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Article: BDNF and KISS-1 Levels in Maternal Serum, Umbilical Cord, and Placenta: The Potential Role of Maternal Levels as Effect Biomarker.

Granitzer, Sebastian / Widhalm, Raimund / Atteneder, Simon / Fernandez, Mariana F / Mustieles, Vicente / Zeisler, Harald / Hengstschläger, Markus / Gundacker, Claudia

Exposure and health

2023 , Page(s) 1–17

Abstract: Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been explored. ... ...

Abstract	Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been explored. The influence of prenatal lead (Pb) and cadmium (Cd) exposure and maternal iron status on BDNF and KISS-1 levels is also unclarified and of concern. In a pilot cross-sectional study with 65 mother-newborn pairs, we analyzed maternal and cord serum levels of pro-BDNF, mature BDNF, and KISS-1, BDNF, and KISS-1 gene expression in placenta, Pb and Cd in maternal and umbilical cord blood (erythrocytes), and placenta. We conducted a series of in vitro experiments using human primary trophoblast cells (hTCs) and BeWo cells to verify main findings of the epidemiological analysis. Strong and consistent correlations were observed between maternal serum levels of pro-BDNF, mature BDNF, and KISS-1 and corresponding levels in umbilical serum and placental tissue. Maternal red blood cell Pb levels were inversely correlated with serum and placental KISS-1 levels. Lower expression and release of KISS-1 was also observed in Pb-exposed BeWo cells. In vitro Pb exposure also reduced cellular BDNF levels. Cd-treated BeWo cells showed increased pro-BDNF levels. Low maternal iron status was positively associated with low BDNF levels. Iron-deficient hTCs and BeWo cells showed a consistent decrease in the release of mature BDNF. The correlations between maternal BDNF and KISS-1 levels, placental gene expression, and umbilical cord serum levels, respectively, indicate the strong potential of maternal serum as predictive matrix for BDNF and KISS-1 levels in placentas and fetal sera. Pb exposure and iron status modulate BDNF and KISS-1 levels, but a clear direction of modulations was not evident. The associations need to be confirmed in a larger sample and validated in terms of placental and neurodevelopmental function. Supplementary information: The online version contains supplementary material available at 10.1007/s12403-023-00565-w.
Language	English
Publishing date	2023-05-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2847071-0
ISSN	2451-9685 ; 2451-9766
ISSN (online)	2451-9685
ISSN	2451-9766
DOI	10.1007/s12403-023-00565-w
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Article: Perfluorooctane sulfonic acid (PFOS) inhibits vessel formation in a human 3D co-culture angiogenesis model (NCFs/HUVECs)

Forsthuber, Martin / Widhalm, Raimund / Granitzer, Sebastian / Kaiser, Andreas Marius / Moshammer, Hanns / Hengstschläger, Markus / Dolznig, Helmut / Gundacker, Claudia

Environmental pollution. 2022 Jan. 15, v. 293

2022

Abstract: Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and ... ...

Abstract	Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and thus possibly fetal development is unknown. Therefore, we investigated 1) the metabolic activity of PFOS-exposed endothelial cells (human umbilical vein endothelial cells, HUVECs), fibroblasts (normal colon fibroblasts, NCFs), and epithelial cells (human colorectal carcinoma cells, HCT116), 2) PFOS-specific inhibition of vascular endothelial growth factor receptor (VEGFR)2 stimulation in KDR/NFAT-RE HEK293 cells, and 3) the antiangiogenic potential of PFOS in a 3D in vitro angiogenesis model of HUVECs and NCFs. In terms of metabolic activity, endothelial cells (HUVECs) were much more sensitive to PFOS than fibroblasts (NCFs) or epithelial cells (HCT116). VEGFR2 signaling in KDR/NFAT-RE HEK293 cells decreased with increasing PFOS concentrations. In co-culture (angiogenesis assay), PFOS treatment resulted in a dose-dependent reduction in tip and branch formation, tip length (μm), and total structural area (μm²) with stable metabolic activity of HUVECs up to high concentrations. We conclude that PFOS possesses antiangiogenic properties. Inhibition of VEGFR2 signaling indicates a possible mechanism of action that can be linked to an existing Adverse Outcome Pathway (AOP43) containing the AO reduced birth weight. Further studies are needed to confirm PFOS-specific adverse effects on angiogenesis, placental perfusion, and fetal growth.
Keywords	adverse outcome pathways ; angiogenesis ; biochemical pathways ; birth weight ; coculture ; colon ; colorectal neoplasms ; dose response ; epithelium ; fetal development ; fibroblasts ; humans ; mechanism of action ; perfluorooctane sulfonic acid ; pollutants ; pollution ; vascular endothelial growth factor receptor-2
Language	English
Dates of publication	2022-0115
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	280652-6
ISSN	1873-6424 ; 0013-9327 ; 0269-7491
ISSN (online)	1873-6424
ISSN	0013-9327 ; 0269-7491
DOI	10.1016/j.envpol.2021.118543
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Article ; Online: Prenatal exposure to per- and polyfluoroalkyl substances and pregnancy outcome in Austria.

