title: Pharmacological modulation of genome and proteome alterations in mice treated with the endocrine disruptor bisphenol A.
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 (32)P 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-beta 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.
authors.affiliation: Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Longobardi
authors.forename: Cristina
authors.initials: C
authors.lastname: Cartiglia
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Agostini
authors.forename: Stefano
authors.initials: S
authors.lastname: Kanitz
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001559:Benzhydryl Compounds; D018736:DNA Adducts / Q000187:drug effects*; D052244:Endocrine Disruptors / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D016678:Genome / Q000187:drug effects*; D017879:Isothiocyanates / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010636:Phenols / Q000494:pharmacology*; D040081:Protein Array Analysis; D020543:Proteome / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D016588:Anticarcinogenic Agents; D001559:Benzhydryl Compounds; D018736:DNA Adducts; D052244:Endocrine Disruptors; D004968:Estrogens, Non-Steroidal; D017879:Isothiocyanates; D010636:Phenols; D020543:Proteome; C058305:phenethyl isothiocyanate; C006780:bisphenol A; D000098826:Bisphenol A Compounds