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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Pharmacology A Study Section (PHRA)
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University of Pennsylvania
Schools of Veterinary Medicine
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Agrawal, Arun K; Shapiro, Bernard H (2005) Neonatal phenobarbital imprints overexpression of cytochromes P450 with associated increase in tumorigenesis and reduced life span. FASEB J 19:470-2
Sharma, Meena R; Periandythevar, Parameswaran; Shapiro, Bernard H (2003) Spurious observation of splenic cyp2b1 expression. Drug Metab Dispos 31:1074-6
Agrawal, Arun K; Shapiro, Bernard H (2003) Constitutive and inducible hepatic cytochrome P450 isoforms in senescent male and female rats and response to low-dose phenobarbital. Drug Metab Dispos 31:612-9
Agrawal, Arun K; Shapiro, Bernard H (2003) Phenobarbital-imprinted overinduction of adult constituent CYP isoforms. Pharmacology 68:204-15
Dhir, Ravindra N; Dworakowski, Wojciech; Shapiro, Bernard H (2002) Middle-age alterations in the sexually dimorphic plasma growth hormone profiles: involvement of growth hormone-releasing factor and effects on cytochrome p450 expression. Drug Metab Dispos 30:141-7
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Agrawal, A K; Shapiro, B H (2001) Intrinsic signals in the sexually dimorphic circulating growth hormone profiles of the rat. Mol Cell Endocrinol 173:167-81
Garcia, M C; Thangavel, C; Shapiro, B H (2001) Epidermal growth factor regulation of female-dependent CYP2A1 and CYP2C12 in primary rat hepatocyte culture. Drug Metab Dispos 29:111-20
Pampori, N A; Agrawal, A K; Shapiro, B H (2001) Infusion of gender-dependent plasma growth hormone profiles into intact rats: effects of subcutaneous, intraperitoneal, and intravenous routes of rat and human growth hormone on endogenous circulating growth hormone profiles and expression of sexually dim Drug Metab Dispos 29:8-16
Agrawal, A K; Shapiro, B H (2000) Latent overexpression of hepatic CYP2C7 in adult male and female rats neonatally exposed to phenobarbital: a developmental profile of gender-dependent P450s. J Pharmacol Exp Ther 293:1027-33

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