Title: Dioxin exposure disrupts the differentiation of mouse embryonic stem cells into cardiomyocytes.

Authors: Wang, Ying; Fan, Yunxia; Puga, Alvaro

Published In Toxicol Sci, (2010 May)

Abstract: Experimental exposure of fish, birds, and rodents to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) causes multiple Ah receptor-mediated developmental abnormalities, an observation consistent with compelling evidence in human populations that TCDD exposure is responsible for a significant incidence of birth defects. To characterize molecular mechanisms that might explain the developmental effects of dioxin, we have studied the consequences of TCDD exposure on the differentiation of mouse embryonic stem (ES) cells in culture and on the expression of genes, including those coding for homeodomain containing transcription factors, with a role in progression of tissue differentiation and embryonic identity during development. We find that TCDD treatment causes expression changes in a number of homeobox genes concomitant with Ah receptor recruitment to the promoters of many of these genes, whether under naïve or dioxin-activated conditions. TCDD exposure also derails temporal expression trajectories of developmentally regulated genes in a wide diversity of differentiation pathways, including genes with functions in neural and cardiovascular development, self-renewal, hematopoiesis and mesenchymal lineage specification, and Notch and Wnt pathways. Among these, we find that TCDD represses the expression of the cardiac development-specific Nkx2.5 homeobox transcription factor, of cardiac troponin-T and of alpha- and beta-myosin heavy chains, inhibiting the formation of beating cardiomyocytes, a characteristic phenotype of differentiating mouse ES cells in culture. These data identify potential pathways for dioxin to act as a developmental teratogen, possibly critical to cardiovascular development and disease, and provide molecular targets that may help us understand the molecular basis of Ah receptor-mediated developmental toxicity.

PubMed ID: 20130022

MeSH Terms: Animals; Cell Differentiation/drug effects; Cell Differentiation/genetics; Cell Line; Embryonic Stem Cells/drug effects*; Environmental Pollutants/toxicity*; Gene Expression Regulation, Developmental/drug effects; Gene Expression/drug effects; Homeobox Protein Nkx-2.5; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Mice; Mice, Inbred C57BL; Myocytes, Cardiac/drug effects*; Myocytes, Cardiac/pathology; Myosin Heavy Chains/genetics; Myosin Heavy Chains/metabolism; Polychlorinated Dibenzodioxins/toxicity*; RNA, Messenger/metabolism; Teratogens/toxicity*; Transcription Factors/genetics; Transcription Factors/metabolism; Troponin T/genetics; Troponin T/metabolism; Ventricular Myosins/genetics; Ventricular Myosins/metabolism