TREATMENT OF RATS DURING PUBERTAL DEVELOPMENT WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ALTERS BOTH SIGNALING KINASE-ACTIVITIES AND EPIDERMAL GROWTH-FACTOR RECEPTOR-BINDING IN THE TESTIS AND THE MOTILITY AND ACROSOMAL REACTION OF SPERM

Different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.1, 1, 5, and 10 mu g/kg body wt) were administered ip to 21-day-old male Sp rague-Dawley rats. Control animals received the same volume of the veh icle (acetone:corn oil, 1:19). Body weight and daily food intake were recorded during the 90-day time course of the study. Random samples of five rats were sacrificed at 34, 49, 62, and 90 days of age. Epiderma l growth factor receptor (EGFR) in whole testis was measured, as were the activities of c-Src kinase, protein tyrosine kinase (PTR), mitogen -activated protein 2 kinase (MAP2K also termed as Erk2), protein kinas e A (PKA), and protein kinase C (PKC). Testicular tissue from 90-day-o ld rats was evaluated for histopathology, and sperm numbers in whole t estis were counted to estimate daily sperm production. The motility of sperm in the vas deferens and caudal segments of the epididymis of 90 -day-old rats was measured by computer assisted sperm analysis (CASA) and the function of the sperm was tested by assessment of acrosome rea ctions. A dose of 10 mu d/kg resulted in testicular atrophy and histop athologic examination revealed a decrease in the diameter of the semin iferous tubules. Sertoli cell nuclei were clearly seen, but the sperma togonial population was totally absent. Lower doses of TCDD did not af fect testicular histology, but doses as low as 1 mu g/kg significantly decreased testicular sperm numbers and affected some sperm functions (motility parameters and acrosome reactions) in 90-day-old rats. Signi ficant decreases in EGFR were found in 34-day-old rats and this effect on EGFR was sustained until the end of the experiment (90 days). Alth ough TCDD significantly increased c-Src kinase activity in immature an d mature rats, opposite effects of TCDD on activities of PTK, PKA, and PKC were found in 34-day-old rats vs 49-, 62-, and 90-day-old rats. W hen 10 mu g TCDD/kg was administered to 21-day-old rat, 24-h after c-S rc kinase inhibitor geldanamycin, there was no testicular atrophy and no change in the daily sperm production was found. These findings prov ide evidence for involvement of Src kinase signaling and EGFR in the m echanism by which TCDD disrupts testicular development and subsequentl y affects testis function. (C) Academic Press.