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

  • Inorganic Compounds
  • Published:
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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.

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Abbreviations

AhR:

Aryl hydrocarbon receptor

ARE:

Antioxidant response element

b.wt:

Body weight

Cd:

Cadmium

CdCl2 :

Cadmium chloride

DRE:

Dioxin response element

EE2 :

17alpha-ethinylestradiol

ER alpha/beta:

Estrogen receptor alpha/beta

ERE:

Estrogen response element

FBS:

Fetal bovine serum

GRE:

Glucocorticoid response element

i.p.:

Intraperitoneal

NRF2:

Nuclear factor (erythroid-derived 2)-like 2 (receptor)

OVX:

Ovariectomized

s.c.:

Subcutaneous

UEH:

Uterus epithelial height

UWW:

Uterus wet weight

ZK:

ZK191703

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Acknowledgments

The authors wish to thank Dr. Claudia Behm for conducting the neutral red assays, Ute Laudenbach-Leschowsky for animal handling, and Jonas Hengevoss and Laura Happ for uterus epithelial height analysis. We also thank Verena Bamberger for assistance with the RNA preparation. Financial support by the Deutsche Forschungsgemeinschaft through DFG graduate college GRK1427 and a stipend to F.K. are gratefully acknowledged.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. 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 M. Kluxen, Patrick Diel, Nicola Höfer & Eugenia Becker

  2. IfADo—Leibniz Research Centre for Working Environment and Human Factors at the TU Dortmund, Ardeystr. 67, 44139, Dortmund, Germany

    Felix M. Kluxen, Nicola Höfer & Gisela H. Degen

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  1. Felix M. Kluxen
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  2. Patrick Diel
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  5. Gisela H. Degen
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Correspondence to Felix M. Kluxen.

Additional information

The work described here is part of the PhD thesis of Felix M. Kluxen.

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Kluxen, F.M., Diel, P., Höfer, N. et al. The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol. Arch Toxicol 87, 633–643 (2013). https://doi.org/10.1007/s00204-012-0971-7

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  • DOI: https://doi.org/10.1007/s00204-012-0971-7

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