SENSITIVITY OF A TIER-I SCREENING BATTERY COMPARED TO AN IN-UTERO EXPOSURE FOR DETECTING THE ESTROGEN-RECEPTOR AGONIST 17-BETA-ESTRADIOL

A Tier I screening battery for detecting endocrine active compounds (E ACs) has been evaluated for its ability to identify 17 beta-estradiol, a pure estrogen receptor agonist. In addition, the responses obtained with the Tier I battery were compared to the responses obtained from F-1 generation rats from a 90-day/one-generation reproduction study wi th 17 beta-estradiol in order to characterize the sensitivity of the T ier I battery against the sensitivity of an in utero exposure for dete cting EACs. The Tier I battery incorporates two short-term in vivo tes ts (5-day ovariectomized female battery; 15-day intact male battery) a nd an in vitro yeast transactivation system (YTS) for identifying comp ounds that alter endocrine homeostasis. The Tier I female battery cons ists of traditional uterotrophic endpoints coupled with biochemical an d hormonal endpoints. It is designed to identify compounds that are es trogenic/antiestrogenic or modulate dopamine levels. The Tier I male b attery consists of organ weights coupled with microscopic evaluations and a comprehensive hormonal assessment. It is designed to identify co mpounds that have the potential to act as agonists or antagonists to t he estrogen, androgen, progesterone, or dopamine receptor; steroid bio synthesis inhibitors (aromatase, 5 alpha-reductase, and testosterone b iosynthesis); or compounds that alter thyroid function. The YTS is des igned to identify compounds that bind to steroid hormone receptors (es trogen, androgen, and progesterone) and activate gene transcription. T he profile generated for 17 beta-estradiol was characteristic of the r esponses expected with a pure estrogen receptor agonist. In the female battery, responses to 17 beta-estradiol included increases in uterine fluid imbibition, uterine weight, estrus conversion, uterine stromal cell proliferation, uterine epithelial cell height, uterine progestero ne receptor content, serum prolactin and estradiol levels, and decreas es in uterine estrogen receptor content and follicle stimulating hormo ne and luteinizing hormone levels. In the male battery, responses to 1 7 beta-estradiol included decreases in absolute testis and epididymide s weights, decreases in relative weights for androgen-dependent tissue s (prostate, seminal vesicles, and accessory sex gland unit), hormonal alterations (decreased serum testosterone, dihydrotestosterone, and L H and increased serum prolactin levels), and microscopic alterations o f the testis and epididymides. In the YTS for the estrogen receptor, 1 7 beta-estradiol had an EC50 value of 7.2 x 10(-9) M, while DHT and pr ogesterone had little cross-activation. The androgen and progesterone receptor systems were less selective in that 17 beta-estradiol activat ed these systems within 3 orders of magnitude of the primary ligand. I n the 90-day/one-generation reproduction study, responses to dietary a dministration of 17 beta-estradiol included alterations in organ weigh ts, developmental landmarks, and hormonal levels. Comparison of the re sponses obtained with our Tier I battery and an in utero exposure demo nstrates that the Tier I screening battery is as sensitive as an in ut ero exposure for detecting 17 beta-estradiol-induced alterations in ho rmonal homeostasis. (C) 1998 Society of Toxicology.