Placental infection with human papillomavirus is associated with spontaneous preterm delivery

Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, 2000 Courtyard Building, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Human Reproduction (Impact Factor: 4.57). 03/2008; 23(3):709-15. DOI: 10.1093/humrep/dem404
Source: PubMed

ABSTRACT We sought to determine if human papillomavirus (HPV) infection of extravillous trophoblast cells reduces cell invasion and if placental infection is associated with adverse reproductive outcomes attributed to placental dysfunction.
We conducted apoptosis and invasion assays using extravillous trophoblast (HTR-8/SVneo) cells that were transfected with a plasmid (pAT-HPV-16) containing the entire HPV-16 genome. In order to associate HPV infection with reproductive outcomes, we conducted a case-control study to detect HPV DNA in the extravillous trophoblast region of placentas from cases of spontaneous preterm delivery, severe pre-eclampsia requiring delivery at <37 weeks and controls who delivered at term.
Rates of apoptosis were 3- to 6-fold greater in transfected cells than in non-transfected cells or cells transfected with an empty plasmid. Invasion of transfected cells through extracellular matrices was 25-58% lower than that of the controls. HPV was detected more frequently in placentas from spontaneous preterm deliveries than in placentas from controls (P = 0.03). Identification of HPV in placentas from cases of pre-eclampsia was not significantly different to controls.
HPV infection of extravillous trophoblast induces cell death and may reduce placental invasion into the uterine wall. Thus, HPV infection may cause placental dysfunction and is associated with adverse pregnancy outcomes, including spontaneous preterm delivery.

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Available from: Deborah B Nelson, Feb 13, 2014
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    • "HPV infection rates in spontaneous abortions of the first and second trimesters have been reported to be in the 50– 70% range [2] [3]. The presence of HPV has been detected in the placentas derived from spontaneous abortions and preterm deliveries cases [2]. The origin of the HPV found in the placental cells was postulated to be circulating cellfree HPV DNA in the blood. "
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    ABSTRACT: Objectives. Human papillomaviruses (HPV) are associated with cell cycle arrest. This study focused on antioxidant selenomethionine (SeMet) inhibition of HPV-mediated necrosis. The objectives were to determine HPV-18 effects on embryonic cells and to evaluate SeMet in blocking HPV-18 effects. Methods. Fertilized mouse embryos were cultured for 5 days to implanted trophoblasts and exposed to either control medium (group 1), HPV-18 (group 2), combined HPV-18 and 0.5 µM SeMet (group 3), or combined HPV-18 and 5.0 µM SeMet (group 4). After 48 hrs, trophoblast integrity and, apoptosis/necrosis were assessed using morphometric and dual-stain fluorescence assays, respectively. Results. HPV-18 exposed trophoblasts nuclei (253.8 ± 28.5 sq·µ) were 29% smaller than controls (355.6 ± 35.9 sq·µ). Supplementation with 0.5 and 5.0 µM SeMet prevented nuclear shrinkage after HPV-18 exposure. HPV-18 infected trophoblasts remained larger with SeMet supplementation. HPV-18 decreased cell viability by 44% but SeMet supplementation sustained cell viability. Apoptosis was lower when SeMet was present. HPV-18 decreased inner cell mass (ICM) viability by over 60%. Conclusions. HPV-18 decreased nuclear size and trophoblast viability but these effects were attenuated by the antioxidant SeMet. SeMet blocked HPV-18 associated apoptosis process in trophoblasts but not ICM cells suggesting involvement of different oxidative stress pathways.
    08/2015; 2015(562567):1-7. DOI:10.1155/2015/562567
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    • "4.2. Inappropriate activation of inflammatory pathways within the gestational compartment has been linked to adverse obstetrical outcomes originated from abnormal placentation Dysregulation of inflammatory mediators within the gestational compartment has been linked to adverse birth outcomes such as intrauterine growth restriction, preeclampsia and preterm birth [50] [51] [52] [53] [54]. For example, high levels of IL-6, IL-8 and PGE2 in the cervicovaginal fluid and amnionic fluid of pregnant women were associated with increased risk for preterm birth [33,55–57]. "
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    ABSTRACT: Tetrabromobisphenol A (TBBPA) is a widely used flame retardant. Despite the presence of TBBPA in gestational tissues and the importance of proper regulation of inflammatory networks for successful pregnancy, there is no prior study on the effects of TBBPA on inflammatory responses in gestational tissues. The present study aimed to investigate TBBPA activation of inflammatory pathways, specifically cytokine and prostaglandin production, in the human first trimester placental cell line HTR-8/SVneo. TBBPA enhanced release of interleukin (IL)-6, IL-8, and prostaglandin E2 (PGE2), and suppressed TGF-β release in HTR-8/SVneo cells. The lowest effective concentration was 10μM TBBPA. A commercial immune response PCR array revealed increased expression of genes involved in inflammatory pathways stimulated by TBBPA in HTR-8/SVneo cells. Because proper regulation of inflammatory mediators in the gestational compartment is necessary for normal placental development and successful pregnancy, further investigation on the impact of TBBPA-stimulated responses on trophoblast function is warranted. Copyright © 2014 Elsevier Inc. All rights reserved.
    Reproductive Toxicology 10/2014; 50C:154-162. DOI:10.1016/j.reprotox.2014.10.005 · 3.23 Impact Factor
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    • "Migration and invasion of extravillous trophoblast into the spiral arteries are critical events during placentation (Brosens et al., 1967; Pijnenborg et al., 1983). It has been suggested that inflammation within the gestational compartment may lead to impaired trophoblast cellular function, contributing to the placental dysfunction seen in pregnancyrelated disorders (Anton et al., 2012) such as IUGR, preeclampsia and preterm birth (Germain et al., 1999; Gomez et al., 2008; Kim et al., 2002; Ness and Sibai, 2006; Riewe et al., 2010). IL-6 has been shown to increase migration and invasion in HTR-8/SVneo cells (Jovanovic et al., 2010; Jovanovic and Vicovac, 2009) and in JEG-3 choriocarcinoma cells (Dubinsky et al., 2010). "
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    ABSTRACT: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20μM BDE-47 for 24h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20μM BDE-47 for 24h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation.
    Toxicology and Applied Pharmacology 10/2014; 281(1). DOI:10.1016/j.taap.2014.09.015 · 3.71 Impact Factor
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