Chick embryos exposed to trichloroethylene in an ex ovo culture model show selective defects in early endocardial cushion tissue formation

Mishima, Noboru; Hoffman, Stanley; Hill, Elizabeth G.; Krug, Edward L.

doi:10.1002/bdra.20283

Cited by 27 publications

(21 citation statements)

References 35 publications

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“…Additionally, the time-course experiments confirmed the results obtained with the 10 ppb TCE exposure (24 h) and indicated that exposure to low concentrations of TCE exerts a long-lasting effect (at least 72 h) on expression levels of the tested genes. Overall, our results are in agreement with data recently published by Drake et al [8,42] and Mishima et al [9] reporting that the effects of TCE on chick cardiac development were dose-and stage-specific. Importantly, our observed alterations in gene expression level between 1 and 10 ppb TCE are consistent with Drake's reported effects on valvuloseptal hypercellularity and reduced hemodynamics in chick embryos exposed to 8 ppb TCE.…”

Section: Real-time Pcr Analysissupporting

confidence: 96%

“…Recently, the National Academy of Sciences issued a report [7] suggesting TCE exerts negative effects on cardiac development, particularly in avian models. In addition, two groups provided independent observations indicating that TCE specifically alters endocardial cushion formation in chick embryos [8,9]. These results are in line with previous data obtained from Boyer et al [10], suggesting that TCE disrupts the endothelial mesenchymal transition (EMT), a process involved in formation of the endocardial cushion in chick embryos.…”

Section: Introductionsupporting

confidence: 91%

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Trichloroethylene and Trichloroacetic Acid Regulate Calcium Signaling Pathways in Murine Embryonal Carcinoma Cells P19

et al. 2008

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Trichloroethylene (TCE) and its metabolite trichloroacetic acid (TCA) are ubiquitous environmental contaminants which have been regarded as risk factors for congenital heart malformations. An increasing body of evidence from in vivo and in vitro studies supports the notion that exposure to TCE and TCA may interfere with normal embryonic heart development. The expression of several genes coding for factors implicated in the regulation of cardiac development has been shown to be modified by TCE or TCA, but the molecular mechanisms that mediate these effects are still obscure. In this study, we investigated the global changes in gene expression caused by exposure of P19 embryonal carcinoma cells to TCE and TCA, and whether or not TCE and/or TCA influence the expression levels of genes encoding for proteins that regulate calcium fluxes in cardiac cells. We report that TCE and TCA disrupt the expression of genes involved in processes important during embryonic development suggesting that exposure to environmentally significant concentrations of TCE may have deleterious effects on specific stages of cardiac differentiation.

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Section: Real-time Pcr Analysissupporting

confidence: 96%

Section: Introductionsupporting

confidence: 91%

Trichloroethylene and Trichloroacetic Acid Regulate Calcium Signaling Pathways in Murine Embryonal Carcinoma Cells P19

et al. 2008

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“…CYP2E1 was implicated as the major TCE metabolizing CYP in both human liver microsomes and the murine model systems, while CYP2E1 is present in low levels in human fetal liver and brain (Brzezinski et al, 1999; Carpenter et al, 1996). We, and others, found that TCE affects cardiovascular development prior to both liver and brain development (Drake et al, 2006b; Makwana et al, 2010; Mishima et al, 2006). If metabolic activation of TCE is relevant to teratogenesis, then the existence and localization of cytochrome P450 enzymes in the early embryo is important to examine.…”

Section: Introductionmentioning

confidence: 68%

Low-Dose Trichloroethylene Alters Cytochrome P450-2C Subfamily Expression in the Developing Chick Heart

et al. 2012

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Trichloroethylene (TCE) is an organic solvent and common environmental contaminant. TCE exposure is associated with heart defects in humans and animal models. Primary metabolism of TCE in adult rodent models is by specific hepatic cytochrome P450 enzymes (Lash et al., 2000). As association of TCE exposure with cardiac defects is in exposed embryos prior to normal liver development, we investigated metabolism of TCE in the early embryo. Developing chick embryos were dosed in ovo with environmentally relevant doses of TCE (8 ppb and 800 ppb) and RNA was extracted from cardiac and extra-cardiac tissue (whole embryo without heart). Real time PCR showed upregulation of CYP2H1 transcripts in response to TCE exposure in the heart. No detectable cytochrome expression was found in extra-cardiac tissue. As seen previously, the dose response was non-monotonic and 8ppb elicited stronger upregulation than 800 ppb. Immunostaining for CYP2C subfamily expression confirmed protein expression and showed localization in both myocardium and endothelium. TCE exposure increased protein expression in both tissues. These data demonstrate that the earliest embryonic expression of phase I detoxification enzymes is in the developing heart. Expression of these CYPs is likely to be relevant to the susceptibility of the developing heart to environmental teratogens.

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“…More recently several groups have reported on possible mechanisms by which TCE may affect heart development. In the chick model, Boyer et al (2000) demonstrated that exposure to 200ppb TCE reduced by 50% EMT of valve progenitors in a collagen gel assay, while lower doses of TCE in ovo enhanced valvuloseptal hypercellularity, endocardial cell proliferation and altered hemodynamic in the embryonic heart (Drake et al, 2006a; Drake et al, 2006b; Mishima et al, 2006). Others found that TCE exposure altered expression of the endothelial nitric oxide synthase and disrupted VEGF-stimulated endothelial proliferation in myocytes, suggesting a possible mechanism for TCE-mediated heart malformations (Ou et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling in the fetal cardiac tissue after folate and low‐dose trichloroethylene exposure

Caldwell

Manziello

Howard

et al. 2009

Birth Defects Research

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Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo.

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Chick embryos exposed to trichloroethylene in an ex ovo culture model show selective defects in early endocardial cushion tissue formation

Abstract: The regional selectivity of these effects in the chick heart suggests a critical window of susceptibility to TCE in the epithelial-mesenchymal transformation of atrioventricular canal endocardium.

Cited by 27 publications

References 35 publications

Trichloroethylene and Trichloroacetic Acid Regulate Calcium Signaling Pathways in Murine Embryonal Carcinoma Cells P19

Trichloroethylene and Trichloroacetic Acid Regulate Calcium Signaling Pathways in Murine Embryonal Carcinoma Cells P19

Low-Dose Trichloroethylene Alters Cytochrome P450-2C Subfamily Expression in the Developing Chick Heart

Gene expression profiling in the fetal cardiac tissue after folate and low‐dose trichloroethylene exposure

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