Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di(2-ethylhexyl)phthalate and the recovery of fertility as adults.

Neonatal and adult rats (1, 2, 3, 6, and 12 weeks of age) were given five daily oral doses of di(2-ethylhexyl) phthalate (DEHP) (0, 10, 100, 1000, 2000 mg/kg) and histological changes in the testes were examined 24 hr after the last dose. Relative testis weights were reduced at doses of 1000 mg/kg in 1, 2, 3, and 6-week-old but not in 12-week-old rats, while doses of 2000 mg/kg were fatal to suckling rats and caused decreased relative testis weight but not death in 6- and 12-week-old rats. In neonatal rats (1 week old), DEHP (1000 mg/kg) caused a 35% decrease in Sertoli cell numbers while 2- and 3-week-old rats showed losses of spermatocytes but not of Sertoli cells. The 6- and 12-week-old rats showed loss of both spermatids and spermatocytes at 1000 and/or 2000 mg/kg. Total testicular zinc concentrations were decreased in 12-week-old but not in suckling (3-week) or weaned (6-week) rats. The results support the hypothesis that the Sertoli cell is the primary testicular target of phthalate ester toxicity since effects were observed at an age when only Sertoli cells were present. Fertility was assessed in mating trials in adult male rats after neonatal exposure to DEHP on Days 6-10. Although Sertoli cell number was reduced 24 hr after the last dose, the numbers were normal at 6 and 13 weeks of age. However, at 6 weeks there was a dose-related decrease in maturation of the spermatids in the tubules. There were no consistent changes in fertility, implantation rate, or numbers of live fetuses in untreated females mated with the DEHP-treated males. However, there were decreases in testis weight and testicular spermatid numbers at 13 and 19 weeks but not at 11, 12, 16, or 23 weeks of age. Therefore, a loss of Sertoli cells due to DEHP exposure neonatally did not affect the fertility of the rats as adults, but may have caused subtle effects on sperm production.