Formaldehyde Crosses the Human Placenta and Affects Human Trophoblast Differentiation and Hormonal Functions

Pidoux, Guillaume; Gerbaud, Pascale; Gadrey, Jean; Thérond, Patrice; Ferreira, F.; Simasotchi, Christelle; Évain-Brion, Danièle; Gil, Sophie

doi:10.1371/journal.pone.0133506

Cited by 29 publications

(23 citation statements)

References 79 publications

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“…with amino groups of mucosal molecules. In the presence of water formaldehyde becomes nearly completely hydrated, thereby forming methylene glycol36.…”

Section: Discussionmentioning

confidence: 99%

Cellular reactions to long-term volatile organic compound (VOC) exposures

Gostner

Zeisler

Alam

et al. 2016

Sci Rep

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Investigations of cellular processes initiated by volatile organic compounds (VOCs) are limited when modelling realistic long-term exposure scenarios at low concentrations. Exposure to indoor VOCs is associated with a range of adverse effects, but data on molecular changes at regulatory threshold limits are lacking. Activity analysis of VOC in vitro can be a valuable complement to inhalation toxicological evaluations. We developed an exposure platform that generates a stable VOC atmosphere and allows the exposure of cells for longer periods. Using formaldehyde as a model analyte, air-liquid interface cultured A549 lung epithelial cells were exposed to critical concentrations of 0.1 and 0.5 ppm for 3 days. Owing to the lack of known exposure biomarkers, we applied a genome-wide transcriptional analysis to investigate cellular responses at these sublethal concentrations. We demonstrate a minor overlap of differentially expressed transcripts for both treatment concentrations, which can be further analyzed for their use as exposure biomarkers. Moreover, distinct expression patterns emerge for 0.1 and 0.5 ppm formaldehyde exposure, which is reflected in significant enrichment of distinct biological processes. More specifically, metabolism of specific compound classes, lipid biosynthesis and lung-associated functions are affected by lower exposure levels and processes affecting proliferation and apoptosis dominate the higher exposure levels.

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“…with amino groups of mucosal molecules. In the presence of water formaldehyde becomes nearly completely hydrated, thereby forming methylene glycol36.…”

Section: Discussionmentioning

confidence: 99%

Cellular reactions to long-term volatile organic compound (VOC) exposures

Gostner

Zeisler

Alam

et al. 2016

Sci Rep

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“…Syncytium formation was followed by monitoring the cellular distribution of desmoplakin and nuclei after fixation and immunostaining as previously described 40 46 47 . Desmoplakin staining at the boundaries of aggregated mononuclear cells gradually disappears during syncytium formation.…”

Section: Methodsmentioning

confidence: 99%

Annexin-A5 organized in 2D-network at the plasmalemma eases human trophoblast fusion

Degrelle

Gerbaud

Leconte

et al. 2017

Sci Rep

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Only a limited number of human cells can fuse to form a multinucleated syncytium. Cell fusion occurs as part of the differentiation of some cell types, including myotubes in muscle and osteoclasts in remodeling bone. In the differentiation of the human placenta, mononuclear cytotrophoblasts aggregate and fuse to form endocrinologically active, non-proliferative, multinucleated syncytia. These syncytia allow the exchange of nutrients and gases between the maternal and fetal circulation. Alteration of syncytial formation during pregnancy affects fetal growth and the outcome of the pregnancy. Here, we demonstrate the role of annexin A5 (AnxA5) in syncytial formation by cellular delivery of recombinant AnxA5 and RNA interference. By a variety of co-immunoprecipitation, immunolocalization and proximity experiments, we show that a pool of AnxA5 organizes at the inner-leaflet of the plasma membrane in the vicinity of a molecular complex that includes E-Cadherin, α-Catenin and β-Catenin, three proteins previously shown to form adherens junctions implicated in cell fusion. A combination of knockdown and reconstitution experiments with AnxA5, with or without the ability to self-assemble in 2D-arrays, demonstrate that this AnxA5 2D-network mediates E-Cadherin mobility in the plasmalemma that triggers human trophoblasts aggregation and thereby cell fusion.

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“…In essence, metabolism in the fetus magnifies the reduction in fetal drug exposure caused by placental clearance. This "site effect" may have clinical implications as fetal toxicity can occur via toxicity to the placenta (e.g., formaldehyde) (Pidoux et al, 2015). In these cases, fetal toxicity cannot be readily ruled out even when fetal exposure to the toxin/drug is low.…”

Section: Downloaded Frommentioning

confidence: 99%

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses

et al. 2017

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Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: 1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug-dosing regimens administered to the mother; 2) predict the impact of gestational age on fetal drug exposure; and 3) demonstrate that a single umbilical venous (UV)/maternal plasma (MP) ratio (even after multiple-dose oral administration to steady state) does not necessarily reflect fetal drug exposure. In addition, we verified the implementation of this m-f-PBPK model by comparing the predicted UV/MP and fetal/MP AUC ratios with those predicted at steady state after an intravenous infusion. Our simulations yielded novel insights into the quantitative contribution of fetoplacental metabolism and/or placental transport on gestational age-dependent fetal drug exposure. Through sensitivity analyses, we demonstrated that the UV/MP ratio does not measure the extent of fetal drug exposure unless obtained at steady state after an intravenous infusion or when there is little or no fluctuation in MP drug concentrations after multiple-dose oral administration. The proposed m-f-PBPK model can be used to predict fetal exposure to drugs across gestational ages and therefore provide the necessary information to assess the risk of drug toxicity to the fetus.

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Formaldehyde Crosses the Human Placenta and Affects Human Trophoblast Differentiation and Hormonal Functions

Cited by 29 publications

References 79 publications

Cellular reactions to long-term volatile organic compound (VOC) exposures

Cellular reactions to long-term volatile organic compound (VOC) exposures

Annexin-A5 organized in 2D-network at the plasmalemma eases human trophoblast fusion

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses

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