The effect of in vivo glutathione depletion with buthionine sulfoximine on rat embryo development

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Abstract
Glutathione is an abundant endogenous nucleophile whose depletion may have adverse effects on a number of cellular processes, including protein and DNA synthesis, amino acid transport, and detoxification of reactive electrophiles. Previous studies have indicated that a certain basal level of glutathione is essential for normal development in vitro in the whole rat embryo culture system. The objective of this study was to determine the effect of glutathione depletion with buthionine sulfoximine on the development of rat embryos in vivo. Timed pregnant Sprague-Dawley rats were treated by gavage on days 10 and 11 of gestation with saline (control) or with L-buthionine-(S,R)-sulfoximine (4 or 8 mmol/kg). Pregnancy outcome was assessed on day 12 or day 20 of gestation. The glutathione content of embryos and of maternal organs was measured on day 12. Glutathione concentrations were significantly decreased in the embryos and in maternal muscle and ovary but not in maternal liver and kidney. Glutathione depletion, when assessed on day 12 of gestation, was found to result in an increase in the numbers of dead and malformed embryos. Treatment with the higher dose of buthionine sulfoximine resulted in the death of 13.2% of the total implanted embryos; of the surviving embryos, 21.7% were malformed. There was also a significant decrease on day 12 after treatment with the higher dose of buthionine sulfoximine in the embryonic total morphological score, a measure of the developmental stage of the embryos (control, 57.7±1.0; 8 mmol/kg buthionine sulfoximine, 52.8±1.8). No significant effect of treatment with either dose of buthionine sulfoximine with respect to growth parameters was observed on day 12 of gestation. Interestingly, no significant effect of treatment with either dose of buthionine sulfoximine on numbers of pups, resorptions, malformations, or fetal weight was found in the litters examined on day 20 of gestation. Thus, after glutathione depletion with buthionine sulfoximine, an increase in malformations and developmental delay is found on day 12 of gestation; however the malformations observed in day 12 embryos apparently do not persist during later development.

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