title: Comparing gene expression during cadmium uptake and distribution: untreated versus oral Cd-treated wild-type and ZIP14 knockout mice.
abstract: The nonessential metal cadmium (Cd) is toxic only after entering the cell. Proteins possibly relevant to intracellular Cd accumulation include the divalent metal transporter-1 (DMT1) and all 14 zinc-like iron-like protein (ZIP) importers, 10 zinc transporter (ZnT) exporters, and metallothionein chaperones MT1 and MT2. Comparing oral Cd-treated ZIP14 knockout (KO) with wild-type (WT) mice, we predicted Cd uptake and distribution would be diminished in the KO-because ZIP14 is very highly expressed in GI tract and liver; this was indeed observed for Cd content in liver. However, the reverse was found in kidney and lung from 6 or 12 h through 10 days of Cd exposure; at these times, Cd accumulation was unexpectedly greater in KO than WT mice; mRNA levels of the 27 above-mentioned genes were thus examined in proximal small intestine (PSI) versus kidney to see if these paradoxical effects could be explained by substantial alterations in any of the other 26 genes. PSI genes highly expressed in untreated WT animals included seven ZIP and five ZnT transporters, DMT1, MT1, and MT2; kidney genes included 11 ZIP and 7 ZnT transporters, DMT1, MT1, and MT2. Over 10 days of oral Cd, a bimodal response was seen for Cd content in PSI and for various mRNAs; initially, acute effects caused by the toxic metal; subsequently, the up- or down-regulation of important genes presumably to combat the sustained adversity. These data underscore the complex interplay between the gastrointestinal tract and renal proteins that might be relevant to Cd uptake and distribution in animals exposed to oral Cd.
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Lucia F
authors.initials: LF
authors.lastname: Jorge-Nebert
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Julio
authors.initials: J
authors.lastname: Landero Figueroa
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Maheshika
authors.initials: M
authors.lastname: Somarathna
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Hojyo
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukada
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, Laboratory for Homeostatic Network, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa 230-0045, Japan, Deutsches Rheuma-Forschungszentrum, Berlin, Osteoimmunology, 10117 Berlin, Germany and Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa, Tokyo 142-8555, Japan dan.nebert@uc.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage* / Q000378:metabolism* / Q000633:toxicity; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D027682:Cation Transport Proteins; D012333:RNA, Messenger; C500556:SLC39A14 protein, mouse; D019256:Cadmium Chloride
keywords: SLC11A2; SLC30 family; SLC39 family; ZIP influxors; ZnT effluxors; divalent metal transporter DMT1; metallothioneins; oral cadmium; pharmacokinetics of metal uptake; zinc transport