Studies conducted in our laboratory have linked primary congenital glaucoma to mutant forms of cytochrome P4501B1 (CYP1B1). The expression of CYP1B1 is affected by wide spectrum of environmental pollutants including known teratogens such as dioxin. We hypothesize that aberrant induction/inhibition of CYP1B1 by xenobiotics may affect the normal development of the anterior chamber angle of the eye. Theoretical framework for such role of CYP1B1 is provided by the local source/dispersed sink (LSDS) model of morphogenesis. The objective of this study is to demonstrate that such mechanism of developmental toxicity operates in the developing eye. We will pursue four specific aims: 1. Our first task will be to characterize several model xenobiotic compounds with regard to their embryonic disposition and ability to induce/inhibit mouse CYP1 B1. 2. Next, we will examine the effect of xenobiotic deregulation of CYP1B1 on the ocular distribution of the morphogen retinoic acid (RA). For this purpose we will utilize transgenic indicator mice carrying a retinoic acid response element (RARE) fused to p-galactosidase. 3. In order to investigate the effect of CYP1B1 deregulation on eye morphogenesis we will monitor the expression of markers for neural crest cells migration, iris/ciliary stroma and the developing optic cup margin by In Situ hybridization. 4. Finally we will use fluorescent programmed cell death assay and comparative histological analysis to search for manifestations of deviant ocular development resulting from aberrant induction or inhibition of CYP1B1. One of the major objectives of teratology is to anticipate risks before they materialize. This is precisely why we believe that the opportunity to investigate the role of environmental factors in the etiology of glaucoma, provided by the CYP1B1 gene, deserves a special attention. Our hypothesis has the potential to clarify the basic mechanisms of developmental toxicity operating during eye development and provides an opportunity to develop screening panels for assessment of ocular toxicity.
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| Choudhary, Dharamainder; Jansson, Ingela; Sarfarazi, Mansoor et al. (2008) Characterization of the biochemical and structural phenotypes of four CYP1B1 mutations observed in individuals with primary congenital glaucoma. Pharmacogenet Genomics 18:665-76 |
| Stoilov, Ivaylo; Rezaie, Tayebeh; Jansson, Ingela et al. (2004) Expression of cytochrome P4501b1 (Cyp1b1) during early murine development. Mol Vis 10:629-36 |
