Craniofacial development is an evolutionarily conserved process regulated by signal transduction pathways that are susceptible to disruption by environmental toxicants. This project will explore a novel mechanism by which the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD;popularly referred to as dioxin) perturbs vertebrate craniofacial development. TCDD is the representative of a family of related polychlorinated compounds found ubiquitously in the environment. It is a known carcinogen and teratogen. Many toxic effects resulting from developmental exposure to TCDD have been documented in organisms as diverse as fish and humans, including severe craniofacial abnormalities. Despite the widespread potential for developmental exposure, mechanisms underlying these well-documented effects remain unclear. This project proposes to use the zebrafish (Danio rerio) in order to take advantage of the powerful and expedient experimental techniques available to this model. This project leverages preliminary data generated in the zebrafish demonstrating that embryonic exposure to environmentally relevant levels of TCDD significantly induces expression levels of Foxq1b, a member of the Forkhead box family of transcription factors. TCDD also alters spatial expression patterns of this gene consistent with its role in jaw development and its role as a potential candidate in a number of human craniofacial syndromes.
The specific aims of this proposal are: 1) determine whether morpholino knockdown of Foxq1b expression is sufficient to rescue TCDD-induced jaw abnormalities;2) determine whether Foxq1b is a direct target of TCDD-activated aryl hydrocarbon receptor 2 (Ahr2) transcriptional up-regulation using reporter constructs;and 3) test the hypothesis that Foxq1b overexpression is sufficient to phenocopy TCDD-induced jaw abnormalities. Results from this project will be instrumental in providing insights into the mechanisms of TCDD action and the role of Foxq1b in vertebrate jaw development and mediation of TCDD-induced craniofacial dysmorphology.
This project will explore a novel mechanism by which the ubiquitous environmental contaminant, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD;popularly referred to as dioxin) perturbs vertebrate craniofacial development. It explores the hypothesis that TCDD perturbs jaw development by upregulating and altering spatial expression of the Foxq1b gene, which is known to be important in jaw development and is a candidate in a number of human craniofacial syndromes. Results from this project will provide novel insights into the mechanisms of TCDD action and the role of Foxq1b in vertebrate jaw development and mediation of TCDD- induced craniofacial abnormalities.
|Cheng, Keith C; Hinton, David E; Mattingly, Carolyn J et al. (2012) Aquatic models, genomics and chemical risk management. Comp Biochem Physiol C Toxicol Pharmacol 155:169-73|
|Planchart, Antonio; Mattingly, Carolyn J (2010) 2,3,7,8-Tetrachlorodibenzo-p-dioxin upregulates FoxQ1b in zebrafish jaw primordium. Chem Res Toxicol 23:480-7|