Posttesticular antifertility action of triptolide in the male rat: Evidence for severe impairment of cauda epididymal sperm ultrastructure

A variety of active diterpene epoxides, including the triptolide (isolated from Tripterygium wilfordii) have been reported to cause infertility in mal e rats. Previously, we showed that oral administration of triptolide at a d osage of 100 mu g/kg per body weight for 70 days completely inhibited ferti lity in male rats, with little or no demonstrable detrimental effect on spe rmatogenesis and Leydig cell function as determined by testicular light mic roscopic appearance and serum and intratesticular testosterone levels. Desp ite the apparent absence of effects on the testes, cauda epididymal sperm w ere abnormal, with complete cessation of sperm motility and some reduction in sperm numbers. This study was undertaken to provide additional insight i nto the subcellular sites and possible mechanisms of action of this compoun d using ultrastructural analysis of the testes and epididymidis. The most s triking effect of triptolide treatment was observed in sperm in the epididy mis. In rats rendered infertile with 100 mu g/kg per body weight of triptol ide daily for 70 days, virtually all cauda epididymal sperm exhibited compl ete absence of plasma membrane over the entire middle and principal piece, premature decondensation of the nuclei, and disorganization of the mitochon drial sheath with many vacuolated mitochondria. No ultrastructural differen ces in the epididymal epithelium were observed between control and triptoli de-treated rats. The testes appeared to be mildly affected after triptolide treatment but exhibited only subtle ultrastructural defects in the germ ce lls. The findings of severe impairment of cauda epididymal sperm ultrastruc ture, along with minimal discernible abnormalities in the fine structural c ytology of the testes, further suggest that the site of action of this comp ound is posttesticular and may be confined to the cauda epididymal sperm. H owever, we cannot rule out an effect of triptolide that occurs during germ cell maturation but is delayed in its manifestation or triggered at the ret e testis and epididymal level.