Kaiser, Andreas-Marius / Forsthuber, Martin / Widhalm, Raimund / Granitzer, Sebastian / Weiss, Stefan / Zeisler, Harald / Foessleitner, Philipp / Salzer, Hans / Grasl-Kraupp, Bettina / Moshammer, Hanns / Hartmann, Christina / Uhl, Maria / Gundacker, Claudia

Ecotoxicology and environmental safety

2023 Volume 259, Page(s) 115006

Abstract: Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent industrial chemicals that can harm reproductive health. PFAS levels were analysed to determine the current sources of exposure and possible associations between prenatal PFAS ... ...

Abstract	Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent industrial chemicals that can harm reproductive health. PFAS levels were analysed to determine the current sources of exposure and possible associations between prenatal PFAS exposure and adverse pregnancy outcome. Samples from 136 mother-newborn pairs recruited between 2017 and 2019 were analysed for the presence of 31 target PFAS in maternal serum, umbilical cord serum, and placental tissue by high-performance liquid chromatography coupled to a tandem mass spectrometer. Questionnaires and medical records were used to survey sources of exposure and pregnancy outcome, including small for gestational age (SGA), fetal growth restriction (FGR), preeclampsia (PE), preterm birth, large for gestational age (LGA) and gestational diabetes mellitus (GDM). Data were analysed for individual PFAS and sum4PFAS (sum of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) serum levels) in logistic regression analyses and categorical regression analyses. Compared to data from a previous Viennese study in 2010-12, sum4PFAS levels were generally lower. Sum4PFAS serum levels of three women (2.2%) exceeded 6.9 µg/L, a level that corresponds to the recently established tolerable weekly intake (TWI) of EFSA for nursing mothers aged 35 years; in the 2010/2012 study it was 13.6%. The large contribution of unidentified extractable organofluorine (EOF) fractions to total PFAS exposure is a concern. Study site, mean maternal corpuscular hemoglobin (MCH), use of facial lotion, and owning upholstered furniture were significantly influencing maternal exposure. While no effect of sum4PFAS on pregnancy outcome could be detected, we found highest placental PFDA levels in SGA births. PFHxS levels in umbilical cord and placenta were highest in preterm births. Further studies are needed to elucidate the relationship of prenatal PFAS exposure and pregnancy outcome, in particular to confirm whether and how placental PFDA levels may contribute to an increased risk for SGA.
MeSH term(s)	Pregnancy ; Humans ; Female ; Infant, Newborn ; Pregnancy Outcome/epidemiology ; Prenatal Exposure Delayed Effects/chemically induced ; Placenta ; Environmental Pollutants ; Austria ; Premature Birth/epidemiology ; Premature Birth/chemically induced ; Fluorocarbons ; Alkanesulfonic Acids/toxicity ; Alkanesulfonates
Chemical Substances	Environmental Pollutants ; Fluorocarbons ; Alkanesulfonic Acids ; perflexane (FX3WJ41CMX) ; Alkanesulfonates
Language	English
Publishing date	2023-05-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2023.115006
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Article ; Online: Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo.

Granitzer, Sebastian / Widhalm, Raimund / Forsthuber, Martin / Ellinger, Isabella / Desoye, Gernot / Hengstschläger, Markus / Zeisler, Harald / Salzer, Hans / Gundacker, Claudia

International journal of molecular sciences

2021 Volume 22, Issue 4

Abstract: The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter ( ... ...

