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Extramural Research

2004 Progress Report: Developmental Neurotoxicity in Offspring Induced by Combined Maternal Exposure of Rats to Nicotine and Chlorpyrifos

EPA Grant Number: R829399
Title: Developmental Neurotoxicity in Offspring Induced by Combined Maternal Exposure of Rats to Nicotine and Chlorpyrifos
Investigators: Abou-Donia, Mohamed B.
Institution: Duke University Medical Center
EPA Project Officer: Laessig, Susan A.
Project Period: October 1, 2001 through September 30, 2004
Project Period Covered by this Report: October 1, 2003 through September 30, 2004
Project Amount: $750,000
RFA: Children's Vulnerability to Toxic Substances in the Environment (2001)
Research Category: Children's Health , Health Effects , Human Health

Description:

Objective:

The objective of this research project is to test the hypothesis that combined exposure to nicotine and chlorpyrifos (CPF) during the critical periods of development of cholinergic pathways in the central nervous system (CNS) disrupts the structural organization of the cholinergic system and interferes with cholinergic transmission, resulting in neurologic deficits such as impairments in learning and memory performance.

Progress Summary:

In the present studies, postnatal day (PND) 90 offspring were evaluated for neurochemical, neurobehavioral, and neuropathological alterations following maternal exposure to nicotine and CPF, alone and in combination. Timed pregnant Sprague-Dawley rats (300-350 g) were treated daily with nicotine (3.3 mg/kg, in bacteriostatic water via s.c. implantation of a mini osmotic pump), CPF (1.0 mg/kg, dermal, ethanol), or a combination of nicotine and CPF on gestational days 4-20. Control animals were treated with bacteriostatic water via s.c. implantation of a mini osmotic pump and dermal application of ethanol. PND 90 offspring were evaluated for neurobehavioral performance, changes in the ligand binding for α7 and α4β2 nicotinic acetylcholine receptors, and neuropathological alterations in the cerebellum. Beam-walk time, incline plane, and forepaw grip strength showed significant impairments in both male and female offspring from mothers treated with nicotine and CPF, alone or in combination. Male offspring showed greater deficits in behavioral performance than female offspring. Female offspring from mothers treated with a combination of nicotine and CPF showed a significant increase in plasma butyrylcholinesterase activity. Brain regional acetylcholinesterase (AChE) activity showed differential changes in male and female offspring. The brainstem and cerebellum of female offspring from mothers treated with nicotine or CPF, alone or in combination, showed a significant increase, whereas the brainstem of male offspring from mothers treated with nicotine alone or a combination of nicotine and CPF showed a significant increase in AChE. Histopathological evaluations using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum. An increase in glial fibrillary acidic protein (GFAP) immunostaining was observed in cerebellum white matter as well as the granular cell layer of the cerebellum. These data suggest that maternal exposure to nicotine and CPF, alone and in combination, produces neurobehavioral deficits in male and female offspring, a decrease in the surviving neurons, and increased expression of GFAP in the cerebellum of the offspring at PND 90.

Future Activities:

In the next year, we will study the mechanism(s) of neurological abnormalities in a dose-dependent manner due to combined exposure to nicotine and chloprpyrifos.


Journal Articles on this Report : 3 Displayed | Download in RIS Format

Other project views: All 9 publications 3 publications in selected types All 3 journal articles

Type Citation Project Document Sources
Journal Article Abdel-Rahman A, Dechkovskaia A, Mehta-Simmons H, Guan X, Khan W, Abou-Donia M. Increased expression of glial fibrillary acidic protein in cerebellum and hippocampus: differential effects on neonatal brain regional acetylcholinesterase following maternal exposure to combined chlorpyrifos and nicotine. Journal of Toxicology and Environmental Health, Part A 2003;66(21):2047-2066. R829399 (2003)
R829399 (2004)
R829399 (Final)
  • Abstract from PubMed
  • Journal Article Abdel-Rahman A, Dechkovskaia AM, Mehta-Simmons H, Sutton JM, Guan X, Khan WA, Abou-Donia MB. Maternal exposure to nicotine and chlorpyrifos, alone and in combination leads to persistently elevated expression of glial fibrilary acidic protein in the cerebellum of the offspring at late puberty. Archives of Toxicology 2004;78(8):467-476. R829399 (2004)
    R829399 (Final)
  • Abstract from PubMed
  • Journal Article Abou-Donia MB, Abdel-Rahman A, Goldstein LB, Dechkovskaia AM, Shah DU, Bullman SL, Khan WA. Sensorimotor deficits and increased brain nicotinic acetylcholine receptors following exposure to chlorpyrifos and/or nicotine in rats. Archives of Toxicology 2003;77(8):452-458. R829399 (2002)
    R829399 (2003)
    R829399 (2004)
    R829399 (Final)
  • Abstract from PubMed
  • Full-text: SpringerLink Full Text
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  • Supplemental Keywords:

    risk assessment, indoor, smoking, infants, neuropathological damage, vulnerable, pregnancy, organophosphorous, chlorpyrifos, nicotine, acetylcholinesterase, muscarinic acetylcholine receptor, nicotinic acetylcholine receptor, neurotoxicity, combined exposure, glial fibrillary acidic protein, cerebellum, genetic susceptibility, children, cigarette smoke, developmental neurotoxicity, developmental toxicants, indoor air, maternal exposure, sensitive populations, tobacco smoke, toxics, health, children’s health, health risk assessment, susceptibility/sensitive population/genetic susceptibility, toxicology, assessment of exposure,, RFA, Health, Scientific Discipline, Toxicology, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, sensitive populations, infants, vulnerability, developmental neurotoxicity, chlorpyrifos, children, neurotoxicity, assessment of exposure, indoor air, cigarette smoke, Nicotine, pregnancy, tobacco smoke, toxics, maternal exposure, developmental toxicants

    Progress and Final Reports:
    Original Abstract
    2002 Progress Report
    2003 Progress Report
    Final Report

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