EFFECTS OF DIETARY 17-BETA-ESTRADIOL EXPOSURE ON SERUM HORMONE CONCENTRATIONS AND TESTICULAR PARAMETERS IN MALE CRL-CD BR RATS

A 90-day/lone-generation reproduction study was conducted in male and female Crl:CD BR rats using dietary levels of 0, 0.05, 2.5, 10, and 50 ppm 17 beta-estradiol. The goals of this study were to set dose level s and evaluate several mechanistic endpoints for inclusion in multigen eration reproduction and combined chronic toxicity/oncogenicity studie s with 17 beta-estradiol. In this report we discuss the effects of die tary 17 beta-estradiol exposure on serum hormonal levels and sperm par ameters from P-1 and F-1 male rats. Sperm parameters were also evaluat ed in recovery P-1 and F-1 male rats that were fed control diets for 1 05 and 103 days, respectively, following 97 and 86-94 days of estradio l exposure, respectively. Measurement of Sertoli cell number from F-1 male rats was performed to test the hypothesis that in utero exposure to estrogens will decrease Sertoli cell number and sperm production. O ther findings from this 90-day/one-generation reproduction study are s ummarized elsewhere. 17 beta-Estradiol produced a dose-dependent decre ase in body weight in P-1 male rats at greater than or equal to 2.5 pp m and in the F-1 male rats at 2.5 ppm. This decrease in body weight wa s due to a combination of reduced food consumption and food efficiency . In the recovery P-1 males, body weight increased in the affected gro ups, albiet not to control levels, due to food consumption returning t o control levels accompanied by an increase in food efficiency. Howeve r, in F-1 males there was no corresponding rebound in body weight. In the P-1 rats, exposure to 17 beta-estradiol decreased testis and epidi dymis weights in the 10 and 50 ppm groups, while no effects were seen in the P-1 2.5 ppm group. In contrast, epididymis weights in the F-1 a nd F-1 recovery 2.5 ppm groups were statistically decreased; however, there were no histopathological effects observed. The decreases in tes tis weights in the P-1 generation correlated with histopathologic evid ence of interstitial cell atrophy and seminiferous tubule degeneration and reduced sperm production. Correlative changes in the epididymides of P-1 rats were characterized by oligospermia or aspermia, the prese nce of germ cell debris in the lumen of tubules, and atrophy of epidid ymal tubules. 17 beta-Estradiol decreased testicular spermatid numbers , epididymal sperm numbers, and sperm motility in the P-1 males in the 10 and 50 ppm groups, but not in the 2.5 ppm group. Following a 105-d ay recovery period in the P-1 males, all sperm parameters and reproduc tive organ weights returned to control values except for the epididyma l sperm count. Overall, the decline in testicular spermatid and epidid ymal sperm numbers in the P-1 rats correlated with the reduced organ w eights and the observed histopathological changes and appeared primari ly related to the decrease in serum testosterone levels. In the F-1 ra ts, no significant decreases were noted in the testicular spermatid nu mber but a slight decrease in epididymal sperm number was seen in the 2.5 ppm group, which showed no evidence of recovery. Using morphometri c analysis, no change was seen in the number of Sertoli cell nuclei pe r testis in F-1 males. The pattern of hormonal responses seen in this study was characteristic of an estrogen receptor agonist such as 17 be ta-estradiol: increased serum prolactin and decreased testosterone, lu teinizing hormone, and follicle stimulating hormone levels. The data d emonstrate that in utero and postnatal dietary administration of 17 be ta-estradiol at levels which increased serum estradiol levels to appro ximately 400% of control and decreased testosterone levels to 33% of c ontrol did not reduce the number of Sertoli cell nuclei per testis. (C ) 1998 Society of Toxicology.