Effects of chloro-s-triazine herbicides and metabolites on aromatase activity in various human cell lines and on vitellogenin production in male carp hepatocytes.
We investigated a potential mechanism for the estrogenic properties of three chloro-s-triazine herbicides and six metabolites in vitro in several cell systems. We determined effects on human aromatase (CYP19), the enzyme that converts androgens to estrogens, in H295R (adrenocortical carcinoma), JEG-3 (placental choriocarcinoma), and MCF-7 (breast cancer) cells; we determined effects on estrogen receptor-mediated induction of vitellogenin in primary hepatocyte cultures of adult male carp (Cyprinus carpio). In addition to atrazine, simazine, and propazine, two metabolites--atrazine-desethyl and atrazine-desisopropyl--induced aromatase activity in H295R cells concentration-dependently (0.3-30 microM) and with potencies similar to those of the parent triazines. After a 24-hr exposure to 30 microM of the triazines, an apparent maximum induction of about 2- to 2.5-fold was achieved. The induction responses were confirmed by similar increases in CYP19 mRNA levels, determined by reverse-transcriptase polymerase chain reaction. In JEG-3 cells, where basal aromatase expression is about 15-fold greater than in H295R cells, the induction responses were similar but less pronounced; aromatase expression in MCF-7 cells was neither detectable nor inducible under our culture conditions. The fully dealkylated metabolite atrazine-desethyl-desisopropyl and the three hydroxylated metabolites (2-OH-atrazine-desethyl, -desisopropyl, and -desethyl-desisopropyl) did not induce aromatase activity. None of the triazine herbicides nor their metabolites induced vitellogenin production in male carp hepatocytes; nor did they antagonize the induction of vitellogenin by 100 nM (EC(50) 17beta-estradiol. These findings together with other reports indicate that the estrogenic effects associated with the triazine herbicides in vivo are not estrogen receptor-mediated, but may be explained partly by their ability to induce aromatase in vitro.
Sanderson
J T
JT
Research Institute for Toxicology, Institute for Risk Assessment Sciences, University of Utrecht, 3508 TD Utrecht, The Netherlands. t.sanderson@iras.uu.nl
Letcher
R J
RJ
Heneweer
M
M
Giesy
J P
JP
van den Berg
M
M
D000818:Animals; D001141:Aromatase / Q000187:drug effects / Q000378:metabolism; D001280:Atrazine / Q000009:adverse effects* / Q000378:metabolism; D002347:Carps / Q000502:physiology*; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D006540:Herbicides / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D012839:Simazine / Q000009:adverse effects* / Q000378:metabolism; D014227:Triazines / Q000009:adverse effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014819:Vitellogenins / Q000096:biosynthesis*
D006540:Herbicides; D011960:Receptors, Estrogen; D014227:Triazines; D014819:Vitellogenins; D001141:Aromatase; D001280:Atrazine; D012839:Simazine; C100043:propazine