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 detrimental effects 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 a unique mouse mutation (hub) that we have identified and characterized as a deficiency in UDP-glucuronosyltransferase activity. The deficiency is a close parallel for Gilbert's Syndrome which affects about 5-7% of the human population. The mutation phenotype is an autosomal recessive transient neonatal jaundice. Recessive females have elevated estradiol levels and mammary deficiency; young males have elevated estradiol and reduced testosterone. Affected individuals of both sexes have an almost 100% incidence of liver cancer compared with less than 5% of heterozygous littermates. 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 and whether there are interactions between combinations of mutagens and pseudoestrogenic compounds. Mice carrying the 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.
