The long-term goal is to understand teratogenic mechanisms at the molecular level. Microphthalmia is a low level effect of methylmercury exposure and can be induced in early mouse embryos to reflect clinical disorders seen in exposed children. Gene expression arrays will be used to recognize fundamental biomolecular parameters that describe critical events leading to this malformation. Preliminary studies identified a critical response involving p53 tumor suppressor (Trp53) and peripheral-type benzodiazepine receptor (Bzrp), leading to the proposed focus on metabolic and regulatory pathways controlling mitochondrial DNA (mtDNA) genome expression. During neurulation, the embryo shifts from an anaerobic (glycolytic) to aerobic (oxidative) metabolism. This diauxic shift requires mtDNA genome expression and, consequently, a tight link between morphogenetic and metabolic differentiation. The investigators hypothesize control by retrograde regulation whereby a signal started in the mitochondrion leads to an adaptive response in the nucleus to culminate in mtDNA biogenesis.
Four specific aims will begin to trace this pathway at the molecular level.
Specific Aim 1, a teratological study, will determine exposure-disease relationships for methylmercury-induced microphthalmia with respect to dose response, genetic susceptibility (Trp53), and therapeutic intervention (Bzrp).
Specific Aim 2 will use expression microarrays to profile gene expression for developing eye across the critical period of vulnerability (days 8-10 of gestation).
Specific Aim 3 will profile exposure-disease pathways for methylmercury-induced microphthalmia with respect to dose-response, genetic susceptibility, and therapeutic intervention.
Specific Aim 4 entails pathway integration to confirm cellular activities as they change over time. At ends we expect to build a searchable transcriptome database for the developing eye and a platform with which to discover the cellular pathways that hypothetically define a temporal sequence in dysmorphogenesis induced with methylmercury and other environmental toxicants.
|Green, M L; Pisano, M M; Prough, R A et al. (2013) Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction. Cell Signal 25:2383-90|
|Green, M L; Singh, A V; Ruest, L B et al. (2011) Differential programming of p53-deficient embryonic cells during rotenone block. Toxicology 290:31-41|
|Singh, Amar V; Rouchka, Eric C; Rempala, Greg A et al. (2007) Integrative database management for mouse development: systems and concepts. Birth Defects Res C Embryo Today 81:1-19|
|Nemeth, Kimberly A; Singh, Amar V; Knudsen, Thomas B (2005) Searching for biomarkers of developmental toxicity with microarrays: normal eye morphogenesis in rodent embryos. Toxicol Appl Pharmacol 206:219-28|
|Singh, Amar V; Knudsen, Kenneth B; Knudsen, Thomas B (2005) Computational systems analysis of developmental toxicity: design, development and implementation of a Birth Defects Systems Manager (BDSM). Reprod Toxicol 19:421-39|
|Knudsen, Kenneth B; Singh, Amar V; Knudsen, Thomas B (2005) Data input module for Birth Defects Systems Manager. Reprod Toxicol 20:369-75|
|Knudsen, Thomas B; Green, Maia L (2004) Response characteristics of the mitochondrial DNA genome in developmental health and disease. Birth Defects Res C Embryo Today 72:313-29|
|Charlap, Jeffrey H; Donahue, Ronald J; Knudsen, Thomas B (2003) Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 3. Intervention with PK11195. Birth Defects Res A Clin Mol Teratol 67:108-15|
|O'Hara, Michael F; Nibbio, Barbara J; Craig, Robert C et al. (2003) Mitochondrial benzodiazepine receptors regulate oxygen homeostasis in the early mouse embryo. Reprod Toxicol 17:365-75|
|O'Hara, Michael F; Charlap, Jeffrey H; Craig, Robert C et al. (2002) Mitochondrial transduction of ocular teratogenesis during methylmercury exposure. Teratology 65:131-44|
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