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(American Journal of Pathology. 2002;160:1047-1056.)
© 2002 American Society for Investigative Pathology

Regular Articles

The Metallothionein-Null Phenotype Is Associated with Heightened Sensitivity to Lead Toxicity and an Inability to Form Inclusion Bodies

Wei Qu*, Bhalchandra A. Diwan{dagger}, Jie Liu*, Robert A. Goyer{ddagger}, Tammy Dawson*, John L. Horton{ddagger}, M. George Cherian§ and Michael P. Waalkes*

From the Inorganic Carcinogenesis Section,*
Laboratoryof Comparative Carcinogenesis, National Cancer Institute at theNational Institute of Environmental HealthSciences,{ddagger}
Research Triangle Park, NorthCarolina; the Science Applications InternationalCorporation,{dagger}
National Cancer Institute atFrederick, Frederick, Maryland; and the University of WesternOntario,§
London, Ontario, Canada

Susceptibility to lead toxicity in MT-null mice and cells, lacking the major forms of the metallothionein (MT) gene, was compared to wild-type (WT) mice or cells. Male MT-null and WT mice received lead in the drinking water (0 to 4000 ppm) for 10 to 20 weeks. Lead did not alter body weight in any group. Unlike WT mice, lead-treated MT-null mice showed dose-related nephromegaly. In addition, after lead exposure renal function was significantly diminished in MT-null mice in comparison to WT mice. MT-null mice accumulated less renal lead than WT mice and did not form lead inclusion bodies, which were present in the kidneys of WT mice. In gene array analysis, renal glutathione S-transferases were up-regulated after lead in MT-null mice only. In vitro studies on fibroblast cell lines derived from MT-null and WT mice showed that MT-null cells were much more sensitive to lead cytotoxicity. MT-null cells accumulated less lead and formed no inclusion bodies. The MT-null phenotype seems to preclude lead-induced inclusion body formation and increases lead toxicity at the organ and cellular level despite reducing lead accumulation. This study reveals important roles for MT in chronic lead toxicity, lead accumulation, and inclusion body formation.




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