The adrenal steroid products, the glucocorticosteroids, appear to play an important role in the expression of hepatic cytochrome P-450 dependent monooxygenases. These liver monooxygenases are also known to be involved in the metabolic activation of chemicals to form chemically-reactive intermediates capable of altering growth and development. The project will assess the effects that environmental chemicals may have on the function of the human fetal adrenal by measuring adrenal steroid production in cell culture. The various adrenal monooxygenases involved in steroidogenesis will be measured by immunoblotting techniques with antibodies to the monooxygenases and by quantitating the levels of adrenal mRNA by dot blotting with specific cDNA probes. The effects of glucocorticosteroids on the expression of hepatic monooxygenases in culture will be measured by enzyme assay, by immunoblotting techniques with antibodies to the hepatic monooxygenases, and by measurement of the levels of mRNA specific for the monooxygenase with in vitro translation assays. We have observed a synergism in the induction of some hepatic monooxygenase activities by polycyclic aromatic hydrocarbons in the presence of a synthetic glucocorticosteroid, dexamethasone. Other inducing agents will be tested for glucocorticosteroid synergism: barbiturates, catatoxic steroids, TCDD, isosafrole, clofibrate, and ethanol. The biochemical mechanism of the synergistic induction will be studied using modern biochemical techniques. Various aspects of the possible interactions between the adrenal and the liver will be tested to establish whether adrenal steroid-mediated expression of hepatic monooxygenase activity correlates with enhanced DNA damage in culture. The interaction between these two organs will also be tested in vivo to establish the role of adrenal steroids on monooxygenase-mediated toxicity in fetal, neonatal, and adult tissue. The information gained will aid in understanding the general processes involved in the maintenance of the hepatic monooxygenases in vivo.
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