Review: Oxygen and trophoblast biology--a source of controversy.
ABSTRACT Oxygen is necessary for life yet too much or too little oxygen is toxic to cells. The oxygen tension in the maternal plasma bathing placental villi is <20 mm Hg until 10-12 weeks' gestation, rising to 40-80 mm Hg and remaining in this range throughout the second and third trimesters. Maldevelopment of the maternal spiral arteries in the first trimester predisposes to placental dysfunction and sub-optimal pregnancy outcomes in the second half of pregnancy. Although low oxygen at the site of early placental development is the norm, controversy is intense when investigators interpret how defective transformation of spiral arteries leads to placental dysfunction during the second and third trimesters. Moreover, debate rages as to what oxygen concentrations should be considered normal and abnormal for use in vitro to model villous responses in vivo. The placenta may be injured in the second half of pregnancy by hypoxia, but recent evidence shows that ischemia with reoxygenation and mechanical damage due to high flow contributes to the placental dysfunction of diverse pregnancy disorders. We overview normal and pathologic development of the placenta, consider variables that influence experiments in vitro, and discuss the hotly debated question of what in vitro oxygen percentage reflects the normal and abnormal oxygen concentrations that occur in vivo. We then describe our studies that show cultured villous trophoblasts undergo apoptosis and autophagy with phenotype-related differences in response to hypoxia.
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ABSTRACT: 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. 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. 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. 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.Placenta 03/2014; · 3.12 Impact Factor
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ABSTRACT: How the turnover of villous trophoblast is regulated is important for understanding normal and complicated pregnancies. There is considerable accord that syncytiotrophoblast (STB) grows and is refreshed by recruiting post-mitotic cells from the deeper cytotrophoblast (CTB). Nuclei in STB exhibit a spectrum of morphologies and packing densities and, until recently, there seemed to be a consensus that this variation reflected a transition from an early undifferentiated CTB-like phenotype to a long pre-apoptotic and brief apoptotic phase. In these later phases, nuclei are sequestered in clusters (syncytial knots) prior to extrusion as part of normal epithelial turnover. Early in gestation, nuclear clustering and formation of protrusions (syncytial sprouts) also occurs as a preliminary to villous sprouting. Nuclei in these clusters have a CTB-like phenotype and some sprouts may also detach from STB and pass into the uteroplacental circulation. However, this apparent consensus has been challenged and new interpretations of events in the proliferative (CTB), terminal differentiation (STB) and deportation compartments have emerged. Several different types of STB fragment are deported in normal pregnancy: larger multinucleate STB fragments, smaller uninucleate elements with CTB-like morphology and anucleate cytoplasmic fragments and microparticles. This review identifies points of agreement and disagreement and offers possible avenues of future research. An obvious need is to standardize best practice in several areas including choosing appropriate references for cell cycle phase labelling indices and combining immunolabelling of cell cycle and apoptosis markers (at LM or TEM levels) with design-based stereological estimates of absolute numbers of cells and nuclei in different compartments throughout normal gestation. This would also provide a surer foundation for interpreting results from different research groups and changes in normal and complicated pregnancies.Placenta 01/2014; · 3.12 Impact Factor
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ABSTRACT: Signs of severe oxidative stress are evident in term placentae of infants born to mothers with preeclampsia (PE), but it is unclear whether this is a cause or consequence of the disease. Here fibroblast lines were established from umbilical cords (UC) delivered by mothers who had experienced early onset PE and from controls with the goal of converting these primary cells to induced pluripotent stem cells and ultimately trophoblast. Contrary to expectations, the oxidative stress responses of these non-placental cells from PE infants were more severe than those from controls.PLoS ONE 01/2014; 9(7):e103110. · 3.53 Impact Factor