Glutathione conjugates of 2-bromohydroquinone (GSylBHQ) cause renal proximal tubular necrosis that is dependent upon the activity of γ-glutamyl transferase (GGT). GGT is present in embryonic yolk sac and its activity increases with gestational age, suggesting that the developing embryo might be at risk from maternal exposure to glutathione conjugates or compounds which are shown to form glutathione conjugates. Studies in pregnant rats exposed on Day 9 of gestation to 400 or 800 μmol/kg BHQ or 20 μmol/kg 2-Br-(di-GSyI)HQ and examined on Day 11 of gestation suggested that the parent compound (BHQ) or a metabolite was nephrotoxic in the adult and dysmorphogenic in the embryo and that 2-Br-(di-GSyJ)HQ was nephrotoxic but not dysmorphogenic at the dose tested (20 μmol/kg). We therefore exposed Day 9 rat embryos to BHQ, 2-Br-6-(GSyl)HQ, or 2-Br-(di-GSyI)HQ in vitro for 48 hr to determine the relative dysmorphogenic activity of the parent compound and the two conjugates. In vitro exposure to BHQ (0-40 μM) resulted in dose-related decreases in somite number (SN), total protein, and developmental score (DEVSC), with no effect on yolk sac diameter (YSD), crown rump length (CR), head length (HL), or percentage abnormal embryos (%AE); 60 μM BHQ was embryolethal. Embryos exposed to 2-Br-6-(GSyl)HQ (0-120 μM) were not affected at concentrations below 120 μM, at which dose there were significant effects on protein. YSD, CR, HL, DEVSC, SN, and %AE. Embryos exposed to 2-Br-(di-GSyl)HQ had a significantly lower DEVSC at the 80 μM concentration and significantly lower YSD, protein, and DEVSC and significantly higher %AE at the 10, 25, and 120 μM concentrations. CR, HL, and SN were not affected at any exposure level with this compound. In conclusion, BHQ was found to be developmentally toxic in vitro and in vivo at doses which also produced severe maternal renal necrosis. The doses of 2-Br-(di-GSyI)HQ in vivo which caused only mild maternal renal necrosis did not produce developmental toxicity. Conjugation of BHQ with either one or two molecules of GSH decreased the embryolethality of BHQ. The conjugates appeared to be of comparable toxicity as measured by the incidence of abnormal embryos in vitro. The role of maternal toxicity and GSH conjugation in 2-BHQ-mediated developmental toxicity remains to be determined.
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