2003 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
Current Institution: Duke University Medical Center
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2001 through September 30, 2004
Project Period Covered by this Report: October 1, 2002 through September 30, 2003
Project Amount: $750,000
RFA: Children's Vulnerability to Toxic Substances in the Environment (2001) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Human Health , Health


The objective of this research project is to determine whether combined exposure to nicotine and chlorpyrifos 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 the cholinergic transmission, resulting in neurologic deficits such as impairments in learning and memory performance.

Progress Summary:

We evaluated the neurotoxic effects in the offspring on postnatal day (PND) 60, following maternal exposure with low doses of nicotine and chlorpyrifos. Female Sprague-Dawley rats (300-350 gm) with known pregnancy date were treated daily with nicotine (1mg/kg, s.c., in normal saline) or chlorpyrifos (0.1 mg/kg, dermal, in ethanol) or a combination of nicotine and chlorpyrifos from gestational days 4-20. Control animals were treated with saline and ethanol. On PND 60, the offspring were evaluated for cholinergic changes and pathological effects. Plasma butyrylcholinesterase activity in the female offspring from chlorpyrifos-treated mothers showed a significant increase (~ 183 percent of control). Male offspring from mothers treated with either chlorpyrifos or nicotine alone showed a significant increase in the acetylcholinesterase (AChE) activity in the brainstem while female offspring from mothers treated with either nicotine or a combination of nicotine and chlorpyrifos showed a significant increase (~ 134 and 126 percent of control, respectively) in AChE activity in the brainstem. No significant changes were observed in the ligand binding densities for a4b2 and a7 nicotinic acetylcholine receptors in the cortex. Histopathological evaluation using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum of the offspring from nicotine-treated mothers. An increase in glial fibrillary acidic protein (GFAP) immunostaining was observed in the cerebellum of the offspring from the mothers treated with nicotine. These results suggest that maternal exposure to real-life levels of nicotine and/or chlorpyrifos causes differential regulation of brainstem AChE activity. Also, nicotine caused a decrease in the surviving neurons and an increased expression of GFAP in cerebellum of the offspring on PND 60.

Future Activities:

In the final year of this research project, the developmental neurotoxicity studies in the PND 90 offspring following maternal exposure to nicotine and chlorpyrifos will be completed. These studies will involve biochemical, neuropathological, and behavioral evaluations in the offspring.

Journal Articles on this Report : 2 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 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
  • Other: SpringerLink PDF
  • Supplemental Keywords:

    risk assessment, indoor, smoking, infants, neuropathological damage, vulnerable, pregnancy, organophosphorous, chlorpyrifos, nicotine, acetylcholinesterase, muscarinic acetylcholine receptor, nicotinic acetylcholine receptor, neurotoxicity, combined exposure, smoking, glial fibrillary acidic protein, cerebellum, genetic susceptibility, assessment of exposure, children, cigarette smoke, developmental neurotoxicity, developmental toxicants, indoor air, maternal exposure, neuropathological damage, sensitive populations, tobacco smoke, toxics., 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
  • Final Report