ENVIRONMENTAL TOXICANT PERTURBATION OF ZEBRAFISH GENE EXPRESSION & DEVELOPMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project #1 Developmental Consequences of exposure to environmental toxicants Objectives: 1) To identify genes a) perturbed by arsenic during vertebrate development; and b) perturbed by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) during jaw development. Results: Arsenic99 genes that respond to low arsenic levels were identified. Nineteen clustered in a regulatory network that is significantly associated with immune response and cancer. Additional studies will help explain the consequences of arsenic-mediated perturbation of the immune system during development. TCDDExposure to TCDD significantly upregulated a Forkhead box gene critical for jaw development. The role of this gene in TCDD-mediated jaw dysmorphology will be determined by knocking down its expression using antisense morpholinos in zebrafish. Project #2 Genomic structure of the ABCB1-4 locus of the Dogfish shark. Objectives: The ABC superfamily is a large family of transport proteins. ABCB1 (B1) and ABCB4 (B4) are critical in multidrug resistance and bile salt detoxification, respectively. The goal of this project is to sequence the shark genomic locus harboring B1 in order to determine if a second B-family gene exists. Results: It has been proposed that the duplication event leading to B1 and B4 occurred in mammals after their divergence from cartilaginous fish. However, genomic sequence analysis of extant non-mammalian vertebrates indicates the duplication event may have occurred earlier. Seven bacterial artificial chromosomes (BAC) from the Squalus acanthias genome were partially sequenced to generate a 150kb scaffold. This analysis should determine the number of ABCB genes within the locus and provide insight into their regulation.