Effect of oxygen on multidrug resistance in term human placenta
Abstract
Introduction The placenta contains efflux transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), that limit the passage of xenobiotics, certain hormones and nutrients from the maternal to the fetal circulation. The expression of these transporters changes with gestational age, yet the mechanisms involved remain unknown. However, the changes in P-gp and BCRP transporter expression coincide with those of oxygen tension in the placenta, and oxygen tension has been shown to modulate P-gp and BCRP expression in other tissues. The objective of this study was to investigate the effects of oxygen tension on P-gp and BCRP expression in the term human placenta.Methods Following equilibration in culture (96 h), term placental explants (n = 7) were cultured in 3% or 20% oxygen for 24 and 48 h. Culture medium was collected every 24 h to measure lactate dehydrogenase (LDH; explant viability) and human chorionic gonadotropin (hCG; syncytiotrophoblast function). P-gp (encoded by ABCB1) and BCRP (encoded by ABCG2) protein and mRNA, as well as VEGFA mRNA were measured using western blot and qRT-PCR. P-gp localization was determined using immunofluorescence.Results Oxygen tension had a significant effect on P-gp expression, with ABCB1/P-gp mRNA and protein levels increased in the hypoxic condition (3% O2) after 48 h (p < 0.05). VEGFA mRNA was elevated by hypoxia at both 24 and 48 h (p < 0.05). In contrast, placental ABCG2/BCRP mRNA and protein expression were stable with changes in oxygen tension. We identified profound differences in the glycosylation of P-gp between cultured and non-cultured placental tissue, with cultured explants expressing deglycosylated P-gp.Conclusions These findings demonstrate that, at term, the expression of placental P-gp, is regulated by oxygen tension. This suggests that changes in oxygenation of the placenta in the third trimester may alter levels of placental P-gp, and in doing so alter fetal exposure to P-gp substrates, including xenobiotics and certain hormones.
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Perturbations of placental barrier function due to mechanical damage, polymorphisms, or environmental factors may lead to increased fetal exposure.
“Nonetheless, perturbations of this function due to mechanical damage, polymorphisms (267), or environmental factors (287), may lead to increased fetal exposure.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [287]
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- Authors
- Javam, M., Audette, M. C., Iqbal, M., Bloise, E., Gibb, W., & Matthews, S. G.
- Affiliations
- University of Toronto (CA)
- University of Ottawa (CA)
- Corresponding author
- Matthews, S.G.
- Venue
- Placenta
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 35
- Issue
- 5
- Pages
- 324-330
- ISSN
- 0143-4004 (ISSN-L)
- OpenAlex
- W1978092597
- Cited by
- 31
- References
- 42
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 4 · 2014: 1
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Placenta (publishedVersion)
- PubMed (publishedVersion)
- TSpace (University of Toronto) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (FRN-57746)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- oxygen partial pressure, hypoxia, multidrug resistance, P-glycoprotein, ABCG2, efflux pumps, VEGF-A, placental explants, term placenta, placental oxygenation
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Female, Gestational Age, Chorionic Gonadotropin, Humans, L-Lactate Dehydrogenase, Neoplasm Proteins, Oxygen, Placenta, Pregnancy, Pregnancy Trimester, Third, Trophoblasts, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, ATP Binding Cassette Transporter, Subfamily B, Member 1
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