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

ABSTRACT: 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.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.Exposure to low doses of TCE (10 ppb) 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.A mechanism by which 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 not protective of the developing embryo.

SUBMITTER: Caldwell PT

PROVIDER: S-EPMC4045246 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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

Caldwell Patricia T PT Manziello Ann A Howard Jamie J Palbykin Brittany B Runyan Raymond B RB Selmin Ornella O

Birth defects research. Part A, Clinical and molecular teratology 20100201 2

<h4>Background</h4>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 epig ...[more]

PMID: 19813261

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Project description:BACKGROUND:The International Agency for Research on Cancer classified radon and its decay-products as Group-1-human-carcinogens, and with the current knowledge they are linked specifically to lung cancer. Biokinetic models predict that radon could deliver a carcinogenic dose to breast tissue. Our previous work suggested that low-dose radon was associated with estrogen-receptor (ER)-negative breast cancer risk. However, there is limited research to examine the role of radon in breast cancer biology at the tissue level. We aim to understand molecular pathways linking radon exposure with breast cancer biology using transcriptome-wide-gene-expression from breast tumor and normal-adjacent tissues. METHODS:Our study included 943 women diagnosed with breast cancer from the Nurses' Health Study (NHS) and NHSII. We estimated cumulative radon concentration for each participant up-to the year of breast cancer diagnosis by linking residential addresses with a radon exposure model. Transcriptome-wide-gene-expression was measured with the Affymetrix-Glue-Human-Transcriptome-Array-3.0 and Human-Transcriptome-Array-2.0. We performed covariate-adjusted linear-regression for individual genes and further employed pathway-analysis. All analyses were conducted separately for tumor and normal-adjacent samples and by ER-status. RESULTS:No individual gene was associated with cumulative radon exposure in ER-positive tumor, ER-negative tumor, or ER-negative normal-adjacent tissues at FDR?<?5%. In ER-positive normal-adjacent samples, PLCH2-reached transcriptome-wide-significance (FDR?<?5%). Gene-set-enrichment-analyses identified 2-upregulated pathways (MAPK signaling and phosphocholine biosynthesis) enriched at FDR?<?25% in ER-negative tumors and normal-adjacent tissues, and both pathways have been previously reported to play key roles in ionizing radiation induced tumorigenesis in experimental settings. CONCLUSION:Our findings provide insights into the molecular pathways of radon exposure that may influence breast cancer etiology.

Dataset Information

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

Publications

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

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