title: Derivation and Evaluation of Putative Adverse Outcome Pathways for the Effects of Cyclooxygenase Inhibitors on Reproductive Processes in Female Fish.
abstract: Cyclooxygenase (COX) inhibitors are ubiquitous in aquatic systems and have been detected in fish tissues. The exposure of fish to these pharmaceuticals is concerning because COX inhibitors disrupt the synthesis of prostaglandins (PGs), which modulate a variety of essential biological functions, including reproduction. In this study, we investigated the effects of well-characterized mammalian COX inhibitors on female fathead minnow reproductive health. Fish (n = 8) were exposed for 96 h to water containing indomethacin (IN; 100 µg/l), ibuprofen (IB; 200 µg/l) or celecoxib (CX; 20 µg/l), and evaluated for effects on liver metabolome and ovarian gene expression. Metabolomic profiles of IN, IB and CX were not significantly different from control or one another. Exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB = 433, CX = 545). In contrast, 2558 genes were differentially expressed in IN-treated fish. Functional analyses (canonical pathway and gene set enrichment) indicated extensive effects of IN on PG synthesis pathway, oocyte meiosis, and several other processes consistent with physiological roles of PGs. Transcriptomic data were congruent with PG data; IN-reduced plasma PG F2α concentration, whereas IB and CX did not. Five putative AOPs were developed linking the assumed molecular initiating event of COX inhibition, with PG reduction and the adverse outcome of reproductive failure via reduction of: (1) ovulation, (2) reproductive behaviors mediated by exogenous or endogenous PGs, and (3) oocyte maturation in fish. These pathways were developed using, in part, empirical data from the present study and other publicly available data.
authors.affiliation: Biology Department, University of St Thomas, Saint Paul, Minnesota 55105.
authors.forename: Dalma
authors.initials: D
authors.lastname: Martinovic-Weigelt
authors.affiliation: Departments of Physiological Sciences and Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32611.|Southern California Coastal Water Research Project, Costa Mesa, California 92626.
authors.forename: Alvine C
authors.initials: AC
authors.lastname: Mehinto
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Berninger
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, Athens, Georgia 30605.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Collette
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, Athens, Georgia 30605.
authors.forename: John M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Departments of Physiological Sciences and Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32611.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Denslow
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Durhan
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Evan
authors.initials: E
authors.lastname: Eid
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, Athens, Georgia 30605.
authors.forename: Drew R
authors.initials: DR
authors.lastname: Ekman
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Jensen
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kahl
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Carlie A
authors.initials: CA
authors.lastname: LaLone
authors.affiliation: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Ecosystems Research Division, Athens, Georgia 30605.
authors.forename: Quincy
authors.initials: Q
authors.lastname: Teng
authors.affiliation: U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, Minnesota 55804.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
mesh_terms: D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D003530:Cyprinidae / Q000254:growth & development* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis* / Q000209:etiology; D005260:Female; D020869:Gene Expression Profiling; D055442:Metabolome / Q000187:drug effects*; D010053:Ovary / Q000187:drug effects* / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases
keywords: cyclooxygenase inhibition; prostaglandins; reproduction; fish; adverse outcome pathway; nonsteroidal anti-inflammatory drugs.