Integrated approach to explore the mechanisms of aromatase inhibition and recovery in fathead minnows (Pimephales promelas).
Aromatase, a member of the cytochrome P450 superfamily, is a key enzyme in estradiol synthesis that catalyzes the aromatization of androgens into estrogens in ovaries. Here, we used an integrated approach to assess the mechanistic basis of the direct effects of aromatase inhibition, as well as adaptation and recovery processes in fish. We exposed female fathead minnows (Pimephales promelas) via the water to 30 μg/L of a model aromatase inhibitor, fadrozole, during 8 days (exposure phase). Fish were then held in clean water for 8 more days (recovery phase). Samples were collected at 1, 2, 4, and 8 days of both the exposure and the recovery phases. Transcriptomics, metabolomics, and network inference were used to understand changes and infer connections at the transcript and metabolite level in the ovary. Apical endpoints directly indicative of endocrine function, such as plasma estradiol, testosterone, and vitellogenin levels were also measured. An integrated analysis of the data revealed changes in gene expression consistent with increased testosterone in fadrozole-exposed ovaries. Metabolites such as glycogen and taurine were strongly correlated with increased testosterone levels. Comparison of in vivo and ex vivo steroidogenesis data suggested the accumulation of steroidogenic enzymes, including aromatase, as a mechanism to compensate for aromatase inhibition.
Institute for Genomics Biocomputing and Biotechnology, Mississippi State University, Starkville, MS 39759, USA. Electronic address: nvinas@igbb.msstate.edu.
Natàlia
N
Garcia-Reyero
US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Athens, GA 30605, USA.
Drew R
DR
Ekman
Badger Technical Services, San Antonio, TX 78216, USA.
Tanwir
T
Habib
US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, MN, USA.
Daniel L
DL
Villeneuve
US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Athens, GA 30605, USA.
Timothy W
TW
Collette
US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposures Research Division, Cincinnati, OH, USA.
David C
DC
Bencic
US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, Duluth, MN, USA.
Gerald T
GT
Ankley
US Army Engineer Research and Development Center, Vicksburg, MS 39180, USA.
Edward J
EJ
Perkins
D000728:Androgens / Q000097:blood; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D003530:Cyprinidae / Q000235:genetics* / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D017316:Fadrozole / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006003:Glycogen / Q000097:blood; D006801:Humans; D008297:Male; D055432:Metabolomics; D013654:Taurine / Q000097:blood; D013739:Testosterone / Q000097:blood; D059467:Transcriptome / Q000187:drug effects; D014819:Vitellogenins / Q000097:blood
D000728:Androgens; D047072:Aromatase Inhibitors; D014819:Vitellogenins; D013654:Taurine; D013739:Testosterone; D004958:Estradiol; D006003:Glycogen; D001141:Aromatase; D017316:Fadrozole
Aromatase; Fadrozole; Fathead minnow; Integrative analysis; Metabolomics; Transcriptomics