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American Journal of Pathology, Vol 137, 1187-1198, Copyright © 1990 by American Society for Investigative Pathology

REGULAR ARTICLES

Flow cytometric analysis of the mechanism of methylmercury cytotoxicity

RM Zucker, KH Elstein, RE Easterling and EJ Massaro
Developmental Toxicology Division (MD-67), United States Environmental Protection Agency, Research Triangle Park, NC 27711.

Flow cytometric analysis of murine erythroleukemic cells (MELC) exposed in vitro to 2.5 to 7.5 mumol/l (micromolar) methylmercury (MeHg) reveals a dose-dependent decrease in the rate of DNA synthesis (rate of passage through the S phase of the cell cycle), manifested as the accumulation of most of the cells in the S phase, and a modest accumulation of cells in the G2/M phase of the cycle. Light microscopy reveals a progressive increase in chromosomal damage (condensation, pulverization). At or above 10 mumol/l MeHg, progression through all the phases of the cell cycle is blocked and mitotic cells are arrested irreversibly in anaphase, with most exhibiting arrangement of chromosomes in a wreathlike ring formation. Also the cells exhibit both nuclear propidium iodide (PI) fluorescence (indicative of loss of viability) and concurrent cytoplasmic carboxyfluorescein (CF) fluorescence (viable cells exhibit CF fluorescence and exclude PI). In addition, there is a dose-dependent increase in cellular refractive index (90 degrees light scatter), an apparent decrease in cell volume (axial light loss), and progressive resistance to detergent (NP-40)- mediated cytolysis. Resistance to detergent-mediated cytolysis is indicative of fixation (protein denaturation, cross-linking, and so on) of the plasma membrane/cytoplasm complex. Our findings indicate that DNA synthesis is the primary target of MeHg cytotoxicity and that apparent targets and degree of cytotoxicity are a complex function of dose.


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T. A. Lewandowski, R. A. Ponce, J. S. Charleston, S. Hong, and E. M. Faustman
Effect of Methylmercury on Midbrain Cell Proliferation during Organogenesis: Potential Cross-Species Differences and Implications for Risk Assessment
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[Abstract] [Full Text] [PDF]


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Copyright © 1990 by the American Society for Investigative Pathology.