title: High concentrations of hexavalent chromium in drinking water alter iron homeostasis in F344 rats and B6C3F1 mice.
abstract: Hexavalent chromium [Cr(VI)] induces hematological signs of microcytic anemia in rodents. Considering that Cr(VI) can oxidize ferrous (Fe(2+)) to ferric (Fe(3+)) iron, and that only the former is transported across the duodenum, we hypothesize that, at high concentrations, Cr(VI) oxidizes Fe(2+) in the lumen of the small intestine and perturbs iron absorption. Herein we report that 90-day exposure to Cr(VI) in drinking water resulted in dose-dependent decreases in Fe levels in the duodenum, liver, serum, and bone marrow. Toxicogenomic analyses from the duodenum indicate responses consistent with Fe deficiency, including significant induction of divalent metal transporter 1 (DMT1, Slc11a2) and transferrin receptor 1 (TFR1, Tfr1). In addition, at ⩾20mg Cr(VI)/L in drinking water, Cr RBC:plasma ratios in rats were increased and exceeded unity, indicating saturation of reductive capacity and intracellular absorption of Cr(VI) into red blood cells (RBCs). These effects occurred in both species but were generally more severe in rats. These data suggest that high concentrations of Cr(VI) in drinking limit Fe absorption and alter iron homeostasis. Furthermore, some effects observed at high doses in recent Cr(VI) chronic and subchronic bioassays may be explained, at least in part, by iron deficiency and disruption of homeostasis.
authors.affiliation: ToxStrategies, Inc., Mission Viejo, CA 92692, United States. Electronic address: msuh@toxstrategies.com.
authors.forename: Mina
authors.initials: M
authors.lastname: Suh
authors.affiliation: ToxStrategies, Inc., Katy, TX 77494, United States. Electronic address: cthompson@toxstrategies.com.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Thompson
authors.affiliation: Summit Toxicology, LLP, Orange Village, OH 44022, United States. Electronic address: ckirman@summittoxicology.com.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Kirman
authors.affiliation: ToxStrategies, Inc., St. Helena Island, SC 29920, United States. Electronic address: mcarakostas@toxstrategies.com.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carakostas
authors.affiliation: ToxStrategies, Inc., Austin, TX 78759, United States. Electronic address: lhaws@toxstrategies.com.
authors.forename: Laurie C
authors.initials: LC
authors.lastname: Haws
authors.affiliation: ToxStrategies, Inc., Katy, TX 77494, United States. Electronic address: mharris@toxstrategies.com.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Harris
authors.affiliation: ToxStrategies, Inc., Mission Viejo, CA 92692, United States. Electronic address: dproctor@toxstrategies.com.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Proctor
mesh_terms: D000818:Animals; D002857:Chromium / Q000032:analysis / Q000633:toxicity*; D060766:Drinking Water / Q000737:chemistry*; D005260:Female; D006706:Homeostasis / Q000187:drug effects* / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D060766:Drinking Water; D002857:Chromium; C074702:chromium hexavalent ion; D007501:Iron
keywords: Anemia; Hexavalent chromium; Iron depletion; Toxicogenomics