AN IN-VIVO BATTERY FOR IDENTIFYING ENDOCRINE MODULATORS THAT ARE ESTROGENIC OR DOPAMINE REGULATORS

We have combined several endpoints into a single 5-day in vivo screeni ng procedure to identify estrogenic compounds and dopaminergic modulat ors, both of which play important roles in enhancing mammary tumorigen esis in rodents. The endpoints evaluated as markers of estrogenicity i ncluded increases in uterine fluid and vaginal cornification incidence , serum prolactin levels, uterine weight, uterine epithelial cell heig ht, uterine stromal cell proliferation, and uterine progesterone recep tor (PR) number and decreases in uterine estrogen receptor (ER) number . The endpoints evaluated for changes in dopamine regulation included increases in prolactin and decreases in growth hormone levels. The est rogen agonists estradiol (E2) and estriol (E3), the mixed estrogen ago nist/antagonist tamoxifen (TAM), the full antiestrogen ICI-182,780 (IC I), and the dopamine modulators haloperidol (HAL) and reserpine (RES) were tested using a three-time/day (8-hr intervals) intraperitoneal do sing regimen in sexually mature ovariectomized female Crl:CD BR rats, All compounds were evaluated over a range of concentrations, This in v ivo battery was used to evaluate the effects of different classes of e ndocrine modulators on the selected endpoints, For example, the estrog en receptor agonists E2 and E3 display a unique profile based oil chan ges in the uterotrophic endpoints (estrus conversion, uterine fluid im bibition, increases in uterine weight, and uterine endometrial cell pr oliferation) where full and partial agonists can be distinguished by t he magnitude of these responses, Both the estrogen receptor antagonist ICI and the dopamine modulators HAL and RES tack these uterotrophic r esponses. Dopamine modulators can be distinguished from estrogen recep tor agonists by the profile of increased prolactin levels with no uter otrophic changes, Estrogen receptor antagonists can be distinguished f rom agonists by comparing their effects on ER, PR, and uterotrophic re sponses. For instance, the full estrogen receptor antagonist ICI decre ased ER (to almost 0) and PR levels, but has no uterotrophic effects, while TAM decreases ER (to almost 0) and increases PR with uterotrophi c effects. The most useful endpoints for distinguishing estrogen agoni sts and dopamine modulators were uterine fluid imbibition, uterine wei ght, uterine stromal cell proliferation, and serum prolactin levels, I n order to distinguish an estrogen agonist from an antagonist, other e ndpoints, such as receptor levels, are necessary. The advantage of an in vivo screen is that it utilizes a metabolically and physiologically defined system which is especially important with highly integrative systems such as the endocrine system, This battery can be used as a sc reening tool to identify potential endocrine modulators as well as to identify mode of action following adverse findings in toxicology studi es. Last, additional endpoints may be added to identify other classes of endocrine modulators. (C) 1996 Society of Toxicology