Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude

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% O2) 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 reduce...