2002 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: Hahn, Intaek
Project Period: October 1, 2001 through September 30, 2004
Project Period Covered by this Report: October 1, 2001 through September 30, 2002
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:

In this research project, we evaluated the neurotoxic effects in the offspring 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 for the gestational days 4-20. Control animals were treated with saline and ethanol.

Following parturition, the body weight and number of litters were recorded. There was no significant difference between the litter size or body weight of the offspring on postnatal days (PND) 2, 9, and 16 between the control and treated groups. Following completion of the lactational period (PND 23), the animals were weighed according to sex. Male offspring from the mothers treated with nicotine alone gained significantly lower weight on PND 30 as compared with the control. On PND 7, there was a significant increase in the brain acetylcholinesterase (AChE) activity in the pups from nicotine and chlorpyrifos group, whereas plasma butyrylcholinesterase (BChE) activity showed a significant increase (approximately 167 and 176 percent of control) from the pups from the mothers treated with either chlorpyrifos alone or in combination with nicotine, respectively.

There was no change in the ligand binding for muscarinic as well as nicotinic acetylcholine receptors in the whole brains from PND 7-day offsprings from any treatment groups. On PND 30, male offspring showed a significant increase in the AChE activity in the brainstem (approximately 134-148 percent of control) and cerebellum (approximately 299-345 percent of control) in all of the treated groups. Females on PND 30 showed a significant increase in the AChE activity in the brainstem of chlorpyrifos alone group and in the cerebellum of the pups from the combination of nicotine and chlorpyrifos. No change was noted in the plasma BChE activity of male or female pups on PND 30. Histopathological evaluation by H&E staining did not show any gross pathological abnormalities.

A significant increase in the immunostaining for glial fibrillary acidic protein was observed in the cortex, the CA1 and CA3 subfields of hippocampus, and dentate gyrus on PND 30 in the pups from nicotine and chlorpyrifos-treated mothers. These data suggest that maternal exposure during the entire gestational period with low doses of nicotine and chlorpyrifos, alone and in combination, does not lead to any significant observable developmental abnormalities in the offspring by PND 30.

Future Activities:

To define the mechanisms of any neuropathological damages occurring at later stages such as PND 60 or 90 following maternal exposure to nicotine and chlorpyrifos, alone and in combination, future studies will evaluate apoptosis in the brain by immunohistochemical staining for p53, Bcl2, and cytochrome c. Generation of oxidative stress in the brain will be assayed by immunohistochemical detection of 8-hydroxyguanosine and 3-nitrotyrosine and biochemical determination of nitric oxide and determination of reduced glutathione.

Journal Articles on this Report : 1 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 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., RFA, Health, Scientific Discipline, Toxicology, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, sensitive populations, infants, developmental neurotoxicity, vulnerability, chlorpyrifos, children, neurotoxicity, assessment of exposure, cigarette smoke, indoor air, pregnancy, tobacco smoke, Nicotine, toxics, maternal exposure, developmental toxicants

    Progress and Final Reports:

    Original Abstract
  • 2003 Progress Report
  • Final Report