The anti-estrogenicity of Ah receptor agonists in carp (Cyprinus carpio) hepatocytes.
Cultured hepatocytes of female carp (Cyprinus carpio) were coexposed for 4 days to 200 nM 17beta-estradiol (E2), and concentration ranges of nine known Ah receptor (AhR) agonists: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3'4,4'5-pentachlorobiphenyl (PCB 126), 2,3'4,4'5-pentachlorobiphenyl (PCB 118), beta-naphthoflavone (BNF), benzo(a)pyrene (BaP), benzo(a)anthracene (BaA), diindolylmethane (DIM), 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) and hexachlorobenzene (HCB). TCDD caused a greater than 100-fold induction of cytochrome P4501A (CYP1A) activity, measured as ethoxyresorufin O-deethylase (EROD), with an EC50 of 6 pM. Based on EC50 values, the order of potency as CYP1A inducers was TCDD > PCB 126 > BNF > BaP > BaA > PCB 118. DIM and MCDF caused a lower maximum CYP1A induction (< 9-fold), whereas HCB caused no EROD induction at concentrations up to 6 microM. TCDD, PCB 126, BNF, BaP, and DIM also caused a concentration-dependent suppression of the secretion of the yolk protein vitellogenin (Vtg), relative to E2-treated hepatocytes. Suppression of Vtg secretion was not directly correlated with EROD activity, and the antiestrogenic effects occurred at higher concentrations than the induction of CYP1A. This indicates that the anti-estrogenicity was not caused by increased metabolism of E2 due to induction of CYP1A. Nevertheless, the order of potency of the tested compounds for suppression of Vtg secretion was comparable to the order of potency for CYP1A induction. This concurrence suggests that the anti-estrogenicity of these compounds is AhR-mediated, but does not involve CYP1A. This could be relevant for feral fish populations, as they are frequently exposed to AhR agonists, to an extent that AhR-mediated effects are observed.
Smeets
J M
JM
Research Institute of Toxicology, Utrecht University, The Netherlands.
van Holsteijn
I
I
Giesy
J P
JP
van den Berg
M
M
D000818:Animals; D002347:Carps / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D014819:Vitellogenins / Q000378:metabolism
D004965:Estrogen Antagonists; D011506:Proteins; D018336:Receptors, Aryl Hydrocarbon; D014819:Vitellogenins; D004958:Estradiol; D019363:Cytochrome P-450 CYP1A1