Academic journal article Environmental Health Perspectives

Disruption of Aryl Hydrocarbon Receptor Homeostatic Levels during Embryonic Stem Cell Differentiation Alters Expression of Homeobox Transcription Factors That Control Cardiomyogenesis

Academic journal article Environmental Health Perspectives

Disruption of Aryl Hydrocarbon Receptor Homeostatic Levels during Embryonic Stem Cell Differentiation Alters Expression of Homeobox Transcription Factors That Control Cardiomyogenesis

Article excerpt

Introduction

The theory of the developmental origins of adult disease proposes that the environment encountered during fetal life and infancy permanently changes the body's structure, function, and metabolism and shapes the long-term control of tissue physiology and homeostasis (Barker 2007). Accordingly, damage during fetal life or infancy resulting from maternal stress, poor nutrition, or exposure to environmental pollutants such as dioxin may be at the heart of adult-onset disease. Work in many laboratories has shown that the young are more sensitive to dioxin than adults and that developmental exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-doxin)--the prototypical dioxin--results in disease conditions in adult fish (Plavicki et al. 2013), birds (Walker and Catron 2000), and mammals (Kopf and Walker 2009). Bruner-Tran and Osteen (2011) reported that dioxin exposure reduced fertility and negatively affected pregnancy outcomes across multiple generations. The developmental toxicity of TCDD is of greater concern for humans because pregnant women transfer a fraction of their dioxin body burden to the fetus during pregnancy and to the infant via breastfeeding (Schecter et al. 2001). In addition, dioxin-like organochlorinated compounds are epidemiologically associated with low birth weight and respiratory distress (Lai et al. 2002) as well as cardiac malformations (Dummer et al. 2003). In their study, Dummer et al. (2003) reported that infants born to mothers living near incinerators that emitted complex mixtures of dioxins, furans, particulates, and heavy metals exhibited a higher incidence of lethal congenital heart diseases. Other studies have shown an epidemiological association between the incidence of hypoplastic left heart syndrome and maternal exposure to halogenated hydrocarbons, dioxins, and polychlorinated biphenyls (PCBs) during pregnancy (Kuehl and Loffredo 2006).

Most biological effects of TCDD are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and a member of the basic-region-helix-loop-helix PER/ARNT/SIM (Bhlh-PAS) superfamily of transcription factors. Members of this superfamily function as sensors of extracellular signals and environmental stresses that may affect growth and development (Gu et al. 2000). Activation by TCDD causes receptor translocation to the nucleus, dissociation from its cytosolic chaperones, and heterodimerization with its AHR nuclear translocator (ARNT) partner, also a member of the bHLH/PAS superfamily (Reyes et al. 1992). Binding of AHR-ARNT complexes to AHR binding sites in the promoters of target genes a) recruits transcription cofactors and associated chromatin remodeling proteins, and b) signals initiation of gene transcription (Schnekenburger et al. 2007). Increasing evidence indicates that, in addition to the well-known xenobiotic metabolism genes in cytochrome P450, family 1 (Cyp1), there are other AHR transcriptional targets, including genes involved in cell-cycle regulation and morphogenetic processes, that may play a vital function during embryonic development (Sartor et al. 2009b). In this context, following a complex alternating pattern of activation and repression in the preimplantation mouse embryo (Wu et al. 2002), AHR expression can be demonstrated in the posti mplantation embryo as early as gestation day (GD) 9.5, followed by widespread expansion into almost all developing organs including brain, heart, liver, somites, and branchial arches (Abbott et al. 1995).

The AHR is a major contributor to cardiovascular homeostasis in all species studied to date. In mice, fish, and avian embryos, the heart is a TCDD target during fetal development, which results in reduced cardiomyocyte proliferation, altered fetal heart size, and disruptions in neovascularization (Ivnitski-Steele and Walker 2005). In utero exposure to TCDD increases the susceptibility to cardiovascular dysfunction in adult life (Aragon et al. …

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