Authors: Plante, Isabelle; Cyr, Daniel G.; Charbonneau, Michel

Source: Toxicological Sciences, Volume 96, Number 1, 14 March 2007 , pp. 47-57(11)

Publisher: Oxford University Press

Abstract:

Hexachlorobenzene (HCB), an epigenetic carcinogen, causes female rats to be more susceptible to liver tumor formation than males. HCB exposure in females downregulates the expression of Cx32, a gap junction protein, through the activation of Akt. The objectives of this study were to determine (1) the implication of different regions of the hepatic Cx32 promoter in the observed sexual dimorphism in the expression of Cx32, (2) the implication of different regions of the hepatic Cx32 promoter in the HCB-induced downregulation of Cx32 in female rat liver, and (3) 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 showed that the intensity of only one nuclear protein-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 (MH<inf>1</inf>C<inf>1</inf>) showed that the formation of the Fr110 protein-DNA complex appears to be controlled by Akt and requires the integrity of a Myb site. Overall, results suggest that both the sexual dimorphism and the downregulation of Cx32 in HCB-treated female rats are mediated by a reduction in the binding of activating transcription factors on the Cx32 promoter.

Keywords: hexachlorobenzene; connexin32; gap junctions; Akt; integrin-linked kinase; promoter; EMSA

Document Type: Research article

DOI: http://dx.doi.org/10.1093/toxsci/kfl181

Publication date: 2007-03-14

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