Neonatal treatment with tamoxifen causes immediate alterations of the sexually dimorphic nucleus of the preoptic area and medial preoptic area in male rats.

Tamoxifen is an antiestrogen widely used for the treatment of breast cancer. Current evolutions in preventive strategies to include healthy premenopausal women warrant the study of its developmental toxicity. Perinatal treatment of male rodents with tamoxifen caused reproductive tract lesions and sexual behavior deficits similar to those induced by diethylstilbestrol (DES). Those abnormalities could originate, at least in part, from lesions of the hypothalamic-pituitary axis. The initial alterations caused by tamoxifen in the hypothalamic medial preoptic area (MPOA) and sexually dimorphic nucleus of the preoptic area (SDN-POA) were studied in 6-day-old male rat pups treated with 100 micrograms tamoxifen (group 1), 1 microgram DES (group 2) or vehicle (group 3) from PN1 to 5. In situ hybridization was performed to analyze the expression of the GAP-43 gene, a marker of neuronal differentiation, and morphometry was used to study the neuronal density in the SDN-POA and MPOA and the volume and number of neurons in the SDN-POA. Tamoxifen reduced severely the volume and neuron numbers in the SDN-POA (46.1% and 47.8% of controls, respectively). The neuronal density of the MPOA was not modified. GAP-43 gene expression was decreased as demonstrated by a greater percentage of unlabeled neurons (grade 0) mirrored by a lesser percentage of intensely labeled ones (grade 2) in the SDN-POA and MPOA. In contrast to the effects of the antiestrogen, DES did not affect the above endpoints. These data indicated that developmental exposure of male rat pups to tamoxifen-induced immediate neuronal loss in one and altered differentiation in two hypothalamic areas crucial to reproduction. How those initial alterations contribute to the pathogenesis of the reproductive disorders observed in the adult male needs further investigation.

Initial uterine alterations caused by developmental exposure to tamoxifen.

Neonatal treatment of rodents with the widely used antiestrogen tamoxifen causes endometrial cancer and reproductive tract lesions reminiscent of the diethylstilbestrol (DES) syndrome. To evaluate the initial alterations induced in the developing uterus by tamoxifen or DES, neonatal Sprague-Dawley rat pups received 100 micrograms of tamoxifen (Group 1), 1 microgram of DES (Group 2), or vehicle (Group 3) subcutaneously on days 1 through 5, and their uteri were studied by light microscopy, 5-bromo-2' deoxyuridine immunohistochemistry, and computer-based morphometry. At Postnatal Day 6, epithelial hypertrophy (184.3% and 237.9% of controls) and myometrial thickening (151.9% and 180.0%) accounted for the uterotrophic effects of tamoxifen and DES. Evidence of secretory activity in epithelial cells, reduction of the epithelial BrdU-labeling index to 18.1% (tamoxifen) and 41.1% (DES) of controls, premature endometrial and myometrial differentiation, and the presence of eosinophils in both treatment groups suggested that tamoxifen exerted a DES-like estrogenic action on the developing uterus. These findings indicate that immediate epithelial and stromal-myometrial uterine alterations are found at Postnatal Day 6 after neonatal tamoxifen treatment.