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 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 goal of this proposal is to investigate the neurotoxic effects of combined exposure, during gestation to the cholinotoxic agents, nicotine and the organophosphorus insecticide, chlorpyrifos on the postnatal development of the cholinergic system and its long-term functional consequences in the rat. Nicotine is a direct cholinergic agonist at the nicotinic acetylcholine receptors (nAChR), delivered by cigarette smoking, and chlorpyrifos is an inhibitor of acetylcholinesterase (AChE) that causes overstimulation of the cholinergic system through the accumulation of acetylcholine at nAChR and muscarinic acetylcholine receptors (mAChR).

The hypothesis to be tested is that 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.


The proposed studies will be carried out in young, prepubertal, pubertal and adult rats born out of the pregnant rats that have been administered the test compounds (nicotine, 1mg/kg/day, sc, and chlorpyrifos, 0.1mg/kg/day, dermal) daily through the gestation days 4-20. For the assessment of cholinergic system, acetylcholinesterase, choline acetyltransferase mAChR, nAChR in different brain regions and plasma butyrylcholinesterase will be assayed. Apoptosis in the brain will be assayed by immunohistochemical and biochemical examination p53, Bcl2, Bax and release of cytochrome c from mitochondria. 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, expression of inducible nitric oxide synthase, and determination of reduced glutathione.

Expected Results:

It is expected that these studies will generate data on inappropriate regulation of not only the cholinergic system, but also on homeostatic mechanisms involved in the generation and maintenance of oxidative stress following co-exposure to nicotine and chlorpyrifos. The proposed studies will contribute greatly to the understanding and broaden our knowledge of the harmful health effects of the children whose mothers are not only smokers, but also exposed to the environmental organophosphorus insecticide, chlorpyrifos.

Publications and Presentations:

Publications have been submitted on this project: View all 9 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 3 journal articles for this project

Supplemental Keywords:

risk assessment, indoor, smoking, infants, neuropathological damage, vulnerable, pregnancy., 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:

  • 2002 Progress Report
  • 2003 Progress Report
  • Final Report