Differential alteration by thalidomide of the glutathione content of rat vs. rabbit conceptuses in vitro

Thalidomide has been shown to cause Limb reduction defects in rabbits with much greater potency than in rats, possibly due to inherent biochemical dif ferences between the two species. Whole embryo culture was used to make dir ect comparisons between thalidomide-sensitive New Zealand White rabbits and thalidomide-resistant Sprague-Dawley rats, focusing on the possible roles of,glutathione (GSH) and cysteine in mechanisms of thalidomide teratogenici ty. Conceptuses were treated by adding thalidomide (0, 5, 15, and 30 mu M) directly to the culture media containing conceptuses of similar gestational stages. Embryos and visceral yolk sacs (VYS) were measured for changes in GSH and cysteine content using HPLC after 24 h of exposure in vitro. Thalid omide-induced (15 and 30 mu M) depletion of VYS GSH occurred only in the ra bbit, where GSH concentrations (pmol/mu g protein) fell significantly to ab out 50% of control. Rat VYS did not show a significant GSH depletion at any thalidomide concentration tested. Comparison between species showed that t he control rabbit VYS contained 35% less GSH than the control rat VYS. Cont rol rat embryos and control rabbit embryos contained similar concentrations of GSH, but thalidomide treatment preferentially depleted GSH in the rabbi t at lower thalidomide concentrations (5 mu M). Cysteine concentrations wer e not significantly altered from control in the embryo or VYS of either spe cies when treated with thalidomide. However, although control cysteine conc entrations did not differ significantly between rat and rabbit VYS, control cysteine levels in rabbit embryos were 65% lower than those in control rat embryos. Rabbit conceptuses displayed lower species-specific GSH and cyste ine levels and a greater propensity for thalidomide-induced GSH depletion t han in rat conceptuses, consistent with the greater sensitivity of the rabb it to thalidomide teratogenicity. These thalidomide-induced and inherent sp ecies differences implicate a possible role for GSH and redox status in the mechanisms of thalidomide teratogenicity. (C) 1999 Elsevier Science Inc. A ll rights reserved.