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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination.

Authors: Slotkin, Theodore A; Oliver, Colleen A; Seidler, Frederic J

Published In Brain Res Dev Brain Res, (2005 Jun 30)

Abstract: The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms other than inhibition of cholinesterase. In the current study, we examined the ability of CPF to evoke lipid peroxidation in the developing brain of fetal and neonatal rats. CPF given to pregnant rats on gestational days 17-20 or to neonatal rats on postnatal days 1-4, failed to elicit increases in thiobarbituric acid-reactive species (TBARS) in brain regions even when the dose was raised above the threshold for systemic toxicity and hepatic damage. In contrast, CPF administration during the second postnatal week, the peak period of neuronal cell differentiation and synaptogenesis, did evoke significant increases in TBARS even at a dose devoid of systemic toxicity. Terbutaline, which is chemically unrelated to CPF and which stimulates neuronal cell metabolism through direct actions on beta-adrenoceptors, also elicited oxidative damage in the developing brain with greater sensitivity in the second postnatal week. These results indicate that diverse compounds can exert convergent effects on brain development through their shared potential to elicit oxidative stress, and that the net outcome is dependent upon specific developmental stages in which metabolic demand is especially high. Furthermore, given the common use of terbutaline in the therapy of preterm labor, and the nearly ubiquitous exposure of the human population to organophosphorus pesticides, the combined oxidative burden of exposure to both agents may contribute to the worsened neurodevelopmental outcomes noted in animal models of such dual exposures.

PubMed ID: 15963356 Exiting the NIEHS site

MeSH Terms: Adrenergic beta-Agonists/toxicity; Age Factors; Animals; Animals, Newborn; Brain Damage, Chronic/chemically induced*; Brain Damage, Chronic/pathology; Brain Damage, Chronic/physiopathology; Brain/drug effects*; Brain/growth & development; Brain/physiopathology; Cell Death/drug effects; Cell Death/physiology; Cell Differentiation/drug effects; Cell Differentiation/physiology; Chlorpyrifos/toxicity*; Cholinesterase Inhibitors/toxicity; Critical Period (Psychology); Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Lipid Peroxidation/drug effects; Lipid Peroxidation/physiology; Nerve Degeneration/chemically induced; Nerve Degeneration/metabolism; Nerve Degeneration/physiopathology; Neurotoxins/toxicity*; Oxidative Stress/drug effects*; Oxidative Stress/physiology; Pregnancy; Prenatal Exposure Delayed Effects*; Rats; Rats, Sprague-Dawley; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.; Terbutaline/toxicity*; Thiobarbituric Acid Reactive Substances/metabolism

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