Abstract
Background
Transport of iron across the placenta is critical for appropriate development of the fetus. Iron deficiency during pregnancy remains a major public health concern, particularly in low- and middle-income countries, often exacerbated by infectious diseases leading to altered iron trafficking via inflammatory responses. Herein, we investigate the role of hepcidin, a master regulator of iron homeostasis, on regulation of iron transport across trophoblast cells.
Methods
We utilized the Jeg-3 choriocarcinoma cell line for analysis of the expression of transferrin receptor, ferritin, and ferroportin as well as the export of 59Fe in the presence of hepcidin. Placental tissue from human term pregnancies was utilized for immunohistochemistry.
Results
Hepcidin treatment of Jeg-3 cells decreased the expression of ferroportin and transferrin receptor (TfR) and reduced the cellular export of iron. Lower expression of TfR on the syncytiotrophoblast was associated with the highest levels of hepcidin in maternal circulation, and ferroportin expression was positively associated with placental TfR. Placentas from small-for-gestational-age newborns had significantly lower levels of ferroportin and ferritin gene expression at delivery.
Conclusions
Our data suggest that hepcidin plays an important role in the regulation of iron transport across the placenta, making it a critical link in movement of iron into fetal circulation.
Impact
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Hepcidin has a direct impact on iron transport across the human placenta.
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This study provides the first evidence of direct regulation of iron efflux from human trophoblast cells by hepcidin.
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These data extend our understanding of iron transport across the maternal–fetal interface, a process critical for fetal health and development.
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Acknowledgements
This work was supported by the National Institute of Allergy and Infectious Diseases [R21AI107520 to J.F.F. and K01AI13068 to E.A.M.] and by the National Institute of Diabetes and Digestive and Kidney Diseases [R01DK110049 to T.B.B.] at the National Institutes of Health.
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Conception and design; acquisition; analysis or interpretation of data; and final approval: all authors; drafting of the article: E.A.M., T.B.B., J.D.K., J.F.F.
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McDonald, E.A., Gundogan, F., Olveda, R.M. et al. Iron transport across the human placenta is regulated by hepcidin. Pediatr Res 92, 396–402 (2022). https://doi.org/10.1038/s41390-020-01201-y
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DOI: https://doi.org/10.1038/s41390-020-01201-y
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