FK506, a calcineurin inhibitor, prevents cadmium-induced testicular toxicity in mice.
Cadmium, a ubiquitous environmental contaminant, damages several major organs in humans and other mammals. The molecular mechanisms for damage are not known. At high doses (5 mg/kg cadmium chloride or higher), testicular damage in mice, rats, and other rodents includes interstitial edema, hemorrhage, and changes in the seminiferous tubules affecting spermatogenesis. Necrosis is evident by 48 h. The goal of this study was to fine map and identify the cdm gene, a gene that when mutated prevents cadmium-induced testicular toxicity in mouse strains with a mutation in this gene. A serine-threonine phosphatase, calcineurin (CN), subunit A, alpha isoform (Ppp3ca), was one of the seven candidates in the cdm region that was narrowed from 5.6 to 2.0 Mb on mouse chromosome 3. An inhibitor of CN, the immunosuppressant, FK506, prevented cadmium-induced testicular damage in five pathological categories, including vascular endothelial and seminiferous epithelial endpoints. Inductively coupled plasma-mass spectrometry revealed that FK506 protected without lowering the amount of cadmium in the testes. Ppp3ca(-/-) mice were investigated but were found to exhibit endogenous testicular abnormalities, making them an inappropriate model for determining whether the inactivation of the Ppp3ca gene would afford protection from cadmium-induced testicular toxicity. The protection afforded by FK506, found by the current study, indicated that CN is likely to be important in the mechanism of cadmium toxicity in the testis and possibly other organs.
Martin
Lisa Joy
LJ
Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles School of Public Health, Los Angeles, CA 90095, USA.
Chen
Haiyan
H
Liao
Xiaoyan
X
Allayee
Hooman
H
Shih
Diana Mouhan
DM
Lee
Grace Sangeun
GS
Hovland
David Norman
DN
Robbins
Wendie Anne
WA
Carnes
Kay
K
Hess
Rex Allen
RA
Lusis
Aldons Jake
AJ
Collins
Michael David
MD
D000818:Animals; D002104:Cadmium / Q000032:analysis; D019256:Cadmium Chloride / Q000633:toxicity*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016559:Tacrolimus / Q000494:pharmacology*; D013733:Testicular Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013737:Testis / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology