Dose-response relationships and pharmacokinetics of vitellogenin in rainbow trout after intravascular administration of 17 alpha-ethynylestradiol

A commonly used endpoint in bioassays testing the estrogenicity of chemical s is the induction of the egg yolk precursor vitellogenin (VTG) in male fis h. However, relatively little is known about the kinetics of induction and elimination of VTG in fish exposed to xenoestrogens. In this study, we admi nistered graded intra-arterial doses (0.001, 0.1, 1.0 and 10.0 mg/kg) of 17 alpha -ethynylestradiol (EE,) to male rainbow trout via a dorsal aortic ca nnula which allowed repetitive blood sampling from individual fish for up t o 48 days after injection. The plasma concentrations of VTG was quantified using an enzyme-linked immunosorbent assay procedure and the simultaneous c oncentrations of EE2 were determined by gas chromatography-mass spectrometr y. The pattern of VTG induction was similar for all doses of EE2, with a 12 -h lag-time before increase from basal levels (0.006-0.008 mug/ml), then in creasing sharply to maximum levels within 7-9 days (C-max = 0.05, 711, 1521 and 2547 mug/ml VTG for the 0.001, 0.1, 1.0 and 10.0 mg/kg doses, respecti vely). After induction by EE2 VTG declined mono-exponentially with an elimi nation half-life of 42-49 h. The half-life of VTG increased to 145 h in the 10 mg/kg treated fish. The pharmacokinetics of EE, were distinctly nonline ar with substantial increases in the elimination half-life with increasing dose. The plasma concentration-time profiles of EE, were influenced by ente rohepatic recirculation that caused multiple or secondary peaks in the prof iles. In a separate experiment, the pharmacokinetics of purified VTG was ch aracterized after intra-arterial injection in trout. After direct injection of VTG, plasma levels declined tri-exponentially with an apparent steady-s tate volume of distribution of 837 ml/kg; total body clearance was 31.1 ml/ h per kg, and the elimination half-life was 43.7 h. (C) 2001 Elsevier Scien ce B.V. All rights reserved.