Effects of Cadmium on MAPK Signalling Pathways and HSP70 Expression in a Human Trophoblast Cell Line

Valbonesi, Paola; Ricci, Lucila Costallat; Franzellitti, Silvia; Biondi, Carla; Fabbri, Elena

doi:10.1016/j.placenta.2008.05.004

Cited by 28 publications

(13 citation statements)

References 41 publications

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“…We found the Ras protein signaling to be induced, which is supported by literature (e.g. [50,51]). Like stress-induced signal transduction pathways, also the enriched Vitamin A (retinoid) metabolism can be related to apoptosis [52] by retinoic acid mediated transcriptional activity [53].…”

Section: Discussionsupporting

confidence: 91%

High throughput nano-liter RT-qPCR to classify soil contamination using a soil arthropod

et al. 2011

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BackgroundTo incorporate genomics data into environmental assessments a mechanistic perspective of interactions between chemicals and induced biological processes needs to be developed. Since chemical compounds with structural similarity often induce comparable biological responses in exposed animals, gene expression signatures can serve as a starting point for the assessment of chemicals and their toxicity, but only when relevant and stable gene panels are available. To design such a panel, we isolated differentially expressed gene fragments from the soil arthropod Folsomia candida, a species often used for ecotoxicological testing. Animals were exposed to two chemically distinct compounds, being a metal (cadmium) and a polycyclic aromatic hydrocarbon (phenanthrene). We investigated the affected molecular responses resulting from either treatment and developed and validated 44 qPCR assays for their responses using a high throughput nano-liter RT-qPCR platform for the analysis of the samples.ResultsSuppressive subtractive hybridization (SSH) was used to retrieve stress-related gene fragments. SSH libraries revealed pathways involved in mitochondrial dysfunction and protein degradation for cadmium and biotransformation for phenanthrene to be overrepresented. Amongst a small cluster of SSH-derived cadmium responsive markers were an inflammatory response protein and an endo-glucanase. Conversely, cytochrome P450 family 6 or 9 was specifically induced by phenanthrene. Differential expressions of these candidate biomarkers were also highly significant in the independently generated test sample set. Toxicity levels in different training samples were not reflected by any of the markers' intensity of expressions. Though, a model based on partial least squares differential analysis (PLS-DA) (with RMSEPs between 9 and 22% and R2s between 0.82 and 0.97) using gene expressions of 25 important qPCR assays correctly predicted the nature of exposures of test samples.ConclusionsFor the application of molecular bio-indication in environmental assessments, multivariate analyses obviously have an added value over univariate methods. Our results suggest that compound discrimination can be achieved by PLS-DA, based on a hard classification of the within-class rankings of samples from a test set. This study clearly shows that the use of high throughput RT-qPCR could be a valuable tool in ecotoxicology combining high throughput with analytical sensitivity.

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Section: Discussionsupporting

confidence: 91%

High throughput nano-liter RT-qPCR to classify soil contamination using a soil arthropod

et al. 2011

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“…REGULATION OF PLACENTAL 11beta-HSD2 BY ERK1/2 cells with 30 lM Cd led to increases in p-JNK and p-p38 MAPK [28], it remains possible that cadmium may activate other signaling pathways besides ERK1/2 in human trophoblast cells with higher concentrations of and/or prolonged exposure to cadmium. To provide direct evidence for the involvement of ERK1/2 in mediating the inhibitory effects of cadmium on placental 11b-HSD2, we pretreated trophoblast cells with the ERK1/2 inhibitor U0126 followed by cadmium.…”

Section: Discussionmentioning

confidence: 99%

The ERK1/2 Signaling Pathway Regulates 11beta-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells Through a Transcriptional Mechanism1

