NUCLEOLAR SEGREGATION AS AN EARLY MARKER FOR DNA-DAMAGE - AN EXPERIMENTAL-STUDY IN RATS TREATED WITH 4-HYDROXYAMINOQUINOLINE 1-OXIDE

Male 6-week-old Sprague Dawley rats were given a single intravenous in jection of 4-hydroxyaminoquinoline 1-oxide (4HAQO) at a dose of 20 mg/ kg in order to produce ultrastructural changes as possible morphologic al biomarkers for toxicity. Immunohistochemically demonstrated formati on of 4HAQO-DNA adduct was correlated with the changes found. Nucleola r alteration, demonstrable by electron microscopy as segregation of nu cleolar components into granular and fibrillar compartments, was evide nt in cells of the target organs, exocrine pancreas and adrenocortex, but not of the non-target liver parenchyma. Sequential observation cla rified that such alteration was highest in frequency 6 h and 4 h after 4HAQO administration in pancreatic acinar cells and adrenocortical ce lls respectively. Electron microscopically, apoptotic changes of acina r cells were evident 2 h after injection of 4HAQO. DNA adduct formatio n was consistently demonstrated in the same target organs showing nucl eolar segregation, the highest frequency being noted 4 h after 4HAQO t reatment in both pancreatic acinar cells and adrenocortical cells. Our results thus indicate an identity of the target cells for nucleolar s egregation and 4HAQO-DNA adduct formation which correlates with 4HAQO- toxicity. We suggest that nucleolar segregation occurs subsequent to t he generation of DNA damage.