title: Altering HIF-1α through 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure affects coronary vessel development.
abstract: Differential tissue hypoxia drives normal cardiogenic events including coronary vessel development. This requirement renders cardiogenic processes potentially susceptible to teratogens that activate a transcriptional pathway that intersects with the hypoxia-inducible factor (HIF-1) pathway. The potent toxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to cause cardiovascular defects by way of reduced myocardial hypoxia, inhibition of angiogenic stimuli, and alterations in responsiveness of endothelial cells to those stimuli. Our working hypothesis is that HIF-1 levels and thus HIF-1 signaling in the developing myocardium will be reduced by TCDD treatment in vivo during a critical stage and in particularly sensitive sites during heart morphogenesis. This inadequate HIF-1 signaling will subsequently result in outflow tract (OFT) and coronary vasculature defects. Our current data using the chicken embryo model showed a marked decrease in the intensity of immunostaining for HIF-1α nuclear expression in the OFT myocardium of TCDD-treated embryos. This area at the base of the OFT is particularly hypoxic during normal development; where endothelial cells initially form a concentrated anastomosing network known as the peritruncal ring; and where the left and right coronary arteries eventually connect to the aortic lumen. Consistent with this finding, anomalies of the proximal coronaries were detected after TCDD treatment and HIF-1α protein levels decreased in a TCDD dose-dependent manner.
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, 1001 Health Sciences Rd, 306D Med Surg II, Irvine, CA 92697, USA. jwikenhe@uci.edu
authors.forename: Jamie
authors.initials: J
authors.lastname: Wikenheiser
authors.forename: Ganga
authors.initials: G
authors.lastname: Karunamuni
authors.forename: Eddie
authors.initials: E
authors.lastname: Sloter
authors.forename: Mary K
authors.initials: MK
authors.lastname: Walker
authors.forename: Debashish
authors.initials: D
authors.lastname: Roy
authors.forename: David L
authors.initials: DL
authors.lastname: Wilson
authors.forename: Michiko
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002642:Chick Embryo; D003331:Coronary Vessels / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072317:Polychlorinated Dibenzodioxins