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Tim Dalton,¹ Kai Fu,¹ George C. Enders,² Richard D. Palmiter,³ and Glen K. Andrews¹

¹Department of Biochemistry and Molecular Biology and ²Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160-7421 USA; ³Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195 USA

Abstract

Exposure to low levels of cadmium reduces fertility. In male mice spermatogenesis is highly sensitive to cadmium, whereas in females the peri-implantation period of pregnancy is sensitive. To examine the potential roles of the cadmium-binding protein, metallothionein (MT) , in the reproductive toxicology of cadmium, we examined a transgenic mouse strain that overexpresses metallothionein-I (MT-I) . These mice had dramatically increased steady-state levels of MT-I mRNA and MT in the testes and in the female reproductive tract during the peri-implantation period of pregnancy, and this overexpression occurred in a cell-specific and temporally regulated manner similar to that of the endogenous MT-I gene. Transgenic and control males were injected with cadmium, and the histology of the testes was examined. An injection of 7.5 mol Cd/kg had no effect on histology of the testes in either transgenic or control mice. In contrast, an injection of 10 mol Cd/kg caused rapid changes in the histology of the testes and resulted in pronounced testicular necrosis in both control and transgenic mice. Female transgenic and control mice were mated and then injected with cadmium (30-45 mol Cd/kg) on the day of blastocyst implantation (day 4) . In both of these groups, injection of cadmium reduced pregnancy rate, and no dramatic protection was afforded by maternal and/or embryonic overexpression of MT. Thus, overexpression of MT-I does not significantly protect against either of these cadmium-induced effects on fertility. Key words: cadmium, metallothionein, peri-implantation, reproductive toxicology, transgenic mice, testes. Environ Health Perspect 104:68-76 (1996)

Address correspondence to G. K. Andrews, Department of Biochemistry and Molecular Biology, BFR 2034, University of Kansas Medical Center, 39th and Rainbow Boulevard, Kansas City, KS 66160-7421 USA.

This work was supported in part by NIH grants (ES-04725, ES-05704, and CA-61262) to G.K. Andrews (CA-61268) , R. D. Palmiter, and G. C. Enders (HD-26639) . T. Dalton was supported by postdoctoral fellowships from the Kansas Health Foundation and the Marion-Merrel Dow Scientific Education Partnership. We are indebted to Jim Geiser for excellent technical assistance and to S. K. Dey for help in immunolocalization studies.

Received 2 August 1995 ; accepted 18 September 1995.