ANALYSIS OF THE EFFECTS OF OVEREXPRESSION OF METALLOTHIONEIN-I IN TRANSGENIC MICE ON THE REPRODUCTIVE TOXICOLOGY OF CADMIUM

Exposure to low levels of cadmium reduces fertility. In male mice sper matogenesis is highly sensitive to cadmium, whereas in females the per i-implantation period of pregnancy is sensitive. To examine the potent ial roles of the cadmium-binding protein, metallothionein (MT), in the reproductive toxicology of cadmium, we examined a transgenic mouse st rain that overexpresses metallothionein-I (MT-I). These mice had drama tically increased steady-state levels of MT-I mRNA and MT in the teste s and in the female reproductive tract during the peri-implantation pe riod of pregnancy, and this overexpression occurred in a cell-specific adn temporally regulated manner similar to that of the endogenous MT- I gene. Transgenic and control males were injected with cadmium, and t he histology of the testes eas examined. An injection of 7.5 mu mol Cd /kg had no effect on histology of the testes in either transgenic or c ontrol mice. In contrast, an injection of 10 mu mol Cd/kg caused rapid changes in the histology of the testes and resulted in pronounced tes ticular necrosis in both control and transgenic mice. Female transgeni c and control mice were mated and then injected with cadmium (30-45 mu mol Cd/kg) on the day of blastocyst implantation (day 4). In both of these groups, injection of cadmium reduced pregnancy rate, and no dram atic protection was afforded by maternal and/or embryonic overexpressi on of MT. Thus, overexpression of MT-I does not significantly protect against either of these cadmium-induced effects on fertility.