The effect of stress on the acute neurotoxicity of the organophosphate insecticide chlorpyrifos

https://doi.org/10.1016/j.taap.2006.11.014Get rights and content

Abstract

A study was conducted to determine if multiple exposures to several stress paradigms might affect the anticholinesterase effect of subsequently administered organophosphate insecticide chlorpyrifos. Male Sprague–Dawley rats were subject to daily periods of restraint, swimming, a combination of the two, or neither of the two (controls) (n = 8/group) for 5 days per week over a six-week period. The most profound stress, as measured by reduced body weight gain and elevated levels of plasma corticosterone, was swimming. On day 39 of the study, shortly after the daily stress episode, one half of the rats in each group was dosed with 60 mg/kg chlorpyrifos subcutaneously. This had no effect on subsequent levels of plasma corticosterone. There were no stress-related differences in the degree of chlorpyrifos-induced inhibition of brain acetylcholinesterase in animals sacrificed on day 43.

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).

Similarly,

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.

References (26)

  • Institute of Medicine

    National Academy of Sciences

    (2003)
  • B.S. Jortner et al.

    Neuropathological studies of rats following multiple exposures to tri-ortho-tolyl phosphate, chlorpyrifos and stress

    Toxicol. Pathol.

    (2005)
  • D. Kaufer et al.

    Acute stress facilitates long-lasting changes in cholinergic gene expression

    Nature

    (1998)
  • Cited by (15)

    • Effect of chlorpyrifos on VEGF gene expression

      2023, Chemico-Biological Interactions
    • Effects of chlorpyrifos on transient receptor potential channels

      2022, Toxicology Letters
      Citation Excerpt :

      The mice in group 1 were treated with 70 mg/kg of CPF dissolved in corn oil, and the mice in group 2 were treated with corn oil as the control. After testing a series of doses between 250 and 5 mg/kg (data not shown), 70 mg/kg CFP was chosen for the current experiments because this dose did not cause any observable clinical effects of cholinesterase inhibition but could cause molecular changes originally noted during our previous in vitro studies (Pung et al., 2006; Hancock et al., 2007; Li and Ehrich, 2013). The route used to deliver the CPF or corn oil in the study was intraperitoneal injection (ip).

    • Influence of immobilization and forced swim stress on the neurotoxicity of lambda-cyhalothrin in rats: Effect on brain biogenic amines and BBB permeability

      2017, NeuroToxicology
      Citation Excerpt :

      The reports of Gulf war syndrome led to realize that stress is a significant contributor in the toxicity of chemicals in the Gulf war veterans as they were exposed to multiple neurotoxic chemicals including cholinesterase inhibitors and insecticides (Abdel-Rahman et al., 2004, 2002; Song et al., 2002). With the demonstration that acute stress may increase the BBB permeability (Friedman et al., 1996), a number of studies have been carried out to assess the effect of drugs and chemicals including metals and pesticides in stress situations (Hancock et al., 2007; Lazarini et al., 2001; Torrente et al., 2005; Terçariol et al., 2011). Studies on the interaction of lead exposure and stress revealed that restraint stress during prenatal period could cause lead induced behavioral and neurochemical changes including alterations in the HPA axis (Rossi-George et al., 2011).

    View all citing articles on Scopus
    View full text