NEONATAL TREATMENT WITH TAMOXIFEN CAUSES IMMEDIATE ALTERATIONS OF THESEXUALLY DIMORPHIC NUCLEUS OF THE PREOPTIC AREA AND MEDIAL PREOPTIC AREA IN MALE RATS

Tamoxifen is an antiestrogen widely used for the treatment of breast c ancer. Current evolutions in preventive strategies to include healthy premenopausal women warrant the study of its developmental toxicity. P erinatal 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 lea st in part, from lesions of the hypothalamic-pituitary axis. The initi al 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 mu g tam oxifen (group 1), 1 mu g DES (group 2) or vehicle (group 3) from PNI t o 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 th e volume and number of neurons in the SDN-POA. Tamoxifen reduced sever ely the volume and neuron numbers in the SDN-POA (46.1% and 47.8% of c ontrols, respectively). The neuronal density of the MPOA was not modif ied. GAP-43 gene expression was decreased as demonstrated by a greater percentage of unlabeled neurons (grade 0) mirrored by a lesser percen tage of intensely labeled ones (grade 2) in the SDN-POA and MPOA. In c ontrast to the effects of the antiestrogen, DES did not affect the abo ve endpoints. These data indicated that developmental exposure of male rat pups to tamoxifen-induced immediate neuronal loss in one and alte red differentiation in two hypothalamic areas crucial to reproduction. How those initial alterations contribute to the pathogenesis of the r eproductive disorders observed in the adult male needs further investi gation. (C) 1997 Wiley-Liss, Inc.