EFFECTS OF 17-BETA-ESTRADIOL ON SERUM HORMONE CONCENTRATIONS AND ESTROUS-CYCLE IN FEMALE CRL-CD BR RATS - EFFECTS ON PARENTAL AND FIRST-GENERATION RATS

The recently passed Food Quality Protection Act of 1996 requires the U .S. EPA to implement screening strategies for endocrine active compoun ds (EACs) within the next 2 years. Interpreting results from screening tests is complicated by the absence of traditional dietary rodent bio assay data with model estrogenic compounds such as 17 beta-estradiol. Thus, a 90-day/one-generation reproduction study with 17 beta-estradio l was designed to: (1) provide such baseline data; (2) set dose levels for multigeneration reproduction and combined chronic toxicity/oncoge nicity studies; and (3) evaluate various mechanistic/biochemical endpo ints for inclusion in these follow-up studies. The current article des cribes the effects of dietary administration of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol on the serum hormone concentrations and estro us cyclicity of female Crl:CD BR rats and evaluates a sampling strateg y for measuring serum hormone levels in cycling female rats. Serum hor mones were measured at three time points during a 90-day dietary expos ure (1 week, 28 days, and 90 days) and in the F-1 generation rats on p ostnatal day 98. Over the course of the 90-day feeding study for the P -1 generation and from postnatal days 21 to 98 for the F-1 generation, the estrous cycle was monitored daily in 10 rats/group. In P-1 genera tion rats, dietary administration of 2.5, 10, and 50 ppm 17 beta-estra diol produced a dose-dependent increase in serum estradiol (E2) concen trations at all time points. In contrast, administration of 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol produced a dose-dependent decrease i n serum progesterone (P4) concentrations on test day 90, which correla ted with an absence of corpora lutea and ovarian atrophy. At 10 and 50 ppm 17 beta-estradiol, serum luteinizing hormone (LH) concentrations were consistently decreased at all time points and were decreased at 2 .5 ppm on test day 90. Serum prolactin (PRL) concentrations were incre ased at 50 ppm 17 beta-estradiol on test day 90. Serum follicle stimul ating hormone (FSH) concentrations were either similar to the control levels or minimally changed at all time points. No F-1 generation rats were produced at 10 or 50 ppm 17 beta-estradiol. In F-1 generation ra ts, serum E2 concentrations were increased and P4 concentrations were decreased at a dietary concentration of 2.5 ppm 17 beta-estradiol, whi le serum concentrations of LH, FSH, and PRL were similar to the contro l. Dietary administration of 17 beta-estradiol at concentrations of 2. 5 (both generations) and 10 and 50 ppm (P-1 generation only) produced marked effects on the estrous cycle: decreased number of cycles, incre ased mean cycle length, and decreased number of normally cycling rats. The estrous cyclicity of rats fed 2.5 ppm 17 beta-estradiol appeared more severely affected in rats of the F-1 generation than in rats of t he P-1 generation. Whether this increase in severity is related to an in utero exposure and/or greater mean daily intake of 17 beta-estradio l in the F-1 generation rats in the postnatal period is unclear. Anoth er goal of this study was to evaluate whether a single time point samp ling strategy using cycling female rats could be used to detect compou nd-related changes in serum hormone concentrations. In evaluating a sa mpling strategy for measuring serum hormone levels, it appears that de tection of compound-related alterations in serum hormone concentration s can be best detected by sampling during diestrus. Since the stage of the cycle dramatically influences hormone concentrations, large sampl e sizes (n = 50) are needed if serum hormone measurements are not matc hed with the stage of the cycle. The data indicate that this strategy of measuring serum hormone concentrations has utility in detecting com pound-related effects within the confines of a traditional guideline s tudy (subchronic, chronic, or multigenerational reproduction study). ( C) 1998 Society of Toxicology.