Pharmacological Modulation of Genome and Proteome Alterations in Mice Treated with the Endocrine Disruptor Bisphenol A

A.      Izzotti; M.      Longobardi; C.      Cartiglia; F.      D'Agostini; S.      Kanitz; S.      De Flora

Abstract

Among endocrine disruptors, the xenoestrogen bisphenol A (BPA) is of particular interest due to the very high production and widespread environmental contamination. We recently demonstrated that the oral administration of BPA to mice results in the formation of DNA adducts not only in liver but also in mammary tissue. The present study aimed at evaluating the modulation of BPA-related DNA adducts and proteome alterations by the chemopreventive agents budesonide (BUD) and phenethyl isothiocyanate (PEITC). Swiss ICR (CD-1) mice received, for 8 days, BPA with the drinking water and either chemopreventive agent with the diet. We measured DNA adducts by 32P postlabeling and 656 proteins by antibody microarray. BPA induced the formation, with similar patterns, of DNA adducts in liver and in mammary tissue. Moreover, BPA dysregulated 13 proteins in mammary tissue, mostly in the sense of upregulation, including estrogen receptor-β and proteins involved in cell proliferation, inhibition of apoptosis, tissue remodeling, inflammation, stress response, and glutathione synthesis. PEITC significantly inhibited the formation of BPA-induced DNA adducts, but only at the highest dose tested, and BUD was totally ineffective. The chemopreventive agents modulated a variety of BPA-induced changes in proteome profiles. However, as shown by both hierarchical cluster analysis and principal component analysis, BUD and especially PEITC were not able to restore the physiological situation in BPA-treated mice. Therefore, the in vivo use of proteome analysis proves to be a sensitive tool for the early prediction not only of protective effects but also of adverse effects of chemopreventive agents.

Keywords: Budesonide, phenethyl isothiocyanate, bisphenol A, mice, liver, mammary tissue, DNA adducts, proteome