The effect of stress on the acute neurotoxicity of the organophosphate insecticide chlorpyrifos
Introduction
Imbalance between environmental demands for survival and the individual's capacity to adapt to these is defined as stress (Marshall et al., 2000, Lazarus and Folkman, 1984, Sapolsky, 1992), and such responses are needed in adapting to demands of ever-changing circumstances. Individuals react to stress by shifting resources from other biological activities (such as reproduction or growth) toward survival. The degree of these responses relates to the intensity and duration of the stress. Milder forms of stress draw on reserve resources, but severe acute or chronic stress may impact on critical metabolic pathways and thus negatively alter homeostatic metabolic events. This results in decreased capability to adapt to changes in ambient temperatures, resist infectious agents, or tolerate exposure to natural and synthetic toxicants.
Adrenocortical trophic hormone-mediated glucocorticoid secretions from the adrenal cortex, such as corticosterone, induced by a complex of brain and hypothalamic–pituitary–adrenal axis reactions, along with catecholamines, are major mediators of stress effects (Sapolsky, 1992, Sapolsky, 1996, Sapolsky, 2000). Physiological effects of such stress-induced hormonal changes include diversion of energy to the exercising muscles (such as by mobilization of stored energy and gluconeogenesis), enhanced cardiovascular tone increasing substrate delivery to muscle and brain, acute stimulation of immune function, and sharpened cognition with increased cerebral glucose utilization.
While beneficial for a short period of time, chronically elevated blood levels of glucocorticoids, as seen with prolonged or severe stress, provoke enhanced demands on the body's resources. This is manifest by protein catabolism, hyperglycemia, immune suppression, and altered immunoregulation with enhanced susceptibility to infection, depression, altered mental performance, and decreased hippocampal volume (Agarwal and Marshall, 1998, McEwen and Stellar, 1993). Under such conditions, stress is thought to enhance development of disease, including that of the nervous system (Sapolsky, 1992, Sapolsky, 1996). Experimental studies in rodents indicate that prolonged or severe stress may damage the brain. Most prominently, stress-induced high blood levels of glucocorticoids mediate deleterious effects in the hippocampus, a region rich in receptors for these hormones (McEwen, 2001, Sapolsky, 1992, Sapolsky, 2000). The elevated glucocorticoids act via several pathways, prominently interacting with excitatory amino acid neurotransmitters (glutamate) in the evolution of the neuropathological effects (Magarinos and McEwen, 2000, Sapolsky, 1996, Sapolsky, 2000).
In addition to possible direct effects on brain, stress hormones may enhance effects of other neuropathic agents. As regards neurotoxicity, there have been a number of investigations of a possible role of stress in enhancing central effects of anti-cholinesterase chemicals, arising from suggestions that this combination may have played an etiologic role in components of the Gulf War Illnesses (Abdel-Rahman et al., 2002, Institute of Medicine, 2003). Most of these studies have focused on stress-associated reduction of the blood–brain barrier efficiency, thus allowing some commonly used drugs, in particular the carbamate pyridostigmine bromide, to elicit central cholinergic effects in laboratory animals. Investigations of whether stress affects the antiesterase effects of organophosphates are few. Single or multiple daily stress exposures had no effect on the acute toxicity of paraoxon or chlorpyrifos (Pung et al., 2006, Shaikh and Pope, 2003), and a model of chronic stress had no effect on delayed neurotoxicity induced by tri-ortho-tolyl phosphate (Jortner et al., 2005). We report the results of a study of the effect of multiple stressors administered over a six-week period to rats on the acute neurotoxicity of the organophosphate insecticide chlorpyrifos. The latter is a commonly employed lipophilic insecticide, which can penetrate the blood–brain barrier.
Section snippets
Animals
Male Sprague–Dawley (Harlan Sprague–Dawley, Dublin, VA) rats were used in this study. They were 66–74 days of age at the onset and were single-cage housed in a standard laboratory animal room at 22–24 °C with a 12-h light/dark cycle. The animals had free access to Harlan Teklad 2018 Rodent Diet and tap water. Animal experiments adhered to the principles stated in the guide for the care and use of laboratory animals (National Research Council, 1996) and were reviewed and approved by the Virginia
Stress effects
Stress was measured by changes in body weight gain and plasma corticosterone over the course of the study, as shown in Fig. 2. There was progressive body weight increase in all stress groups (n = 8/group). This was greatest for controls (Group 1) and less for the three groups exposed to stress. The difference was statistically significant only for the swim rats (Group 4) over the 18- to 42-day period (Fig. 2). Chlorpyrifos had no effect on body weight gain measured on day 42 (Fig. 2).
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Discussion
There has been considerable interest in the role of stress in exacerbating neurotoxic effects, in particular as it relates to cholinesterase inhibition. Repeated acute stress has been reported to diminish acetylcholinesterase activity and transcription of genes coding for acetylcholinesterase (Kaufer et al., 1998). The role of stress-related alteration of the action of anticholinesterase agents has been extensively studied for the carbamate pyridostigmine bromide, stemming from reviews of Gulf
Acknowledgment
Supported by the Department of the Army of the United States DAMD17-1-01-0775. Information contained herein does not necessarily represent the position or policy of the U.S. government.
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