Guan

Sun

Yang

2013

Biology of Reproduction

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The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) plays a key role in fetal development, but its regulation is incompletely understood. We previously demonstrated that p38 MAPK was a positive regulator of placental 11beta-HSD2. However, it remains unknown if the other two MAPKs, ERK1/2 and JNK, were also involved. In the present study, we identified ERK1/2 as an important regulator of placental 11beta-HSD2. We showed that inhibition of ERK1/2 with the pharmacological inhibitor U0126 led to a 3-fold increase in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. In contrast, the JNK inhibitor SP600125 had no effect. Furthermore, U0126 increased the HSD11B2 promoter activity by 300%, indicating that ERK1/2 regulates placental 11beta-HSD2 expression through a transcriptional mechanism. Importantly, siRNA-mediated knockdown of ERK1/2 caused a similar increase in 11beta-HSD2 protein. In addition, given that we previously showed that cadmium reduced placental 11beta-HSD2 expression via a transcriptional mechanism, but the signal transduction pathways involved remain unclear, we also addressed this question and found that treatment of trophoblast cells with cadmium led to rapid activation of ERK1/2. Importantly, U0126 completely abrogated the inhibitory effects of cadmium on placental 11beta-HSD2. Taken together, the present study not only identifies the ERK1/2 signaling pathway as a potent negative regulator of placental 11beta-HSD2 but also demonstrates that this pathway mediates cadmium repression of placental 11beta-HSD2. Thus, our present study reveals 11beta-HSD2 as an important target through which ERK1/2 may regulate human placental function and consequently fetal development.

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“…Valbonesi et al (2008) reported that cadmium triggers di erent stress responses in human placental trophoblast cells involving mitogen-activated protein kinase (MAPK)-dependent pathways that play crucial roles during pregnancy and concluded that such cadmium-related, nonphysiological activation disrupts normal functions in trophoblast cells.…”

Section: Discussionmentioning

confidence: 99%

Metals in human placenta: focus on the effects of cadmium on steroid hormones and leptin

Stasenko

Bradford

Piasek

et al. 2009

J of Applied Toxicology

106

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Cadmium and other metallic ions can act as metalloestrogens and endocrine disruptors of reproductive tissues and fetal development in mammals, including humans. The detrimental effects occur with respect to the synthesis of both steroid and polypeptide hormones in the placenta. Leptin is produced by the trophoblast and may regulate fetal organogenesis and development. In human term placentas, concentrations of toxic metals and their effects on steroidogenesis were assessed in healthy parturients (109 non-smokers and 99 smokers) in relation to tobacco smoking. Trace elements (cadmium, lead, iron, zinc and copper) were analyzed in placentas using atomic absorption spectroscopy, and steroid hormones (progesterone and estradiol) were assayed in placental samples by an enzyme-immunometric method. Cadmium concentrations were doubled in placentas of smokers as compared with non-smokers, and placental lead and zinc concentrations increased significantly. Placental concentrations of iron, copper, progesterone and estradiol did not differ. In addition, human trophoblast cells were co-cultured with 0, 5, 10 or 20 microm CdCl(2) for 96 h and leptin mRNA assessed by quantitative polymerase chain reaction. Leptin mRNA declined dose-responsively as a result of CdCl(2) exposure. Collectively, the results confirm that human placental tissue offers a unique opportunity to biomonitor cadmium exposure in both the maternal and the internal fetal environments. In addition, the results strongly suggest that cadmium may cause a decline in placental leptin synthesis, as we have previously shown for placental progesterone production. This may constitute further evidence of the endocrine-disrupting effects of cadmium, as a constituent of tobacco smoke, on reproduction in women.

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Effects of Cadmium on MAPK Signalling Pathways and HSP70 Expression in a Human Trophoblast Cell Line

Cited by 28 publications

References 41 publications

High throughput nano-liter RT-qPCR to classify soil contamination using a soil arthropod

High throughput nano-liter RT-qPCR to classify soil contamination using a soil arthropod

The ERK1/2 Signaling Pathway Regulates 11beta-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells Through a Transcriptional Mechanism1

Metals in human placenta: focus on the effects of cadmium on steroid hormones and leptin

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