It is now well established that neonatal androgen production imprints the metabolism of steroids and many xenobiotics to produce permanent alterations detectable at sexual maturity. These metabolic alterations are produced at the level of the hepatic microsomal mixed function oxidase system (MFOS). This imprinting is different from the normal transitory induction of MFOS activity in that it is permanent and can be detected in the adult animal. This permanent alteration of MFOS activity may not only modify detoxification, but may also modify the susceptibility of an animal to a chemical carcinogen requiring metabolic activation to an ultimate carcinogen. Human neonates may be exposed to a wide variety of xenobiotics through: (1) therapeutic drug usage; (2) direct exposure to environmental xenobiotics; (3) milk from the lactating mother exposed to drugs and environmental xenobiotics; (4) prenatal transplacental exposure. This exposure may produce permanent alterations of xenobiotic biodisposition which could result in increased risks of chronic toxicities such as cancer in adult life. This research will investigate neonatal xenobiotic imprinting from various aspects to understand the phenomena and to assess its ability to alter susceptibility to carcinogens. This will be accomplished through a determination of the basic parameters such as the time course of altered MFOS activity, relationship between neonatal androgen and the xenobiotic in producing imprinting and the possibility of in utero xenobiotic imprinting. The MFOS will be characterized with respect to the activities of its components and substrate specificity when imprinted by either phenobarbital or beta-naphthaflavone. Factors such as sex, species, and genetic differences will be investigated. Imprinted cytochrome P-450s will be investigated with antibodies against subfractionated cytochrome P-450s. Susceptibility to hepatocarcinogens will be determined by the ability of carcinogens to be activated in vivo to DNA binding products and the production of preneoplastic (hyperplastic) foci. This will aid in determining the human health significance of xenobiotic imprinting and understanding the mechanisms of imprinting.
| Bagley, D M; Hayes, J R (1985) Neonatal phenobarbital imprinting of hepatic microsomal enzymes in adult rats: modulation by neonatal testosterone presence. Toxicol Appl Pharmacol 79:227-35 |
| Bagley, D M; Hayes, J R (1985) Xenobiotic imprinting of hepatic metabolic enzyme systems: effect of neonatal 3-methylcholanthrene administration. Biochem Pharmacol 34:2569-73 |
| Bagley, D M; Hayes, J R (1985) Xenobiotic imprinting of the hepatic monooxygenase system. Effects of neonatal phenobarbital administration. Biochem Pharmacol 34:1007-14 |
