title: Metabolite profiling and a transcriptional activation assay provide direct evidence of androgen receptor antagonism by bisphenol A in fish.
abstract: Widespread environmental contamination by bisphenol A (BPA) has created the need to fully define its potential toxic mechanisms of action (MOA) to properly assess human health and ecological risks from exposure. Although long recognized as an estrogen receptor (ER) agonist, some data suggest that BPA may also behave as an androgen receptor (AR) antagonist. However, direct evidence of this activity is deficient. To address this knowledge gap, we employed a metabolomic approach using in vivo exposures of fathead minnows (FHM;  Pimephales promelas ) to BPA either alone or in a binary mixture with 17β-trenbolone (TB), a strong AR agonist. Changes in liver metabolite profiles in female FHM in response to these exposures were determined using high resolution (1)H NMR spectroscopy and multivariate and univariate statistics. Using this approach, we observed clear evidence of the ability of BPA to mitigate the impact of TB, consistent with an antiandrogenic MOA. In addition, a transcriptional activation assay with the FHM AR was used to confirm the AR antagonistic activity of BPA in vitro. The results of these in vivo and in vitro analyses provide strong and direct evidence for ascribing an antiandrogenic MOA to BPA in vertebrates.
authors: Ecosystems Research Division, US EPA, Athens, Georgia 30605, United States. ekman.drew@epa.gov
authors: D R
authors: DR
authors: Ekman
authors: P C
authors: PC
authors: Hartig
authors: M
authors: M
authors: Cardon
authors: D M
authors: DM
authors: Skelton
authors: Q
authors: Q
authors: Teng
authors: E J
authors: EJ
authors: Durhan
authors: K M
authors: KM
authors: Jensen
authors: M D
authors: MD
authors: Kahl
authors: D L
authors: DL
authors: Villeneuve
authors: L E
authors: LE
authors: Gray
authors: T W
authors: TW
authors: Collette
authors: G T
authors: GT
authors: Ankley
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003530:Cyprinidae / Q000235:genetics / Q000378:metabolism*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014204:Trenbolone Acetate / Q000494:pharmacology; D000098826:Bisphenol A Compounds
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D001559:Benzhydryl Compounds; D004785:Environmental Pollutants; D010636:Phenols; D011944:Receptors, Androgen; D014204:Trenbolone Acetate; C006780:bisphenol A; D000098826:Bisphenol A Compounds