title: Estrogen-like effects of diet-derived cadmium differ from those of orally administered CdCl(2) in the ERE-luc estrogen reporter mouse model.
abstract: Cadmium (Cd), an environmental and dietary contaminant, has been described to mimic the effects of 17β-estradiol (E(2)) in selected model systems when studied as an inorganic salt. However, inorganic Cd salts do not represent the main form of Cd exposure in general human populations. The aims of this study were to compare the estrogen-like effects and the bioavailability of dietary Cd to inorganic CdCl(2). Adult ovariectomized ERE-luc reporter mice were administered two bread based diets containing different concentrations of Cd (17.57 and 49.22μg/kg, corresponding to oral intakes of 1.8 and 5.1μg/kg body weight (bw) per day, respectively), inorganic CdCl(2) (1μg/kg bw per day by gavage) or E(2) (5μg/kg bw per day pellet) for 21 days. The effects on estrogen signaling were investigated by studying the uterine weights, luciferase activation, and expression of endogenous estrogen target genes. The uterine weight was significantly increased by both CdCl(2) and E(2) but not by the Cd containing diets. All treatments modulated the expression of luciferase and the endogenous estrogen target genes; however, there was no consistent overlap between the responses triggered by the bread diets and the responses stimulated by CdCl(2) or E(2). Oral exposure to Cd was calculated and the concentrations in liver and kidneys quantified to estimate the amount of absorbed Cd retained in tissues. The results suggest significantly lower absorption and/or tissue retention of dietary Cd compared to CdCl(2) following oral exposure. Altogether, our results support previous reports on in vivo estrogenicity of CdCl(2) but do not suggest the same activity for diet bound Cd. This study calls for caution when extrapolating results from pure compound studies (e.g. estrogenicity of CdCl(2)) to dietary exposure scenarios (e.g. estrogenicity of diet bound Cd). Further basic research is needed on the mechanisms of interaction between Cd and the estrogen signaling, biologically active species of Cd, and biomarkers of estrogen-like effects of Cd in vivo before human health risk assessment on the hormone disruptive effects of Cd can be carried out.
authors.affiliation: Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, Via Balzaretti, 9 I-20123 Milan, Italy. balajiphd@gmail.com
authors.forename: Balaji
authors.initials: B
authors.lastname: Ramachandran
authors.forename: Sari
authors.initials: S
authors.lastname: Mäkelä
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cravedi
authors.forename: Marika
authors.initials: M
authors.lastname: Berglund
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
authors.forename: Pauliina
authors.initials: P
authors.lastname: Damdimopoulou
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002104:Cadmium / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D047628:Estrogen Receptor alpha; D011971:Receptors, Immunologic; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; C086486:prothymosin alpha receptor; D002104:Cadmium; D012313:RNA