Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation.
Immature Sprague-Dawley rats received daily doses of indole-3-carbinol (I3C, 0-1.5 g/kg/day), 3,3'-diindolymethane (DIM, 0-400 mg/kg/day), tamoxifen (TAM, 0-0.5 mg/kg/day), or vehicle to determine if their antiestrogenic effects occur by the same mechanism and whether I3C's action is mediated by DIM. Follicular development was induced on day 24 of age by equine chorionic gonadotropin (eCG, 5 IU) 1 day after the initial dose. In a hormone replacement study, human chorionic gonadotropin (hCG, 10 IU sc, 48 h post-eCG) was used to mimic a normal preovulatoy luteinizing hormone (LH) surge following treatment with either I3C or TAM. Blood and ovaries were collected throughout follicular development and the number of ova shed was measured on the morning following expected ovulation (72 h post-eCG). I3C but not TAM reduced body weight gain at higher doses after 4 days of dosing. Ovarian weight gain and ovulation were inhibited by both I3C and TAM in a dose-dependent fashion. During the preovulatory period, both I3C and TAM blocked normal LH and follicle-stimulating hormone (FSH) surges and suppressed serum progesterone (P(4)) profoundly without changing circulating levels of estrogen (E(2)). At the time of expected ovulation, serum E(2) was increased in rats receiving I3C or tamoxifen, whereas serum P(4) was dose-dependently decreased. DIM exerted no significant effects on any of the endpoints studied, even at the highest dose, indicating that the antiestrogenic effects of I3C are not mediated by this metabolite of I3C. hCG successfully restored ovarian weight gain and ovulation in TAM-treated rats. However, hCG only partially reversed the blockage of ovulation by I3C, although ovarian weight gain was restored to normal. In summary, both I3C and TAM block ovulation by altering preovulatory concentrations of LH and FSH, but I3C appears to exert its effect(s) by (a) different mechanism(s) of action. I3C seems to act at both the ovarian and hypothalamic levels by mechanisms similar to those seen in TCDD-treated rats, whereas TAM appears to act only on the hypothalamic-pituitary axis as an anti-estrogen.
Gao
Xin
X
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160, USA.
Petroff
Brian K
BK
Oluola
Okunola
O
Georg
Gunda
G
Terranova
Paul F
PF
Rozman
Karl K
KK
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006062:Gonadotropins / Q000097:blood; D007211:Indoles / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D010060:Ovulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000097:blood; D013629:Tamoxifen / Q000494:pharmacology*
D006062:Gonadotropins; D007211:Indoles; D013256:Steroids; D013629:Tamoxifen; C016517:indole-3-carbinol