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. In order to study the effects of cadmium exposure on the developing zebrafish cardiovascular system, we tested the experimental conditions reported to elicit vessel patterning defects in late stage zebrafish embryos. We found that 100uM Cd chloride treatment alters cranial vessel patterning, in agreement with published results. Endogenous endothelial alkaline phosphatase activity, and endothelial fli-1:eGFP expression in transgenic embryos, revealed reduced vessel structure in cranial networks, but did not reveal the dramatic loss of complexity in the trunk vasculature previously found with dye-injection techniques. The difference may be biologically relevant if poor cardiac perfusion restricts the angiogram dye to more mature vessels in treated embryos. We will address this discrepancy by pairing angiography with alkaline phosphatase staining and eGFP analysis in the same individuals. After finding a low incidence of cranial hemorrhages in Cd treated embryos, we are also examining endothelial integrity in embryos with a genetic predisposition to cranial hemorrhaging. Preliminary results suggest that exposure of these embryos to Cd increases the severity of the hemorrhages and appears to reduce the hemorrhage threshold in genetically compromised heterozygote carriers. Of great interest, we find that embryos exposed to Cd concentrations as low as 0.5uM develop atrio-ventricular conduction delay in a concentration-dependent manner. Acute incubation in Cd after 48 hours post fertilization results in a more severe phenotypic abnormalities than chronic exposure at the same concentrations. The initial overall appearance of Cd-treated embryos is normal through 48 hours post fertilization and pericardial edema is only slightly noticeable through 72 hours, but the arrhythmia and associated circulation problems are associated with in a lethal failure to inflate the swim bladder. We are examining Cd accumulation and clearing in the early embryo and plan to look into mechanisms for the enhanced sensitivity in acutely-treated subjects.
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