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

Selmin, Ornella I.; Thorne, Patricia A.; Caldwell, Patricia T.; Taylor, Mallory

doi:10.1007/s12012-008-9014-2

Cited by 21 publications

(18 citation statements)

References 40 publications

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“…Calcium signaling is a crucial pathway for heart function (Table 3), and these findings corroborate those previously reported by our group, using in vitro models (Caldwell et al, 2008; Selmin et al, 2008). It is notable that only three out of 414 genes were altered in the 2CTL v 2TCE group and absolutely no changes were observed in the 0CTL v 0TCE level.…”

Section: Discussionsupporting

confidence: 91%

“…Previous work from our laboratory demonstrated that TCE exposure altered calcium regulation in cardiac myocytes and the expression of genes involved in calcium homeostasis (Caldwell et al, 2008; Selmin et al, 2008), suggesting a possible mechanism by which cardiac malformations occur. To identify other key contributing pathways that may be altered in the embryonic heart after exposure to TCE, we used DNA microarray technology to profile gene expression patterns in mice.…”

Section: Introductionmentioning

confidence: 87%

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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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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 87%

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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“…Further studies in mice and in a rat cardiomyocyte cell line highlighted transcriptional regulation of Serca2a and additional mediators of Ca 2+ homeostasis by TCE exposure by doses as low as 10 ppb (Caldwell et al, 2010; Selmin et al, 2008). These results were confirmed in the H2C9 murine cardiomyocyte cell line by Caldwell et al (2008) which show alterations in expression of the Ca 2+ pumps, Ryr2 and Serca2a, after low dose TCE exposure with concomitant altered Ca 2+ handling.…”

Section: Discussionmentioning

confidence: 99%

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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“…Subsequent studies using an in vitro culture model of mouse embryonal carcinoma P19 cells, showed that low level exposure to TCE perturbed expression of additional calcium homeostatic molecules (Selmin et al 2008). The embryonic heart requires the regulated release and uptake of intracellular calcium for both function and growth.…”

Section: Discussionmentioning

confidence: 99%

Exposure to Low-Dose Trichloroethylene Alters Shear Stress Gene Expression and Function in the Developing Chick Heart

et al. 2010

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Trichloroethylene is an organic solvent used as an industrial degreasing agent. Due to its widespread use and volatile nature, TCE is a common environmental contaminant. Trichloroethylene exposure has been implicated in the etiology of heart defects in human populations and animal models. Recent data suggest misregulation of Ca2+ homeostasis in H9c2 cardiomyocyte cell line after TCE exposure. We hypothesized that misregulation of Ca2+ homeostasis alters myocyte function and leads to changes in embryonic blood flow. In turn, changes in cardiac flow are known to cause cardiac malformations. To investigate this hypothesis, we dosed developing chick embryos in ovo with environmentally relevant doses of TCE (8 ppb and 800 ppb). RNA was isolated from control and treated embryos at specific times in development for real-time PCR analysis of blood flow markers. Effects were observed on Endothelin-1 (ET-1), Nitric Oxide Synthase-3 (NOS-3) and Krüppel-Like Factor 2 (KLF2) expression relative to TCE exposure and consistent with reduced flow. Further, we measured function in the developing heart after TCE exposure by isolating cardiomyocytes and measuring half-width of contraction and sarcomere lengths. These functional data showed a significant increase in half-width of contraction after TCE exposure. These data suggest that perturbation of cardiac function contributes to the etiology of congenital heart defects in TCE-exposed embryos.

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

Cited by 21 publications

References 40 publications

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

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

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

Exposure to Low-Dose Trichloroethylene Alters Shear Stress Gene Expression and Function in the Developing Chick Heart

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