Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor

• Published in: Environmental health perspectives 2009-04, Vol.117 (4), p.624-631
• Main Authors: Villeneuve, Daniel L., Mueller, Nathaniel D., Martinović, Dalma, Makynen, Elizabeth A., Kahl, Michael D., Jensen, Kathleen M., Durhan, Elizabeth J., Cavallin, Jenna E., Bencic, David, Ankley, Gerald T.
• Format: Article
• Language: English
• Subjects: Animals; Aromatase Inhibitors - analysis; Aromatase Inhibitors - toxicity; Bioassay; Chemical hazards; Cleaning; Coding; Compensation; Cyprinidae - genetics; Cyprinidae - metabolism; Cytochromes P450; Environmental agencies; Enzymes; Estradiol - analysis; Estradiol - blood; Estrogens; Exposure; Fadrozole - analysis; Fadrozole - toxicity; Female; Females; First appearance datums; Fish; Fishes; Freshwater; Gene Expression Regulation - drug effects; Genetic aspects; Health; Hormones; Hormones - metabolism; Inhibitors; Mathematical models; Messenger RNA; Minnows; Oocytes; Ovaries; Physiological aspects; Pimephales promelas; Polymerase chain reaction; Receptors; Recovery; RNA; RNA, Messenger - metabolism; Steroids; Steroids - blood; Steroids - metabolism; Synthesis; Testosterone - analysis; Testosterone - blood; Toxicity Tests; Vitellogenins - blood; Vitellogenins - drug effects
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.11891

Background: Several chemicals in the environment have the potential to inhibit aromatase, an enzyme critical to estrogen synthesis. Objectives: The objective of this study was to provide a detailed characterization of molecular and biochemical responses of female fathead minnows to a model aromatase inhibitor, fadrozole (FAD). Methods: Fish were exposed via water to 0, 3, or 30 μg FAD/L for 8 days and then held in clean water for 8 days, with samples collected at four time points during each 8-day period. We quantified ex vivo steroid production, plasma steroids, and plasma vitellogenin (Vtg) concentrations and analyzed relative transcript abundance of 10 key regulatory genes in ovaries and 3 in pituitary tissue by real-time polymerase chain reaction. Results: Ex vivo 17β-estradiol (E₂) production and plasma E₂ and Vtg concentrations were significantly reduced after a single day of exposure to 3 μg or 30 μg FAD/L. However, plasma E₂ concentrations recovered by the eighth day of exposure in the 3-μg/L group and within 1 day of cessation of exposure in the 30-μg/L group, indicating concentration- and time-dependent physiologic compensation and recovery. Concentration-dependent increases in transcripts coding for aromatase (A isoform), cytochrome P450 side-chain cleavage, steroidogenic acute regulatory protein, and follicle-stimulating hormone receptor all coincided with increased E₂ production and recovery of plasma E₂ concentrations. Conclusions: Results of this research highlight the need to consider compensation/adaptation and recovery when developing and interpreting short-term bioassays or biomarkers or when trying to predict the effects of chemical exposures based on mode of action.