Whereas peripartum consumption of drugs may be therapeutic, or at least nontoxic to the mother, they could produce irreparable damage to the unborn child. It has become almost axiomatic to define a teratogen as a substance capable of producing a structural malformation. Although often overlooked, due to their less dramatic (ie, visible) effects, it is now becoming apparent that many drugs as well as environmental chemicals can also produce more subtle biochemical and physiological teratogenic defects in the fetus. While these may be """"""""delayed"""""""" defects that are not apparent at birth or even during childhood, they are both long term and permanent defects. As a preponderance of drugs and environmental chemicals easily pass through the placental """"""""barrier"""""""" as well as the mammary epithelium into the milk, susceptibility to the teratogenic effects of maternally administered drugs continues from conception, through fetal development, parturition and during nursing. We have demonstrated that perinatal exposure to therapeutic or dietary-like levels of phenobarbital (PB), monosodium glutamate (MSG) and monosodium aspartate (MSA) can produce delayed, but permanent defects in the drug metabolizing enzyme system that unknowingly could compromise the efficacy of drug therapy or the susceptibility to chemically-induced cancers in adulthood. In some cases the defects are """"""""silent"""""""" and could only be expressed when the system was challenged with an inducing agent. Using MSG and PB as paradigms of """"""""soft"""""""" teratogens, we now propose to investigate our hypothesis that at the time of perinatal exposure, these compounds interfere with the differentiation of the """"""""pituitary growth hormone (GH)-hepatic p450 axis"""""""" resulting in a permanent disruption in the normal responsiveness of hepatic P450 isoforms to GH regulation. By measuring expression levels of hepatic isoforms of P450 in transplanted hepatocytes and GH-manipulated neonatally MSG- and PB-exposed rats we plan to determine: 1) how teratogens induce their defects at the time of exposure and 2) identify the actual defects responsible for the abnormal drug metabolism in adulthood.
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