Journal Article

FK506, a Calcineurin Inhibitor, Prevents Cadmium-Induced Testicular Toxicity in Mice

Lisa Joy Martin, Haiyan Chen, Xiaoyan Liao, Hooman Allayee, Diana Mouhan Shih, Grace Sangeun Lee, David Norman Hovland, Wendie Anne Robbins, Kay Carnes, Rex Allen Hess, Aldons Jake Lusis and Michael David Collins

in Toxicological Sciences

Volume 100, issue 2, pages 474-485
Published in print December 2007 | ISSN: 1096-6080
Published online September 2007 | e-ISSN: 1096-0929 | DOI:
FK506, a Calcineurin Inhibitor, Prevents Cadmium-Induced Testicular Toxicity in Mice

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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 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, α 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.

Keywords: cadmium; testes; cdm; calcineurin; Ppp3ca; FK506; multinucleated germ cells; SSeCKS

Journal Article.  7251 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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