Abstract	The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.
MeSH term(s)	Apoptosis ; Cell Survival ; Cells, Cultured ; Female ; Glutathione/metabolism ; Humans ; Large Neutral Amino Acid-Transporter 1/metabolism ; Methylmercury Compounds/analysis ; Methylmercury Compounds/pharmacology ; Oxidative Stress/drug effects ; Placenta/drug effects ; Placenta/metabolism ; Placenta/pathology ; Pregnancy ; Protective Agents/analysis ; Protective Agents/pharmacology
Chemical Substances	Large Neutral Amino Acid-Transporter 1 ; Methylmercury Compounds ; Protective Agents ; SLC7A5 protein, human ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2021-02-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22041707
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Article ; Online: The transplacental transfer efficiency of per- and polyfluoroalkyl substances (PFAS): a first meta-analysis.

Appel, Mareike / Forsthuber, Martin / Ramos, Romualdo / Widhalm, Raimund / Granitzer, Sebastian / Uhl, Maria / Hengstschläger, Markus / Stamm, Tanja / Gundacker, Claudia

Journal of toxicology and environmental health. Part B, Critical reviews

2021 Volume 25, Issue 1, Page(s) 23–42

Abstract: Per- and polyfluorinated substances (PFAS), ubiquitously present in the environment and biota, are transferred to the fetus via the placenta. PFAS can be distinguished, among other things, by their different carbon chain lengths and functional groups. ... ...

Abstract	Per- and polyfluorinated substances (PFAS), ubiquitously present in the environment and biota, are transferred to the fetus via the placenta. PFAS can be distinguished, among other things, by their different carbon chain lengths and functional groups. The aim of this study was to provide comprehensive evidence on PFAS transfer rates across the human placental barrier by means of a meta-analysis based upon a systematic review. The available literature up to April 2021 was reviewed and transplacental transfer efficiencies (TTEs) of PFAS assessed. A total of 39 studies reporting data on 20 PFAS were included in the systematic review. Of these, 20 studies with data on 19 compounds were included in the meta-analysis. Comprehensive Meta-Analysis (CMA v3.0) was used for quantitative, statistical analyses with random effects models. A curvilinear relationship was found with short and long chains of perfluorocarboxylic acids (PFCAs) exhibiting higher TTE than compounds with intermediate chain length. Among the less well studied PFAS, perfluorohexanoic acid (PFHxA), 6:2 fluorotelomersulfonic acid (6:2 FTS) and perfluorobutanoic acid (PFBA) stood out the most with a high TEEs. The dependence of TTEs on chain length and functional group is clearly shown in this first meta-analysis on PFAS transfer across the human placenta. More data on effects of less well studied PFAS in pregnant women and neonates are needed to assess the potential risk for fetal exposure.
MeSH term(s)	Caproates/metabolism ; Environmental Exposure/adverse effects ; Environmental Pollutants/adverse effects ; Environmental Pollutants/chemistry ; Female ; Fluorocarbons/chemistry ; Fluorocarbons/metabolism ; Humans ; Infant, Newborn ; Placenta/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects
Chemical Substances	Caproates ; Environmental Pollutants ; Fluorocarbons ; fluorotelomer sulfonic acids ; perfluorobutyric acid (375-22-4) ; perfluorohexanoic acid (ZP34Q2220R)
Language	English
Publishing date	2021-12-20
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Systematic Review
ZDB-ID	1415246-0
ISSN	1521-6950 ; 1093-7404
ISSN (online)	1521-6950
ISSN	1093-7404
DOI	10.1080/10937404.2021.2009946
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Article ; Online: Perfluorooctane sulfonic acid (PFOS) inhibits vessel formation in a human 3D co-culture angiogenesis model (NCFs/HUVECs).

