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

Details

• Personal Author:
  Allayee H ; Carnes K ; Chen H ; Collins MD ; Hess RA ; Hovland DN Jr. ; Lee GS ; Liao X ; Lusis AJ ; Martin LJ ; Robbins WA ; Shih DM
• Description:
  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, a 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. [Description provided by NIOSH]
• Subjects:
  Animals Cadmium Genetics Occupational Health Safety Toxicology Urogenital System
• Keywords:
  Animal Studies Author Keywords: Cadmium Calcineurin Cdm FK506 Gene Mutation Genes Multinucleated Germ Cells Ppp3ca Reproductive Effects Reproductive Hazards SSeCKS Testes Toxic Effects

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Alabama ; California ; Illinois ; New Jersey ; OSHA Region 2 ; OSHA Region 4 ; OSHA Region 5 ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  474-485
• Volume:
  100
• Issue:
  2
• NIOSHTIC Number:
  nn:20058421
• Citation:
  Toxicol Sci 2007 Dec; 100(2):474-485
• Contact Point Address:
  Michael David Collins, Department of Environmental Health Sciences, Interdepartmental Program in Molecular Toxicology, University of California, Los Angeles School of Public Health CHS 71-297, 10833 LeConte Avenue, Los Angeles, CA 90095-1772
• Email:
  mdc@ucla.edu
• CAS Registry Number:
  Cadmium (CAS RN 7440-43-9)
• Federal Fiscal Year:
  2008
• Performing Organization:
  University of California Los Angeles
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Toxicological Sciences
• End Date:
  20270630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b2ae63df1153e3c4d52aaaf26fd2b87ce19b86588f62808630cb0f4b687923f2828af6632e860bfa4bceb07f01b97b41053db9bae11e83b367dfa543cf73c472
• Download URL:
  https://stacks.cdc.gov/view/cdc/221515/cdc_221515_DS1.pdf
• File Type:
  [PDF - 1.22 MB ]