The basis for this project is the hypothesis that developmental stage and normally benign moderate deficiencies in metabolism of compounds may combine in certain individuals to predispose abnormally high risk of mutation from exposure to single or multiple chemicals. Parameters associated with this hypothesis will be tested using a transgenic marker for mutation in normal C57BL/6 mice and in mice deficient for UDP-glucuronosyltransferase enzyme activity. The deficiency is a close parallel for Gilbert's Syndrome which affects about 5-7% of the human population. The hypothesis will be tested using a new and unique mouse mutation (hub) that we have identified and characterized as a deficiency in UDP-glucuronosyltransferase activity. The mutation is characterized by an autosomal recessive transient neonatal jaundice; Gilbert's syndrome is a close parallel in the human population. Recessive females have elevated estradiol levels and mammary deficiency; young males have elevated estradiol and reduced testosterone. Affected individuals of both sexes have liver hyperplasia associated with increased mitosis, cytomegaly, and single cell necrosis; a pleiotropic characteristic that has particular interest, is the presence of many hepatic eosinophilic foci. Our goals are to 1) evaluate the effect of the deficiency on spontaneous and induced somatic mutagenesis and 2) determine whether deficient individuals are hypersensitive to induced tumorgenesis. Mice carrying the recessive deficiency have been made transgenic for a recoverable phage mutation marker. Mice that are homozygous for both the deficiency and the marker will be used to investigate the potential for increased sensitivity to both mutagenic and carcinogenic agents among deficient individuals as a function of dose and developmental stage.
