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Title: Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research

Abstract

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting thatmore » CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [4];  [5]
  1. Department of Pediatrics, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1 (Canada)
  2. Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba (Canada)
  3. Departments of Internal Medicine and, Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba (Canada)
  4. (Canada)
  5. Department of Pediatrics, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1 (Canada). E-mail: hasans@ucalgary.ca
Publication Date:
OSTI Identifier:
20976832
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 218; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.10.019; PII: S0041-008X(06)00398-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL STRESS; CHEMOTHERAPY; CLEARANCE; CORTICOSTERONE; HUMAN POPULATIONS; INFANTS; NICOTINE; PREGNANCY; RADIATION DOSES; RATS; TOBACCO SMOKES; TOXICITY

Citation Formats

Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, and Hasan, Shabih U. Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.10.019.
Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, & Hasan, Shabih U. Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research. United States. doi:10.1016/j.taap.2006.10.019.
Hussein, Jabeen, Farkas, Svetlana, MacKinnon, Yolanda, Ariano, Robert E., Sitar, Daniel S., Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, and Hasan, Shabih U. Mon . "Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research". United States. doi:10.1016/j.taap.2006.10.019.
@article{osti_20976832,
title = {Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research},
author = {Hussein, Jabeen and Farkas, Svetlana and MacKinnon, Yolanda and Ariano, Robert E. and Sitar, Daniel S. and Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba and Hasan, Shabih U.},
abstractNote = {Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderate to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.},
doi = {10.1016/j.taap.2006.10.019},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 218,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}