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ToxSci Advance Access published online on December 5, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl181
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sexual Dimorphism in the Regulation of Liver Connexin32 Transcription in Hexachlorobenzene-Treated Rats

Isabelle Plante, Daniel G. Cyr* and Michel Charbonneau*

INRS-Institut Armand-Frappier, Université du Québec, 245 Hymus boulevard, Pointe-Claire, QC, Canada, H9R 1G6

* Address for correspondence: Dr. Michel Charbonneau, INRS-Institut Armand Frappier, Université du Québec, 245 Hymus boulevard, Pointe-Claire, QC, H9R 1G6, Tel. (514) 630-8831; Fax (514) 630-8850; e-mail: michel.charbonneau{at}iaf.inrs.ca. Dr. Daniel G. Cyr, INRS-Institut Armand Frappier, Université du Québec, 245 Hymus boulevard, Pointe-Claire, QC, H9R 1G6. Tel. (514) 630-8833; Fax (514) 630-8850; e-mail: daniel.cyr{at}iaf.inrs.ca

Received September 22, 2006; accepted November 20, 2006


  Abstract

Hexachlorobenzene (HCB), an epigenetic carcinogen, causes female rats to be more susceptible to liver tumor formation than males. HCB exposure in females down-regulates the expression of Cx32, a gap junction protein, through the activation of Akt. The objectives of this study were to determine the implication of different regions of the hepatic Cx32 promoter in (1) the observed sexual dimorphism in the expression of Cx32; (2) the HCB-induced down-regulation of Cx32 in female rat liver; and (3) to determine if HCB exposure modulates the binding of transcription factors on the Cx32 promoter through Akt activation. Male and female rats were exposed to HCB during 5 consecutive days and sampled 45 days later. Electrophoresis Mobility Shift Assays (EMSA) showed that the intensity of only one nuclear proteins-DNA complex differed between males and females. The formation of this complex requires two binding sites to be intact in a fragment of the basal promoter (Fr26). Following HCB exposure, the intensity of two complexes (Fr26 and Fr110) was decreased in females, but not in males, consistent with the decrease in Cx32 expression observed only in HCB-treated females. In vitro studies using a rat hepatocyte cell line (MH1C1) showed that the formation of the Fr110 protein-DNA complex appears to be controlled by Akt, and require the integrity of a Myb site. Overall, results suggest that both the sexual dimorphism and the down-regulation of Cx32 in HCB-treated female rats are mediated by a reduction in the binding of activating transcription factors on the Cx32 promoter.

Key Words: Hexachlorobenzene; Connexin32; Gap Junctions; Akt; Integrin-Linked kinase; Promoter; EMSA.


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