Effect of Arsenic on Regulatory T Cells

Hernández-Castro, Berenice; Doníz-Padilla, Lesly; Salgado‐Bustamante, Mariana; Rocha, Danilo D.; Ortiz-Pérez, M. D.; Jiménez‐Capdeville, María E.; Portales-Pérez, Diana Patricia; Quintanar‐Stephano, Andrés; González‐Amaro, Roberto

doi:10.1007/s10875-009-9280-1

Cited by 68 publications

(40 citation statements)

References 32 publications

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“…The motivation of adjusting for cell types was due to the potential confounding effects of cell type compositions with respect to the association of arsenic exposure with DNA methylation, caused by the association of arsenic exposure with cell type compositions [20–23]. Our assessment on the correlations between total arsenic exposure and estimated cell type proportions also supported the potential confounding-role of cell types (Additional file 1: Material S1).…”

Section: Resultssupporting

confidence: 54%

Comparison of different cell type correction methods for genome-scale epigenetics studies

et al. 2017

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BackgroundWhole blood is frequently utilized in genome-wide association studies of DNA methylation patterns in relation to environmental exposures or clinical outcomes. These associations can be confounded by cellular heterogeneity. Algorithms have been developed to measure or adjust for this heterogeneity, and some have been compared in the literature. However, with new methods available, it is unknown whether the findings will be consistent, if not which method(s) perform better.Results Methods: We compared eight cell-type correction methods including the method in the minfi R package, the method by Houseman et al., the Removing unwanted variation (RUV) approach, the methods in FaST-LMM-EWASher, ReFACTor, RefFreeEWAS, and RefFreeCellMix R programs, along with one approach utilizing surrogate variables (SVAs). We first evaluated the association of DNA methylation at each CpG across the whole genome with prenatal arsenic exposure levels and with cancer status, adjusted for estimated cell-type information obtained from different methods. We then compared CpGs showing statistical significance from different approaches. For the methods implemented in minfi and proposed by Houseman et al., we utilized homogeneous data with composition of some blood cells available and compared them with the estimated cell compositions. Finally, for methods not explicitly estimating cell compositions, we evaluated their performance using simulated DNA methylation data with a set of latent variables representing “cell types”. Results: Results from the SVA-based method overall showed the highest agreement with all other methods except for FaST-LMM-EWASher. Using homogeneous data, minfi provided better estimations on cell types compared to the originally proposed method by Houseman et al. Further simulation studies on methods free of reference data revealed that SVA provided good sensitivities and specificities, RefFreeCellMix in general produced high sensitivities but specificities tended to be low when confounding is present, and FaST-LMM-EWASher gave the lowest sensitivity but highest specificity.ConclusionsResults from real data and simulations indicated that SVA is recommended when the focus is on the identification of informative CpGs. When appropriate reference data are available, the method implemented in the minfi package is recommended. However, if no such reference data are available or if the focus is not on estimating cell proportions, the SVA method is suggested.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1611-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 54%

Comparison of different cell type correction methods for genome-scale epigenetics studies

et al. 2017

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“…Additionally, these results suggested that prenatal arsenic exposure had an exposure-dependent effect on specific T cell subpopulations and, to a lesser extent, B cell subpopulations in cord blood. While these observations have not been confirmed in an experimental model and the biological effects of these epigenetic changes are unknown, these findings complement in vitro and in vivo studies that show that arsenic reduces lymphocyte proliferation, CD4 + cell counts, CD4 + :CD8 + cell ratios, and reduced T-regulatory cells in exposed adults and children 38,34 and that arsenic alters DNA methylation. [10][11][12][13][14] Conceptually, white blood cell populations could be acting as a confounder or a mediator for arsenicrelated toxicity (Fig.…”

Section: Discussionmentioning

confidence: 62%

“…We hypothesized that in utero exposure to arsenic would be associated with altered epigenome-wide methylation after controlling for cell mixture. Based on experimental evidence that arsenic alters the development, activation and proliferation of T-cells, [26][27][28][29][30][31][32][33][34][35][36][37] we further hypothesized that prenatal arsenic exposure would independently influence the immune response, which would be associated with altered leukocyte subpopulations in cord blood.…”

Section: Introductionmentioning

confidence: 99%

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

et al. 2014

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“…Cyclophosphamide, CD25 monoclonal antibodies, and cytotoxic T lymphocyte-associated protein 4 monoclonal antibodies have been shown to reduce the number of Tregs [12], but these drugs only transiently reduce the number of Tregs [13]. Hernandez et al first reported that As 2 O 3 could increase the Treg ratio in the spleen of myelitis rats [14]. Subsequently, Thomas et al found that As 2 O 3 reduced the proportion of Tregs in the spleen of a colon cancer subcutaneous rat model [15].…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide inhibits lung metastasis of mouse colon cancer via reducing the infiltration of regulatory T cells

Wang

et al. 2016

Tumor Biol.

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The purpose of this study was to investigate the effects of arsenic trioxide (As2O3) on the infiltration of regulatory T cells (Tregs) in the local lung metastasis of mouse colon cancer in vivo and the regulation of Tregs in cytokine-induced killer cells (CIKs) in vitro. A high Tregs infiltration mouse colon cancer lung metastasis model was established by intravenous injection of CT26 murine colon carcinoma cells. Tumor-bearing mice were randomly divided into three groups: control group, low-dose As2O3 group, and high-dose As2O3 group. For in vitro studies, CIKs were treated with vehicle control or 0.1, 1, or 5 μM As2O3. The level of Tregs was detected via flow cytometry, Foxp3 expression was assessed by immunohistochemistry and reverse transcription–polymerase chain reaction (RT-PCR), the level of interferon gamma (IFN-γ) was evaluated by enzyme-linked immunoassay (ELISA), and the cytotoxic activity of As2O3-treated CIKs was assessed through a lactate dehydrogenase (LDH) release assay. Obvious lung metastasis was observed 3 days after CT26 murine colon carcinoma cell injection. The numbers of Tregs in the lungs and spleens of tumor-bearing mice were significantly higher than those of the normal group (p < 0.01). As2O3 treatment increased the mouse weight as well as reduced the number of metastatic lung nodules and the lung/body weight ratio (p < 0.01). Moreover, As2O3 treatment significantly reduced the Tregs proportion and the Foxp3 messenger RNA (mRNA) levels in metastatic lung tissues (p < 0.01). In vitro, As2O3 significantly reduced the Tregs proportion and the Foxp3 mRNA levels (p < 0.01) and significantly increased the cytotoxic activity of CIKs and the IFN-γ levels in the supernatant of cultured CIKs (p < 0.01). As2O3 might inhibit lung metastasis of colon cancer by reducing the local infiltration of Tregs and increase the cytotoxic activity of CIKs by suppressing Tregs.

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Effect of Arsenic on Regulatory T Cells

Abstract: Our data indicate that As seems to have a relevant and complex effect on nTreg cells.

Cited by 68 publications

References 32 publications

Comparison of different cell type correction methods for genome-scale epigenetics studies

Comparison of different cell type correction methods for genome-scale epigenetics studies

Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood

Arsenic trioxide inhibits lung metastasis of mouse colon cancer via reducing the infiltration of regulatory T cells

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