Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

Friday 25 May 2007

Toxicology and Applied Pharmacology 222 (2007) 129 – 140, Elsevier Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination


Nora Benachour a , Safa Moslemi a,b , Herbert Sipahutar a,c , Gilles-Eric Seralini a, ⁎

aLaboratoire de Biochimie, EA2608, IBFA, Université de Caen, Esplanade de la Paix, 14032 Caen, France
bLaboratoire de Biochimie du Tissu Conjonctif, EA3214, CHU Côte de Nacre, Caen, France
cDepartment of Biology, State University of Medan, Indonesia

Received 25 January 2007; revised 19 March 2007; accepted 19 March 2007 Available online 25 May 2007



Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure,
combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability
and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p′-DDT, vinclozolin (VZ), p,p′-DDE, bisphenol A
(BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic
293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was
affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at
non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4–10 μM, and aromatase activity by 50% in
some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH
metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by
inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT
and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of
these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment.
© 2007 Elsevier Inc. All rights reserved.

Keywords: Xenobiotics; Endocrine disrupters; Aromatase; Cytochrome P450 reductase; Steroidogenesis; Pesticides; PCB; Bisphenol A; Diethylstilbestrol; Nonylphenol; Human 293 embryonic cells; Equine testis; Combined effects


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