Developmental toxicity of bromohydroquinone (BHQ) and BHQ-glutathione conjugates in vivo and in whole embryo culture.
Glutathione conjugates of 2-bromohydroquinone (GSyl-BHQ) cause renal proximal tubular necrosis that is dependent upon the activity of gamma-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 mumol/kg BHQ or 20 mumol/kg 2-Br-(di-GSyl)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-GSyl)HQ was nephrotoxic but not dysmorphogenic at the dose tested (20 mumol/kg). We therefore exposed Day 9 rat embryos to BHQ, 2-Br-6-(GSyl)HQ, or 2-Br-(di-GSyl)HQ in vitro for 48 hr to determine the relative dysmorphogenic activity of the parent compounds and the two conjugates. In vitro exposure to BHQ (0-40 microM) 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 microM BHQ was embryolethal. Embryos exposed to 2-Br-6-(GSyl)HQ (0-120 microM) were not affected at concentrations below 120 microM, 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 microM concentration and significantly lower YSD, protein, and DEVSC and significantly higher %AE at the 10, 25, and 120 microM 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-GSyl)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.
Andrews
J E
JE
Developmental Toxicology Division, USEPA, Research Triangle Park, North Carolina 27711.
Rogers
J M
JM
Ebron-McCoy
M
M
Logsdon
T R
TR
Monks
T J
TJ
Lau
S S
SS
D000818:Animals; D046508:Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005978:Glutathione / Q000633:toxicity*; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D006873:Hydroquinones; D007555:Isoxazoles; C042377:2-bromohydroquinone; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin