title: The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol.
abstract: Cadmium (Cd) affects the expression of estrogen receptor (ER) and aryl hydrocarbon receptor (AhR)-associated genes in rat uterus and elicits estrogen-like activity in vitro. The small intestine is highly exposed to dietary Cd which may mimic or antagonize estrogen action in this tissue. We investigated the effects of Cd and 17-alpha-ethinylestradiol (EE₂) on AhR-associated gene expression after oral exposure of ovariectomized female Wistar rats, and metallothionein (Mt1a) expression as a typical metal-response marker. Mt1a in the small intestine was strongly induced by co-treatment with CdCl₂ at 2 mg/kg b.wt (Cd 2) and 0.1 mg/kg b.wt EE2 than by the single compound (3-day gavage). The Cd 2-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was not antagonized by pure anti-estrogen (2.5 mg/kg b.wt ZK191703 s.c., ZK). Interestingly, the EE₂-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was antagonized by Cd 2 in vivo and in colon cancer cell lines (HT-29 and CaCo-2, treated 5 days with Cd 1 µM and/or E₂ 0.01 µM) with low or no ER-beta expression. Dose dependency was studied after Cd exposure with drinking water (5 and 50 ppm CdCl₂ equivalent to 0.4 and 4 mg/kg b.wt; Cd 0.4, Cd 4) for 28 days and EE₂ as reference. Intestinal Mt1a expression was dose dependently induced, while AhR target genes were down-regulated by Cd 0.4 similar to EE₂ and more pronounced than by Cd 4. We propose that Cd modulates intestinal AhR-associated gene expression similar to estrogens, but (contrary to its effects in uterus) via ER-independent and/or ER-beta-mediated mechanisms. Our new data suggest interference of Cd with estrogen and AhR signaling in the small intestine.
authors.affiliation: Department of Molecular and Cellular Sports Medicine, Institute of Cardiovascular Research and Sports Medicine, German Sports University Cologne, Am Sportpark Müngersdorf 6, 50933 Köln, Germany. felix.kluxen@gmail.com
authors.forename: Felix M
authors.initials: FM
authors.lastname: Kluxen
authors.forename: Patrick
authors.initials: P
authors.lastname: Diel
authors.forename: Nicola
authors.initials: N
authors.lastname: Höfer
authors.forename: Eugenia
authors.initials: E
authors.lastname: Becker
authors.forename: Gisela H
authors.initials: GH
authors.lastname: Degen
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D019256:Cadmium Chloride / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D005466:Fluorocarbons; D005786:Gene Expression Regulation / Q000187:drug effects*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000473:pathology
chemical_list: C541120:11-fluoro-7-(14,14,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)estra-1,3-5(10)-triene-3,17-diol; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D005466:Fluorocarbons; D007527:Isoenzymes; C491055:Mt2A protein, rat; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D004997:Ethinyl Estradiol; D004958:Estradiol; D008668:Metallothionein; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D019256:Cadmium Chloride