title: Approaches for predicting effects of unintended environmental exposure to an endocrine active pharmaceutical, tamoxifen.
abstract: Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget species (i.e., a fish), (2) compare biologically-active metabolites across species, (3) assess whether in vitro assays predict in vivo results, and (4) investigate metabolomic profiles in tamoxifen-treated fish to better understand the biological mechanisms of tamoxifen toxicity. In reproductive assays, tamoxifen exposure caused a significant reduction in egg production and significantly increased ovarian aromatase activity in spawning adult cunner fish (Tautogolabrus adspersus). In plasma from tamoxifen-exposed cunner, the predominant metabolite was 4-hydroxytamoxifen, while in rats it was N-desmethyltamoxifen. Because 4-hydroxytamoxifen is a more biologically active metabolite than N-desmethyltamoxifen, this difference could result in a different level of risk for the two species. The results of in vitro assays with fish hepatic microsomes to assess tamoxifen metabolism did not match in vivo results, indicating probable differences in excretion of tamoxifen metabolites in fish compared with rats. For the first time, a complete in vitro characterization of the metabolism of tamoxifen using fish microsomes is presented. Furthermore, a metabolomic investigation of cunner gonad extracts demonstrates that tamoxifen alters the biochemical profile in this nontarget species. Understanding the consequence of tamoxifen exposure in nontarget species, and assessing the discrepancies between sex- and species-mediated endpoints, is a step toward understanding how to accurately assess the risks posed by EAPs, such as tamoxifen, in the aquatic environment. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1834-1850, 2016.
authors: Atlantic Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S. EPA), Narragansett, Rhode Island, 02882, USA.
authors: Lesley J
authors: LJ
authors: Mills
authors: Ecosystems Research Division, National Exposure Research Laboratory (NERL), ORD, U.S. EPA, Athens, Georgia, 30605, USA.
authors: W Matthew
authors: WM
authors: Henderson
authors: Atlantic Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S. EPA), Narragansett, Rhode Island, 02882, USA.
authors: Saro
authors: S
authors: Jayaraman
authors: Atlantic Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S. EPA), Narragansett, Rhode Island, 02882, USA.
authors: Ruth E
authors: RE
authors: Gutjahr-Gobell
authors: Atlantic Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S. EPA), Narragansett, Rhode Island, 02882, USA.
authors: Gerald E
authors: GE
authors: Zaroogian
authors: Atlantic Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S. EPA), Narragansett, Rhode Island, 02882, USA.
authors: Doranne Borsay
authors: DB
authors: Horowitz
authors: Toxicity Assessment Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina, 27711, USA.
authors: Susan C
authors: SC
authors: Laws
mesh_terms: D000818:Animals; D001681:Biological Assay; D004531:Eggs; D004781:Environmental Exposure; D005260:Female; D008862:Microsomes, Liver / Q000378:metabolism; D010473:Perciformes / Q000502:physiology*; D012098:Reproduction / Q000187:drug effects; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000633:toxicity*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D020845:Selective Estrogen Receptor Modulators; D014874:Water Pollutants, Chemical; D013629:Tamoxifen; C016601:afimoxifene; C028787:N-desmethyltamoxifen
keywords: aromatase activity; endocrine active pharmaceuticals; fish; in vitro; in vivo; metabolism; metabolomics; microsomes; reproduction; tamoxifen