Histopathology and histomorphometry of the urogenital tract in 15-month old male and female rats treated neonatally with SERMs and estrogens.
In this study, two selective estrogen receptor modulators (SERMs), tamoxifen (TAM) and toremifene (TOR) or two estrogens, ethinylestradiol (EE) and diethylstilbestrol (DES) were administered to newborn male and female Sprague-Dawley rats (days 1-5) to investigate the occurrence of developmental abnormalities in the adulthood. The compounds were dosed (s.c.) at an equimolar dose of 24.9 micromol/kg. During the follow-up period, mortality occurred mainly in DES-treated male rats (3/4), associated with obstructive urinary calculi and suppurative renal inflammation in 2/3 rats. Similar lesions were not evident in other groups. At the age of 15 months, the animals were necropsied and organs were collected for histopathology and histomorphometry. Treatment-related abnormalities were restricted to the reproductive organs. Chronic prostatitis and epithelial abnormalities in the vas deferens were observed in all treatment groups. The columnar epithelium of vas deferens showed hyperplasia and development of subepithelial glandular structures resembling epididymal cysts reported in humans exposed in utero to DES. Testicular atrophy was observed especially in estrogen-treated rats. Mainly in SERM-treated female rats, the uterus showed luminal dilation or obstruction, loss of endometrial glands and myometrium disorganization including foci of muscular disruption. TOR-treated female rats showed polyp-like nodules (incidence 4/15) and a high incidence (9/15) of a simple cuboidal epithelium in cervical regions normally occupied by multilayered epithelia. In conclusion, the vas deferens is a main target organ following neonatal administration of SERMs and estrogens. In addition, female rats were significantly more susceptible to SERM treatment than to treatment with estrogens.
Karlsson
Stefan
S
Orion Pharma, Department of Toxicology, P.O. Box 425, FIN-20101 Turku, Finland. stefan.karlsson@orionpharma.com
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004054:Diethylstilbestrol / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000633:toxicity; D005260:Female; D052776:Female Urogenital Diseases / Q000139:chemically induced / Q000401:mortality / Q000473:pathology*; D008136:Longevity / Q000187:drug effects; D008297:Male; D052801:Male Urogenital Diseases; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000401:mortality / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity*; D015996:Survival Rate; D013629:Tamoxifen / Q000633:toxicity; D017312:Toremifene / Q000633:toxicity; D014545:Urinary Calculi / Q000139:chemically induced / Q000401:mortality / Q000473:pathology; D014566:Urogenital System / Q000187:drug effects* / Q000473:pathology; D014649:Vas Deferens / Q000187:drug effects / Q000473:pathology
D004967:Estrogens; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D004997:Ethinyl Estradiol; D004054:Diethylstilbestrol; D017312:Toremifene