The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol

Patrick Diel, Nicola Höfer, Eugenia Becker, Gisela H Degen, Wilhelm Bloch

Publication: Contribution to journalJournal articlesResearchpeer-review

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.

Original languageEnglish
JournalArchives of toxicology
Volume87
Issue number4
Pages (from-to)633-43
Number of pages11
ISSN0340-5761
DOIs
Publication statusPublished - 01.04.2013

Research areas and keywords

  • Animals
  • Caco-2 Cells
  • Cadmium Chloride
  • Cell Survival
  • Cytochrome P-450 CYP1A1
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Estradiol
  • Estrogen Receptor Modulators
  • Estrogens
  • Ethinyl Estradiol
  • Female
  • Gene Expression Regulation
  • Glutathione Transferase
  • Humans
  • Intestine, Small
  • Isoenzymes
  • Metallothionein
  • NAD(P)H Dehydrogenase (Quinone)
  • Organ Size
  • Ovariectomy
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Receptors, Aryl Hydrocarbon
  • Uterus

Fingerprint

Dive into the research topics of 'The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol'. Together they form a unique fingerprint.

Citation