title: Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.
abstract: BACKGROUND
  Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently.
  
  
  RESULTS
  We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor.
  
  
  CONCLUSIONS
  This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Franziska
authors.initials: F
authors.lastname: Denk
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK.|Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, V6T 1Z3, BC, Canada.
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Ramer
authors.affiliation: International Collaboration On Repair Discoveries, University of British Columbia, Vancouver, V5Z 1 M9, BC, Canada.
authors.forename: Erin L K S
authors.initials: EL
authors.lastname: Erskine
authors.affiliation: Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nassar
authors.affiliation: Wolfson Institute for Biomedical Research (WIBR), University College London (UCL), Cruciform Building, London, WC1E 6BT, UK.
authors.forename: Yury
authors.initials: Y
authors.lastname: Bogdanov
authors.affiliation: Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Signore
authors.affiliation: Wolfson Institute for Biomedical Research (WIBR), University College London (UCL), Cruciform Building, London, WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: International Collaboration On Repair Discoveries, University of British Columbia, Vancouver, V5Z 1 M9, BC, Canada. ramer@icord.org.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Ramer
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009420:Nervous System / Q000166:cytology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D037121:Plant Lectins / Q000235:genetics / Q000378:metabolism; D010938:Plant Oils / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D009419:Nerve Tissue Proteins; D037121:Plant Lectins; D010938:Plant Oils; D020845:Selective Estrogen Receptor Modulators; C034981:tomato lectin; D013629:Tamoxifen; D014810:Vitamin E; C050055:wheat germ oil; D002784:Cholesterol; D004851:Epoxide Hydrolases; C019885:cholesterol-5 alpha,6 alpha-epoxide hydrase; D015740:Calcitonin Gene-Related Peptide