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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD016358-09
Application #
3313649
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1983-09-01
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Kaufhold, Antje; Nigam, Prabhat K; Dhir, Ravindra N et al. (2002) Prevention of latently expressed CYP2C11, CYP3A2, and growth hormone defects in neonatally monosodium glutamate-treated male rats by the N-methyl-D-aspartate receptor antagonist dizocilpine maleate. J Pharmacol Exp Ther 302:490-6
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) Differential expression of gender-dependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat. J Pharmacol Exp Ther 292:228-37

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