DRUG METABOLISM: SUSCEPTIBILITY TO DELAYED TERATOGENESIS

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During the past two decades there has been a dramatic increase in the consumption of drugs by pregnant women. While these drugs may be therapeutic, or at least nontoxic to the mother, they could produce irreparable damage to the unborn child. It has been shown that drugs taken during pregnancy may act as teratogens producing structural malformations in the fetus. Many drugs 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 longterm and permanent defects. As a preponderance of drugs easily pass through the placental "barrier" as well as the mammary epithelium into the milk, the developing mammal remains susceptible to the teratogenic effects of maternally administered drugs from conception, through fetal development, parturition and during nursing. Just as maternal drug consumption can threaten the health of the unborn child, a far more insidious danger may result from the inadvertent exposure of the perinate to a "sea" of pervasive environmental chemicals. Many of the chemicals in our air, water and food supply can cause malformations, and like certain drugs, we have proposed that they may also produce more subtle biochemical defects. In support of our hypothesis, we have found that peripartum exposure to therapeutic or dietary levels of phenytoin, phenobarbital, monosodium glutamate (MSG) and monosodium aspartate (MSA) can all produce latent, but permanent defects in the hepatic monooxygenase system. In some cases the defects are "silent", and are only expressed when the system is challenged with an inducing agent. In future studies we propose to examine two fundamental questions. 1) How do the teratogens induce their defects at the time of exposure? 2) How are the latent defects expressed in adulthood? We plan to examine these questions by a) determining the susceptible forms of P450 and their mRNAs, b) identifying the defects in the induction mechanisms, c) studying the role of endogenous hormones in the induction and expression of the monooxygenase defects, and d) investigating the ability of hormones to reverse the abnormalities.