title: Genotoxic, epigenetic, and transcriptomic effects of tamoxifen in mouse liver.
abstract: Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of breast cancer in women; however, there is evidence that tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that tamoxifen may cause non-alcoholic fatty liver disease (NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of tamoxifen on NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m. tamoxifen-containing diet for 12 weeks resulted in an accumulation of tamoxifen-DNA adducts, (E)-α-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-TAM) and (E)-α-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM DNA adducts in tamoxifen-treated mice were 578 and 340 adducts/108 nucleotides, respectively, while the extent of global DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of NAFLD-associated liver injury in mice treated with tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (Pparγ), which may prevent the development of NAFLD. The results of the present study demonstrate that the resistance of mice to tamoxifen-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Mona I
authors.initials: MI
authors.lastname: Churchwell
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Latendresse
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA.
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. Electronic address: igor.pogribny@fda.hhs.gov.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D013045:Species Specificity; D013629:Tamoxifen / Q000633:toxicity*; D013997:Time Factors
chemical_list: D018736:DNA Adducts; D004965:Estrogen Antagonists; D006657:Histones; D013629:Tamoxifen
keywords: DNA adducts; Epigenetics; Gene expression; Liver; Mouse; Tamoxifen