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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg102
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 23, 2003; accepted March 24, 2003
© 2003 Society of Toxicology

Endocrine Toxicology

UV Filters with Antagonistic Action at Androgen Receptors in the MDA-kb2 Cell Transcriptional-Activation Assay

Risheng Ma 1, Bea Cotton 1, Walter Lichtensteiger 1, Margret Schlumpf 1*

1 Institute of Pharmacology and Toxicology, University of Zurich, CH-8057, Zurich, Switzerland

* To whom correspondence should be addressed. E-mail: schlumpm{at}pharma.unizh.ch.


  Abstract

The fact that certain UV filters used in cosmetics display estrogenic activity, prompted us to study potential actions on androgen receptors (AR) in the human breast carcinoma cell line MDA-kb2 which expresses functional endogenous AR and glucocorticoid receptors (GR), and is stably transfected with a luciferase reporter plasmid. Dihydrotestosterone (DHT), methyltrienolone (R1881), methyltestosterone, danazol and androstenedione increased luciferase activity with EC50 values between 0.11nM (R1881), 0.14nM (DHT), and 73.5nM (androstenedione). DHT-induced luciferase gene expression was inhibited by non-steroidal antiandrogens, hydroxyflutamide, flutamide, bicalutamide and vinclozolin. In contrast, the steroidal AR agonist/antagonist cyproterone actetate showed agonistic activity in the absence and presence of DHT, which was not blocked by hydroxyflutamide and thus seems not to be mediated by AR. GR-mediated activation of luciferase by dexamethasone was 100 times less potent than DHT and was not antagonized by hydroxyflutamide. The cell line was used for screening of UV filters, benzophenone-3 (Bp-3), benzophenone-4, 3-benzylidene camphor, 4-methylbenzylidene camphor, butyl-methoxy-dibenzoylmethane, homosalate (HMS), octyl-dimethyl-PABA, and octyl-methoxycinnamate. Two of these, Bp-3 and HMS, antagonized DHT-induced AR activation below cytotoxic concentrations, with IC50 of 5.57 10-6 M (HMS) and 4.98 10-6 M (Bp-3). None of the eight UV filters displayed agonistic activity when tested alone, but high concentrations of Bp-3 induced an increase of luciferase activity in the presence of dexamethasone, which was not blocked by hydroxyflutamide or the estrogen antagonist, ICI 182,780. These data indicate that the UV filters Bp-3 and HMS possess antiandrogenic activity in vitro in addition to estrogenic activity.

Key Words: MDA-kb2 cells, androgen receptor, androgen, antiandrogen, endocrine disruptor, pesticide, UV filter .


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