The DOI matches its Crossref record; 61 of the 62 references it cites were found in a registry or an index.
Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude
Open accessAbstract
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.—Yung, H. W., Cox, M., Tissot van Patot, M., Burton, G. J. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude. FASEB J. 26, 1970‐1981 (2012). www.fasebj.org
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“Mild activation of the UPR, with phosphorylation of eIF2α alone, has been reported in the high-altitude human placenta, where it may mediate homeostatic adaptations to the hypobaric hypoxia experienced (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“Equally, evidence of translational arrest has been reported in human placentas from normal healthy pregnancies at high altitude (3,100 m) where growth of the villus tree is impaired (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“These placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“However, there is evidence for a decrease in protein synthesis in the placenta of non-native women at high altitude (598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
In the citing paper
“Most of the data relating to regulation of protein synthesis in response to hypoxia come from the cancer field (542, 585, 586), but it appears that the same pathways are operative in the placenta under physiological and pathological conditions (596, 598).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [598]
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Gingras, A., Raught, B., & Sonenberg, N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.913 · Cited by 2,103
Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword?
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A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress
Boyce, M., Bryant, K. F., Jousse, C., Long, K., Harding, H. P., Scheuner, D. L., Kaufman, R. J., Ma, D., Coen, D. M., Ron, D., et al. (2005) · Science · doi:10.1126/science.1101902 · Cited by 1,403
Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis
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Coping with stress: eIF2 kinases and translational control
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- 10.1002/(SICI)1096-8644(1998)107:27 <25::AID-AJPA3>3.0.CO;2-L · DOI
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Whole Transcriptome Analysis of the Mouse Placenta Following Radiation-Induced Growth Restriction
Sreetharan, S., Tharmalingam, S., Hourtovenko, C., Tubin, F., McTiernan, C. D., Thome, C., Khaper, N., Boreham, D. R., Lees, S. J., & Tai, T. C. (2025) · Radiation · doi:10.3390/radiation5040035 · Cited by 1
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PPO.20 The effect of high altitude on cell proliferation, apoptosis and fusion in the human placenta
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Self-citationSome Aspects of the Physiology of the Placenta
Longo, L. D. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7921-5_8
Sightings edited by John W. Severinghaus
(2012) · High Altitude Medicine & Biology · doi:10.1089/ham.2012.1334
O’Callaghan, J. L. (2023) · Queensland University of Technology · doi:10.5204/thesis.eprints.244719
Ng, P. K., Khadka, V. S., Howe, C., Riel, J. M., Lee, M., & Kendal‐Wright, C. E. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48090900
Metadata
- Authors
- Yung, H. W., Cox, M., van Patot, M. T., & Burton, G. J.
- Affiliations
- University of Cambridge (GB)
- Centre for Trophoblast Research University of Cambridge Cambridge UK
- Corresponding author
- Burton, Graham J.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2012-01-20
- Volume
- 26
- Issue
- 5
- Pages
- 1970-1981
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC3336782
- OpenAlex
- W2115115666
- Cited by
- 112
- References
- 62
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 5 · 2013: 10 · 2012: 4
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The FASEB Journal (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (084804/2/08/Z)
- Topics
- Health Sciences › Medicine › Physiology (medical) › High Altitude and Hypoxia
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- endoplasmic reticulum stress, hypoxia, high altitude, placenta, protein synthesis inhibition, eIF2α phosphorylation, 4E-BP1, Akt phosphorylation, PI3K signaling, salubrinal, cell proliferation, low birth weight, trophoblast
- MeSH terms
- Altitude, Endoplasmic Reticulum, Female, Humans, Phosphoproteins, Phosphorylation, Placenta, Pregnancy, Protein Biosynthesis, Blotting, Western, Eukaryotic Initiation Factor-2, Oxidative Stress, Cell Cycle Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Real-Time Polymerase Chain Reaction
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