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ToxSci Advance Access published online on September 21, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi325
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 4, 2005
Accepted September 12, 2005

In Vitro Toxicology

Inhibition and Induction of Aromatase (CYP19) Activity by Brominated Flame Retardants in H295R Human Adrenocortical Carcinoma Cells

Rocío F. Cantón 1*, Thomas Sanderson 2, Robert J. Letcher 3, Åke Bergman 4, and Martin van den Berg 1

1 Institute for Risk Assessment Sciences, IRAS Utrecht University, Utrecht, The Netherlands
2 Institut National de la Recherche Scientifique, Institut Armand-Frappier (INRS-IAF), Université du Québec, Montréal, Québec, H9R 1G6, Canada
3 National Wildlife Research Centre, Canadian Wildlife Service, Environment Canada, Ottawa, Ontario K1A 0H3 Canada
4 Department of Environmental Chemistry and Analytical Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden

* To whom correspondence should be addressed.
Rocío F. Cantón, E-mail: r.Fernandez{at}iras.uu.nl


  Abstract

Brominated flame retardants (BFRs) are persistent and ubiquitous chemicals in the environment, and are found at increasing levels in tissues of wildlife and humans. Previous in vitro studies with the BFR class of polybrominated diphenyl ethers (BDEs) have shown endocrine disrupting properties. Our study assessed the potential effects of nineteen BDEs, five hydroxylated BDEs (OH-BDEs), one methoxylated BDE (CH3O-BDE), tetrabromobisphenol-A (TBBPA), its dibromopropane ether derivative (TBBPA-DBPE), and the brominated phenols/anisols 2,4,6-tribromophenol (TBP), 4-bromophenol (4BP) and 2,4,6-tribromoanisole (TBA) on the catalytic activity of the steroidogenic enzyme aromatase (CYP19) in H295R human adrenocortical carcinoma cells. Effects were studied in the concentration range from 0.5 to 7.5 µM; exposures were for 24 h. 6-OH-BDE47 and 6-OH-BDE99 showed an inhibitory effect on aromatase activity at concentrations > 2.5 µM and > 5 µM, respectively. However, 6-OH-BDE47 also caused a statistically significant increase in cytotoxicity (based on mitochondrial MTT reduction and lactate dehydrogenase-leakage (LDH)) at concentrations > 2.5 µM that could explain in part the apparent inhibitory effect on aromatase activity. Compared to 6-OH-BDE47, the methoxy analogue (6-CH3O-BDE47) did not elicit a cytotoxic effect, while significant inhibition of aromatase remained. TBP caused a concentration-dependent induction of aromatase activity between 0.5 and 7.5 µM (with a maximum of 3.8 fold induction at 7.5µM). This induction was not observed when a OH- group replaced the CH3O- group or bromines atoms adjacent to this OH- group were absent. These in vitro results provide a basis for studies of more detailed structure-activity relationships between these brominated compounds and the modulation of aromatase activity.

Keywords: brominated flame retardants (BFRs); BDEs; OH-PBDEs; CH3O-PBDEs; aromatase (CYP19); H295R human adrenocortical cell line.
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