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ToxSci Advance Access published online on June 12, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg151
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received January 21, 2003; accepted May 5, 2003
© 2003 Society of Toxicology

Reproductive and Developmental Toxicology

Effect of Methylmercury on Midbrain Cell Proliferation During Organogenesis: Potential Cross-Species Differences and Implications for Risk Assessment

T. A. Lewandowski 1, R. A. Ponce 2, J. S. Charleston 3, S. Hong 4, and E. M. Faustman 5*

1 Department of Environmental Health, University of Washington, Seattle WA 98105; Gradient Corporation, Mercer Island WA 98040
2 Department of Environmental Health, University of Washington, Seattle WA 98105; Zymogenetics Inc., Seattle WA 98102
3 ICOS Corporation, Bothell WA 98021
4 Department of Environmental Health, University of Washington, Seattle WA 98105
5 Department of Environmental Health, University of Washington, Seattle WA 98105; Center for Child Environmental Health Risks Research, Seattle WA 98105

* To whom correspondence should be addressed. E-mail: faustman{at}u.washington.edu.


  Abstract

We employed 5'-bromodeoxyuridine (BrdU) labeling to explore the effects of methylmercury (MeHg) on cell cycle kinetics in the developing rat midbrain during gestational days (gd) 11 to 14. Contrary to what has been previously reported in mice, no effects of MeHg on cell cycle kinetics were observed up to embryonic brain concentrations of 3-4 µg/g. The absence of an effect was confirmed using stereology and counts of midbrain cell number. Treatment with colchicine, the positive control, resulted in significant effects on cell cycle kinetics in the developing rat midbrain. We subsequently used the parallelogram method, borrowed from genetic toxicology, to place our own data in the context of previously collected in vitro and in vivo data on MeHg developmental neurotoxicity. This required developing a common dose metric (µg Hg/g cellular tissue) to allow in vitro and in vivo study comparisons. Our evaluation suggested that MeHg's effects on neuronal cell proliferation show a reasonable degree of concordance across mice, rats and humans, spanning approximately an order of magnitude. Comparisons among the in vivo data suggest that humans are at least or more sensitive than the rodent and that mice may be a slightly better model for human developmental neurotoxicity than the rat. Such comparisons can provide both a quantitative and a qualitative framework for utilizing both in vivo and in vitro data in human health risk assessment.

Key Words: Methylmercury, cell cycle, parallelogram, inter-species, stereology, midbrain .


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