Oxygen and trophoblast biology - a source of controversy. Placenta 32(Suppl 2):S109-S118

Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA.
Placenta (Impact Factor: 3.29). 03/2011; 32 Suppl 2(2):S109-18. DOI: 10.1016/j.placenta.2010.12.013
Source: PubMed

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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Available from: Mark S. Longtine, Jan 16, 2015
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    • "Early identification of at risk pregnancies can improve outcomes through early intervention and improved monitoring of the pregnancy. While symptoms often do not present until late in pregnancy, defective trophoblast invasion in the first trimester is a primary insult in the development of preeclampsia [2]. This leads to reduced oxygen tension in the placenta and subsequently, altered trophoblast development, reoxygenation stress, and increased shedding of syncytiotrophoblast particles into the mother's blood. "
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    ABSTRACT: Maternal preeclampsia is associated with altered placental development in the first trimester of pregnancy. Confined placental trisomy 16 mosaicism (CPM16) is a genetic abnormality of the placenta that is highly predisposing to preeclampsia. We previously demonstrated widespread alterations in DNA methylation in 3rd trimester placentae associated with chromosomally normal early-onset preeclampsia (EOPET) and questioned whether similar changes would be associated with CPM16, making this condition a potential model for studying EOPET-associated changes early in pregnancy. Using the Illumina Infinium HumanMethylation450 BeadChip, 3rd trimester CPM16 placental samples (N = 10) were compared to gestational age matched controls, and to 1st trimester trisomy 16 placentae (N = 5). DNA methylation differences associated with CPM16 were identified at 2254 CpGs using stringent criteria (FDR < 0.01, Δβ > 0.15). A subset of these differences (11%; p < 0.0001) overlapped those observed in chromosomally normal EOPET using similarly stringent criteria (FDR < 0.01; Δβ > 0.125). Importantly, the majority of EOPET-associated CpGs were significantly altered (p < 0.05) in CPM16 with a similar Δβ distribution. This was true for CPM16 with (N = 5) and without (N = 5) EOPET, although EOPET cases showed a tendency towards larger changes. Of the shared CPM16/EOPET associated changes, three CpGs near two genes (ARGHEF37 and JUNB) were also altered in 1st trimester trisomy 16 placentae. Despite the limited sample size, widespread DNA methylation changes are observed in Trisomy 16 that overlap those seen previously in chromosomally normal EOPET. Hence, Trisomy 16 may provide a model to study the progression of placental changes that occurs in EOPET across different gestational ages.
    Placenta 01/2014; 35(3). DOI:10.1016/j.placenta.2014.01.001 · 3.29 Impact Factor
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    • "Oxygen is essential during embryo development (Tuuli et al., 2011). Following fertilization in the oviduct, the early embryo encounters a decreasing oxygen gradient when moving down the reproductive tract. "
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    ABSTRACT: Embryo development relies on the complex interplay of the basic cellular processes including proliferation, differentiation and apoptotic cell death. Precise regulation of these events is the basis for the establishment of embryonic structures and the organ development. Beginning with fertilization of the oocyte until delivery the developing embryo encounters changing environmental conditions such as varying levels of oxygen, which can give rise to reactive oxygen species (ROS). These challenges are met by the embryo with metabolic adaptations and by an array of antioxidative mechanisms. ROS can be deleterious by modifying biological molecules including lipids, proteins and nucleic acids and may induce abnormal development or even embryonic lethality. On the other hand ROS are vital players of various signaling cascades that affect the balance between cell growth, differentiation and death. An imbalance or dysregulation of these biological processes may generate cells with unrestricted growth and is therefore potentially teratogenic and tumorigenic. Thus, a precise balance between processes generating ROS and those decomposing ROS is critical for normal embryo development. One tier of the cellular protective system against ROS constitutes the family of selenium-dependent glutathione peroxidases (GPx). These enzymes reduce hydroperoxides to the corresponding alcohols at the expense of reduced glutathione. Of special interest within this protein family is the moonlighting enzyme glutathione peroxidase 4 (GPx4) that is a scavenger of lipophilic hydroperoxides on one hand, but on the other hand can be transformed into an enzymatically inactive cellular structural component. GPx4 deficiency – in contrast to all other GPx family members – leads to abnormal embryo development and finally produces a lethal phenotype in mice. This review is aimed at summarizing the current knowledge on GPx isoforms during embryo development and tumor development with an emphasis on GPx4.
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