesis, both in vivo and in vitro approaches were used. Placental tissues from pregnant women residing at 3100 m were studied, and placental cells were incubated under hypoxia. In the 3100-m placentas, we observed dilation of endoplasmic reticulum (ER) cisternae, increased phosphorylation of eukaryotic initiation factor 2 subunit α (P-eIF2α), reduced AKT phosphorylation, and reduced P-4E-BP1 but increased 4E-BP1 protein compared to sea level controls. These findings suggest the presence of ER stress and protein synthesis inhibition. Hypoxia (1% O(2)) reduced proliferation of trophoblast-like JEG-3 cells, BeWo cells, and placental fibroblasts by ∼40, ∼60, and ∼18%, respectively. Sublethal dosage of salubrinal, an eIF2α phosphatase inhibitor, increased P-eIF2α and reduced BeWo cell and placental fibroblast proliferation by ∼50%. Administration of the PI-3K inhibitor LY294002 also reduced JEG-3 proliferation. Our results demonstrate that exposure to chronic hypobaric hypoxia causes mild placental ER stress, which, in turn, modulates protein synthesis and slows proliferation. These effects may account for the reduced placental villous volume, and contribute to the low birth weight that typifies high-altitude populations.
authors.affiliation: Centre for Trophoblast Research, Physiology Laboratory, Downing St., Cambridge, CB2 3EG, UK.
authors.forename: Hong Wa
authors.initials: HW
authors.lastname: Yung
authors.forename: Mathew
authors.initials: M
authors.lastname: Cox
authors.forename: Martha
authors.initials: M
authors.lastname: Tissot van Patot
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Burton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000531:Altitude; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D006801:Humans; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D015852:Eukaryotic Initiation Factor-2; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt