Elsevier

Toxicology

Volume 229, Issue 3, 18 January 2007, Pages 194-205
Toxicology

Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids

https://doi.org/10.1016/j.tox.2006.10.015Get rights and content

Abstract

Pyrethroids are a class of insecticides involved in different neurological disorders. They cross the blood–brain barrier and exert their effect on dopaminergic system, contributing to the burden of oxidative stress in Parkinson's disease through several pathways. The aim of the present study was to evaluate the effect of neonatal exposition to permethrin and cypermethrin (1/10 of DL50) in rats from the eighth to the fifteenth day of life. Open-field studies showed increased spontaneous locomotor activity in the groups treated with permethrin and the one treated with cypermethrin, while a higher number of center entries and time spent in the center was observed for the cypermethrin-treated group. Lower dopamine and higher homovanillic acid levels were measured in the striatum from both treated groups. A reduction of blood glutathione peroxidase content was measured, while no change in blood superoxide dismutase was observed. Carbonyl group formation increased in striatum, but not in erythrocytes. Lipid peroxidation occurred in erythrocytes, but not in striatum. No changes in fluidity at different depths of plasma membrane were measured in striatum or erythrocytes. The activation of monocyte NADPH oxidase by phorbol esters (PMA) shows that superoxide anion production was reduced in the pyrethroid-treated groups compared to the control group. Our studies suggest that neonatal exposition to permethrin or cypermethrin induces long-lasting effects after developmental exposure giving changes in open-field behaviors, striatal monoamine level, and increased oxidative stress. Although the action of pyrethroids on various target cells is different, a preferential interaction with the extracellular side of plasma membrane proteins can be observed.

Introduction

The pyrethroid insecticides are members of a chemical class of heavily used compounds, and hazards from exposure to insecticides exist from their manufacture, storage, and spraying, as well as through contact with insecticide-contaminated food or areas.

They can be divided into two classes. Type I has no cyano-group at the carboxyl α position (α-carboxyl), whereas Type II presents this cyano-group (Verschoyle and Aldridge, 1980). Permethrin (PERM) is claimed to be one of the most potent Type I insecticides, whereas cypermethrin (CY) belongs to Type II.

It has long been known that exposure to pyrethroid insecticides can induce neurobehavioral effects in rodents, as well as in others species, including humans (Eriksson and Fredricksson, 1991, Ray and Cremer, 1979, Shettgen et al., 2002). Studies have documented effects of the pyrethroids on dopaminergic nerve pathways, which may be a contributory factor in the etiology of environmentally induced Parkinson's disease. There is a consistent epidemiological linkage between insecticide exposure and the incidence of Parkinson's disease (Semchuk et al., 1992, Butterfield et al., 1993, Gorell et al., 1998). Although pyrethroid neurotoxicity to adults has been well characterized, and several comprehensive reviews of pyrethroid toxicity, metabolism, and actions are available (Shafer et al., 2005, Kolaczinski and Curtis, 2004, Fry and Ray, 2006), information regarding the potential developmental neurotoxicity of this class of compounds is limited. Developmental neurotoxicity involves alterations in behavior, neurohistology, neurochemistry, and/or dysmorphology of the central nervous system occurring in the adult age, as a result of neonatal exposure to pyrethroids. Eriksson's group has reported that mice exposed to deltamethrin and bioallethrin during postnatal days (PND) 10–16 exhibited increased motor activity and changes in cholinergic muscarinic receptor after cessation of exposure (Eriksson and Fredricksson, 1991). Similar to the muscarinic cholinergic system, the dopaminergic system may be affected by developmental exposure to pyrethroids: some studies on adult rats have reported that the pyrethroid class can modulate the dopaminergic system by up-regulation of dopamine transporter (Gillette and Bloomquist, 2003) and marked increase in dopamine turnover (Brodie and Opacka, 1985, Karen et al., 2001). Both deltamethrin (Lazarini et al., 2001) and bioallethrin (Shafer et al., 2005) were reported to increase 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the adult striatum after prenatal exposure of dams to a non-toxic deltamethrin dose. Nevertheless, the relationships between biochemical alterations and pyrethroid-induced developmental neurotoxicity have yet to be established by better characterization of the neurochemical mode of action.

Our previous studies on adult rats orally treated with different concentrations of CY and PERM, showed biochemical alterations, such as oxidative stress, in the plasma membrane and antioxidant enzymatic activity of erythrocytes (Nasuti et al., 2003) as well as DNA damage in lymphocytes (Gabbianelli et al., 2004).

The aim of the present work was to investigate in rats the long-lasting effects after developmental exposure (from PND6 to PND15) to Type I (PERM) or Type II (CY) pyrethroids at a dose that does not induce acute toxicity in pups. Subsequently, open-field behaviors as well as striatal monoamine levels in adulthood were examined. In addition, in an attempt to assess whether pyrethroids can cause oxidative stress in striatum, and to shed some light on the mechanisms involved in the reported neurotoxicity of pyrethroids, we have performed an exhaustive investigation of oxidative stress caused by pyrethroid exposure, examining the effect of both pyrethroid types on plasma membrane fluidity, lipid peroxidation, protein oxidation in striatum, and erythrocytes of rats.

Section snippets

Materials

All reagents were of pure analytical grade. Technical grade (62.8:37.2, trans:cis; 92.4% purity) (R,S) α-cyano-3-phenoxybenzyl (1R,S)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylate, CY (NRDC 149) and technical grade (75:25, trans:cis; 94% purity) 3-phenoxybenzyl-(1R,S)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxyl-ate, PERM (NRDC 143) were generously donated by Dr. A. Stefanini of ACTIVA, Milan, Italy. Corn oil, 5,5 dithio-bis(2 nitrobenzoic acid)

General findings

Rats treated daily from PND8 to PND15 with 1/10 of DL50 of CY and PERM by intragastric tubing showed no signs of pyrethroid poisoning or gross behavioral abnormalities throughout the experimental period.

Data on body weight in rats treated with CY, PERM and control are reported in Fig. 1. As shown, body weight values increased as a function of age and no significant differences were observed in the body weight of exposed versus control rats during treatment.

Open-field behavior

In order to evaluate the dopaminergic

Discussion

It is known that DA is the major neurotransmitter involved in the control of the motor system. Some authors (Bernardi et al., 1981) showed that locomotion and rearing frequencies observed in an open-field might be used to detect drug-induced dopaminergic interference. Since the pyrethroid acute neurotoxicity to adults has been well characterized, but the information regarding the potential neurotoxic development of this class of compounds is limited, we decided to investigate the potential

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