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Cadmium modulates expression of aryl hydrocarbon receptor-associated genes in rat uterus by interaction with the estrogen receptor

  • Toxicogenomics
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Abstract

Estrogen-like effects of the heavy metal cadmium have been reported in both in vitro and in vivo studies. Yet, the molecular mechanisms involved in the hormonal activity of cadmium ions have not been fully elucidated. There are extensive data on cross-talk between aryl hydrocarbon receptor (AhR) and estrogen receptor (ER). Recently, 17β-estradiol (E2) was found to modulate the expression of AhR and AhR-regulated genes in rat uterus (Kretzschmar et al. in Mol Cell Endocrinol 321:253–257, 2010). Thus, we hypothesized that cadmium may also affect AhR signaling and examined whether cadmium or E2 modulate AhR-associated genes via the ER in rat uterus. Ovariectomized Wistar rats received E2 (0.5 mg/kg bw) or cadmium chloride (0.05 and 2 mg/kg bw i.p.) alone and in combination with the pure anti-estrogen ZK191703. We also co-treated a group with E2 and cadmium 2 mg/kg bw to assess how they act in concert. Uterus wet weight, uterus epithelial height, complement C3 mRNA, and progesterone receptor (PR) protein expression served as estrogen response parameters, and expression of Mt1a mRNA was analyzed as a cadmium responsive gene. The expression of AhR protein and AhR-associated gene expression, i.e., Ahr, Arnt1, Arnt2, Cyp1a1, and Gsta2, were analyzed to examine effects on AhR-mediated signaling pathways in the uterus of all groups. Both, E2 and cadmium induced C3 and PR expression, and this was antagonized by ZK191703. Mt1a expression was clearly induced by cadmium but slightly reduced by E2 compared to controls. Uterine Ahr, Arnt1, Arnt2, and Cyp1a1 expression was modulated by E2 via the ER since down-regulation by E2 was reversed by anti-estrogen. Cadmium apparently also modulated Cyp1a1 expression via the ER. Furthermore, cadmium-induced AhR was antagonized by E2, and anti-estrogen-induced Gsta2 expression was antagonized by cadmium. Together our findings provide evidence for cross-talk of ER and AhR in the rat uterus.

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Abbreviations

AhR:

Arylhydrocarbon receptor

ARE:

Antioxidant response element

bw:

Body weight

CdCl2 :

Cadmium chloride

DRE:

Dioxin response element

E2 :

17β-estradiol

ERalpha/beta:

Estrogen receptor alpha/beta

ERE:

Estrogen response element

i.p:

Intraperitoneal

Mt1a:

Metallothionein 1a

OVX:

Ovariectomized

ZK:

ZK191703

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Acknowledgments

Financial support by the Deutsche Forschungsgemeinschaft through DFG graduate college GRK1427 and a stipend to F.M.K. are gratefully acknowledged. We thank Ute Laudenbach-Leschowsky for animal handling and Jonas Hengevoß for uterine epithelial height analysis.

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Authors and Affiliations

  1. Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, German Sports University Cologne, Am Sportpark Müngersdorf 6, 50933, Köln, Germany

    Felix M. Kluxen, Nicola Höfer & Patrick Diel

  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

  3. Molecular Cell Physiology & Endocrinology, Institute of Zoology, Technische Universität Dresden, Zellescher Weg 20, 01062, Dresden, Germany

    Georg Kretzschmar

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  1. Felix M. Kluxen
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  2. Nicola Höfer
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  3. Georg Kretzschmar
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  4. Gisela H. Degen
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Correspondence to Gisela H. Degen.

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Kluxen, F.M., Höfer, N., Kretzschmar, G. et al. Cadmium modulates expression of aryl hydrocarbon receptor-associated genes in rat uterus by interaction with the estrogen receptor. Arch Toxicol 86, 591–601 (2012). https://doi.org/10.1007/s00204-011-0787-x

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