Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 2). Testicular toxicity in rats treated orally with ethinylestradiol for 2 weeks.
Parameters of ethinylestradiol-induced testicular toxicity were evaluated with organ weight determination, histopathological examination and quantitative morphometry. Male Sprague-Dawley rats were administered ethinylestradiol orally at 3 or 10 mg/kg/day for 2 weeks and 3 mg/kg/day for 4 weeks. Final body weights in all treated groups were lower than in the respective control group. Decreased absolute and/or relative organ weights of epididymides, prostate, seminal vesicles and testes were observed in all treated groups. In the testes, apoptosis of round spermatids, atrophy of seminiferous tubules, exfoliation of spermatids or spermatocytes, and vacuolar degeneration of Sertoli cells were only observed with 4 weeks treatment. Apoptosis of pachytene spermatocytes and atrophy of Leydig cells were also more marked in the 4 week treated group than after 2 weeks. Therefore, degenerative histopathological changes in testes were more remarkable after 4 weeks treatment than in the 2 weeks treatment groups. However, retention of spermatids was less after 4 weeks treatment and the TUNEL index, calculated as the number of TUNEL-positive spermatocytes or spermatids, was increased in all treated groups. These results suggest that ethinylestradiol-induced testicular toxicity can be detected in male rats administered the compound for 2 weeks and that the TUNEL method for in situ detection of apoptosis is effective for evaluation of testicular toxicity.
Miyamoto
Y
Y
Safety Assessment Laboratory, Pharmaceuticals Research Laboratories, Toray Industries, Inc., 3-1-2 Sonoyama, Otsu, Shiga 520-0842, Japan.
Ueda
K
K
Oshida
K
K
Ohmori
E
E
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D045166:Estradiol Congeners / Q000008:administration & dosage / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D009929:Organ Size / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018675:Toxicity Tests
D045166:Estradiol Congeners; D018809:Proliferating Cell Nuclear Antigen; D004997:Ethinyl Estradiol; D004247:DNA