title: Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity.
abstract: The highly conserved human and mouse SLC39A8 gene encodes the divalent cation/bicarbonate symporter ZIP8 expressed ubiquitously in most cell types. Our bacterial artificial chromosome-transgenic BTZIP8-3 line has 3 additional copies of the Slc39a8 gene in addition to its constitutive diploid pair found in wild-type (WT) mice. In liver, kidney, lung, testis, gastrointestinal tract, and brain, BTZIP8-3 mice are known to express ∼2.5 times greater amounts of ZIP8, compared with WT mice. Herein we administered cadmium chloride (CdCl₂) in drinking water (100 mg/L through week 2, 200 mg/L through week 4, 400 mg/L through week 8, 800 mg/L through week 12, and 1600 mg/L through week 20, when the experiment was concluded). We postulated that Cd uptake and distribution--and, therefore, toxicity in certain tissues--would be enhanced in BTZIP8-3, compared with WT mice. BTZIP8-3 and WT groups ingested comparable amounts of Cd. Compared with WT, BTZIP8-3 mice showed tissue specific: increases in Cd, zinc, and manganese content and decreases in calcium content. Both Cd-exposed BTZIP8-3 and WT were similar in lower urinary pH; increased plasma alanine and aspartate aminotransferase activities; elevated iron and copper content in liver, kidney, lung, and testis; and higher blood urea nitrogen and kidney weight. Histological changes in liver, kidney, lung, and testis were minimal. In summary, at the daily oral Cd exposures chosen for this study, 5 versus 2 Slc39a8 gene copies result in no differences in Cd toxicity but do cause differences in tissue-specific content of Cd, zinc, manganese, calcium, iron, and copper.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA. Email: dan.nebert@uc.edu.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Schneider
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Marian L
authors.initials: ML
authors.lastname: Miller
authors.forename: Scott E
authors.initials: SE
authors.lastname: Afton
authors.forename: Manoocher
authors.initials: M
authors.lastname: Soleimani
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000141:Acidosis, Renal Tubular / Q000209:etiology*; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D019256:Cadmium Chloride / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D002105:Cadmium Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018628:Gene Dosage; D048550:Hepatic Insufficiency / Q000209:etiology*; D007408:Intestinal Absorption; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D027682:Cation Transport Proteins; D008670:Metals; C499256:Slc39a8 protein, mouse; D019256:Cadmium Chloride
keywords: BAC-transgenic mouse line; ZIP8 zinc & iron divalent cation transporter; heavy metal uptake; heavy metal-induced toxicity; inductively-coupled plasma mass spectrometry