ToxSci Advance Access published online on September 4, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm229
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FK506, a calcineurin inhibitor, prevents cadmium-induced testicular toxicity in mice
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* Interdepartmental Program in Molecular Toxicology, UCLA School of Public Health, 10833 LeConte Avenue, Los Angeles CA 90095
Department of Human Genetics, David Geffen School of Medicine at UCLA, 695 Charles E. Young Drive South, Los Angeles, CA 90095
Center for Occupational and Environmental Health, Factor Building, UCLA, Los Angeles, CA 90095
Department of Veterinary Biosciences, University of Illinois, 2001 S. Lincoln Avenue, Urbana, IL 61802
5 Correspondence to: Michael Collins, Ph.D. Department of Environmental Health Sciences, Interdepartmental Program in Molecular Toxicology, UCLA School of Public Health CHS 71-297, 10833 LeConte Avenue, Los Angeles CA 90095-1772, Telephone: 310-206-6730, Fax: 310-206-9903, Email: mdc{at}ucla.edu
Received July 13, 2007; revision received August 28, 2007; accepted August 28, 2007
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Abstract |
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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 hours. 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, 
isoform (Ppp3ca), was one of seven candidates in the cdm region that was narrowed from 5.6 to 2.0 Mb on mouse chromosome 3. An inhibitor of calcineurin, 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.
Key Words: cadmium; testes; cdm; calcineurin; Ppp3ca; FK506; multinucleated germ cells; SSeCKS.
1 Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, 1530 3rd Ave South Birmingham, AL 35294
2 Department of Preventive Medicine, Keck School of Medicine USC, 1441 Eastlake Avenue, Los Angeles, CA 90089
3 Schering-Plough Research Institute, 556 Morris Ave., Summit, NJ 07901
4 Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320