Forsthuber, Martin / Widhalm, Raimund / Granitzer, Sebastian / Kaiser, Andreas Marius / Moshammer, Hanns / Hengstschläger, Markus / Dolznig, Helmut / Gundacker, Claudia

Environmental pollution (Barking, Essex : 1987)

2021 Volume 293, Page(s) 118543

Abstract	Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and thus possibly fetal development is unknown. Therefore, we investigated 1) the metabolic activity of PFOS-exposed endothelial cells (human umbilical vein endothelial cells, HUVECs), fibroblasts (normal colon fibroblasts, NCFs), and epithelial cells (human colorectal carcinoma cells, HCT116), 2) PFOS-specific inhibition of vascular endothelial growth factor receptor (VEGFR)2 stimulation in KDR/NFAT-RE HEK293 cells, and 3) the antiangiogenic potential of PFOS in a 3D in vitro angiogenesis model of HUVECs and NCFs. In terms of metabolic activity, endothelial cells (HUVECs) were much more sensitive to PFOS than fibroblasts (NCFs) or epithelial cells (HCT116). VEGFR2 signaling in KDR/NFAT-RE HEK293 cells decreased with increasing PFOS concentrations. In co-culture (angiogenesis assay), PFOS treatment resulted in a dose-dependent reduction in tip and branch formation, tip length (μm), and total structural area (μm
MeSH term(s)	Alkanesulfonic Acids ; Cell Proliferation ; Coculture Techniques ; Female ; Fluorocarbons ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Placenta ; Pregnancy ; Vascular Endothelial Growth Factor A
Chemical Substances	Alkanesulfonic Acids ; Fluorocarbons ; Vascular Endothelial Growth Factor A ; perfluorooctane sulfonic acid (9H2MAI21CL)
Language	English
Publishing date	2021-11-17
Publishing country	England
Document type	Journal Article
ZDB-ID	280652-6
ISSN	1873-6424 ; 0013-9327 ; 0269-7491
ISSN (online)	1873-6424
ISSN	0013-9327 ; 0269-7491
DOI	10.1016/j.envpol.2021.118543
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Article ; Online: Reduced Birth Weight and Exposure to Per- and Polyfluoroalkyl Substances: A Review of Possible Underlying Mechanisms Using the AOP-HelpFinder.

Gundacker, Claudia / Audouze, Karine / Widhalm, Raimund / Granitzer, Sebastian / Forsthuber, Martin / Jornod, Florence / Wielsøe, Maria / Long, Manhai / Halldórsson, Thórhallur Ingi / Uhl, Maria / Bonefeld-Jørgensen, Eva Cecilie

Toxics

2022 Volume 10, Issue 11

Abstract: Prenatal exposure to per- and polyfluorinated substances (PFAS) may impair fetal growth. Our knowledge of the underlying mechanisms is incomplete. We used the Adverse Outcome Pathway (AOP)-helpFinder tool to ... ...

Abstract	Prenatal exposure to per- and polyfluorinated substances (PFAS) may impair fetal growth. Our knowledge of the underlying mechanisms is incomplete. We used the Adverse Outcome Pathway (AOP)-helpFinder tool to search
Language	English
Publishing date	2022-11-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2733883-6
ISSN	2305-6304 ; 2305-6304
ISSN (online)	2305-6304
ISSN	2305-6304
DOI	10.3390/toxics10110684
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Article ; Online: Methylmercury Uptake into BeWo Cells Depends on LAT2-4F2hc, a System L Amino Acid Transporter.

Balthasar, Christina / Stangl, Herbert / Widhalm, Raimund / Granitzer, Sebastian / Hengstschläger, Markus / Gundacker, Claudia

International journal of molecular sciences

2017 Volume 18, Issue 8

Abstract: The organic mercury compound methylmercury (MeHg) is able to target the fetal brain. However, the uptake of the toxicant into placental cells is incompletely understood. MeHg strongly binds to thiol-S containing molecules such as cysteine. This MeHg-l- ... ...

Abstract	The organic mercury compound methylmercury (MeHg) is able to target the fetal brain. However, the uptake of the toxicant into placental cells is incompletely understood. MeHg strongly binds to thiol-S containing molecules such as cysteine. This MeHg-l-cysteine exhibits some structural similarity to methionine. System L plays a crucial role in placental transport of essential amino acids such as leucine and methionine and thus has been assumed to also transport MeHg-l-cysteine across the placenta. The uptake of methylmercury and tritiated leucine and methionine into the choriocarcinoma cell line BeWo was examined using transwell assay and small interfering (si)RNA mediated gene knockdown. Upon the downregulation of large neutral amino acids transporter (LAT)2 and 4F2 cell-surface antigen heavy chain (4F2hc), respectively, the levels of [³H]leucine in BeWo cells are significantly reduced compared to controls treated with non-targeting siRNA (
Language	English
Publishing date	2017-08-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms18081730
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Article ; Online: Human placental cell line HTR-8/SVneo accumulates cadmium by divalent metal transporters DMT1 and ZIP14.

Widhalm, Raimund / Ellinger, Isabella / Granitzer, Sebastian / Forsthuber, Martin / Bajtela, Robert / Gelles, Katharina / Hartig, Pia-Yael / Hengstschläger, Markus / Zeisler, Harald / Salzer, Hans / Gundacker, Claudia

Metallomics : integrated biometal science

2020 Volume 12, Issue 11, Page(s) 1822–1833

Abstract: Cadmium (Cd) is a global pollutant that accumulates in the placenta and can cause placental dysfunction. Although iron transporters have been suggested to participate in placental Cd uptake, it is still unknown which transporters are actually involved in ...

Abstract	Cadmium (Cd) is a global pollutant that accumulates in the placenta and can cause placental dysfunction. Although iron transporters have been suggested to participate in placental Cd uptake, it is still unknown which transporters are actually involved in this process. We specifically aimed to study the role of three iron transporters in the uptake of Cd into the placental cell line HTR-8/SVneo. For this purpose, Divalent Metal Transporter (DMT)1 and ZRT/IRT like protein (ZIP)8 and ZIP14 were downregulated and changes in cellular Cd levels analysed in relation to controls. As clearly shown by the reduction of the Cd content by ∼60% in DMT1- and ZIP14-downregulated cells, the two proteins are essential for Cd accumulation in HTR-8/SVneo cells. Using a validated antibody, we show DMT1 to be localised in situ in trophoblast and stromal cells. We further wanted to investigate how placental cells cope with Cd loading and which metallothionein (MT) isoforms they express. Cd-exposed cells accumulate Cd in a dose-dependent manner and upregulate MT2A accordingly (up to 15-fold induction upon 5 μM CdCl
MeSH term(s)	Biological Transport/drug effects ; Cadmium/metabolism ; Cadmium/toxicity ; Cation Transport Proteins/metabolism ; Cell Count ; Cell Line ; Female ; Humans ; Metallothionein/metabolism ; Models, Biological ; Placenta/cytology ; Pregnancy
Chemical Substances	Cation Transport Proteins ; MT2A protein, human ; SLC39A14 protein, human ; SLC39A8 protein, human ; solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 ; Cadmium (00BH33GNGH) ; Metallothionein (9038-94-2)
Language	English
Publishing date	2020-11-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2474317-3
ISSN	1756-591X ; 1756-5901
ISSN (online)	1756-591X
ISSN	1756-5901
DOI	10.1039/d0mt00199f
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Article ; Online: In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta.

Granitzer, Sebastian / Ellinger, Isabella / Khan, Rumsha / Gelles, Katharina / Widhalm, Raimund / Hengstschläger, Markus / Zeisler, Harald / Desoye, Gernot / Tupova, Lenka / Ceckova, Martina / Salzer, Hans / Gundacker, Claudia

Archives of toxicology

2020 Volume 94, Issue 11, Page(s) 3799–3817

Abstract: Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells ... ...

Abstract	Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.
MeSH term(s)	ATP-Binding Cassette Transporters/metabolism ; Amino Acid Transport Systems/metabolism ; Animals ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Dogs ; Endothelial Cells ; Female ; Gene Knockdown Techniques ; Glutathione/metabolism ; Humans ; Immunohistochemistry ; Madin Darby Canine Kidney Cells ; Methylmercury Compounds/adverse effects ; Methylmercury Compounds/metabolism ; Multidrug Resistance-Associated Proteins/physiology ; Oxidative Stress ; Placenta/metabolism ; Pregnancy
Chemical Substances	ATP-Binding Cassette Transporters ; Amino Acid Transport Systems ; Methylmercury Compounds ; Multidrug Resistance-Associated Proteins ; dimethyl mercury (C60TQU15XY) ; Glutathione (GAN16C9B8O) ; multidrug resistance-associated protein 1 (Y49M64GZ4Q)
Language	English
Publishing date	2020-09-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-020-02900-5
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