title: Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries.
abstract: Recent studies documented that the selective estrogen receptor modulator tamoxifen prevents follicle loss and promotes fertility following in vivo exposure of rodents to irradiation or ovotoxic cancer drugs, cyclophosphamide and doxorubicin. In an effort to characterize the ovarian-sparing mechanisms of tamoxifen in preantral follicle classes, cultured neonatal rat ovaries (Day 4, Sprague Dawley) were treated for 1-7 days with active metabolites of cyclophosphamide (i.e., 4-hydroxycyclophosphamide; CTX) (0, 1, and 10 μM) and tamoxifen (i.e., 4-hydroxytamoxifen; TAM) (0 and 10 μM) in vitro, and both apoptosis and follicle numbers were measured. CTX caused marked follicular apoptosis and follicular loss. TAM treatment decreased follicular loss and apoptosis from CTX in vitro. TAM alone had no effect on these parameters. IGF-1 and IGF-1 receptor were assessed in ovarian tissue showing no impact of TAM or CTX on these endpoints. Targeted mRNA analysis during follicular rescue by TAM revealed decreased expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr), cytokine binding (Il1r1, Il2rg ), apoptosis (Tnfrsf1a), second messenger signaling (Mapk1, Mapk14, Plcg1), as well as tissue remodeling and vasodilation (Bdkrb2, Klk15). The results suggest that TAM protects the ovary from CTX-mediated toxicity through direct ovarian actions that oppose follicular loss.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Joanna
authors.initials: J
authors.lastname: Piasecka-Srader
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Blanco
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Devora H
authors.initials: DH
authors.lastname: Delman
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: James L
authors.initials: JL
authors.lastname: Geiser
authors.affiliation: Department of Animal Physiology, University of Warmia and Mazury, Olsztyn, Poland.
authors.forename: Renata E
authors.initials: RE
authors.lastname: Ciereszko
authors.affiliation: Diagnostic Companion Animal and Population Health Laboratory, Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan bpetroff@msu.edu.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Petroff
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D003520:Cyclophosphamide; D017526:Receptor, IGF Type 1
keywords: environmental contaminants and toxicants; ovary; premature ovarian failure; toxicology
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