Genetic background but not metallothionein phenotype dictates sensitivity to cadmium-induced testicular injury in mice.
Sensitivity to cadmium (Cd)-induced testicular injury varies greatly among mouse strains. For instance, 129/SvJ (129) mice are highly sensitive while C57BL/6J (C57) mice are refractory to Cd-induced testicular injury. Metallothionein (MT), a Cd-binding protein, is thought to be responsible for the strain susceptibility to Cd toxicity. In this study, MT-I/II knockout (MT-null) and wild-type 129 mice were used to determine the role of MT in Cd-induced testicular injury. Two additional strains of mice (C57 and the C57 x 129 F1cross) were also used to help define the role of genetic background in Cd toxicity. Mice were given 5-20 micromol/kg ip CdCl(2) and testicular injury was examined 24 h later by histopathology and testicular hemoglobin concentration. Cd produced dose-dependent testicular injury in all strains of mice, except for C57 mice, in which testicular injury could not be produced. MT-null mice were more sensitive than C57 x 129 mice but were equally sensitive as 129 mice to Cd-induced testicular injury. Fourteen days after 15 micromol/kg ip Cd administration, testicular atrophy was evident in MT-null, 129, and C57 x 129 mice but was absent in C57 mice. The resistance of C57 mice to Cd-induced testicular injury could not be attributed solely to a decreased uptake of (109)Cd nor to a greater amount of testicular MT. Microarray analysis revealed a higher expression of glutathione peroxidase in the testes of C57 mice, as well as genes encoding antioxidant components and DNA damage/repair, but their significance to Cd-induced injury is not immediately clear. Thus, this study demonstrates that it is genetic strain, not MT genotype, that is mechanistically important in determining susceptibility to Cd-induced testicular injury.
Liu
J
J
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Corton
C
C
Dix
D J
DJ
Liu
Y
Y
Waalkes
M P
MP
Klaassen
C D
CD
D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D003433:Crosses, Genetic; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics; D008297:Male; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010641:Phenotype; D013045:Species Specificity; D013733:Testicular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000378:metabolism / Q000473:pathology
D002104:Cadmium; D008668:Metallothionein; D005979:Glutathione Peroxidase