Dopaminergic system modulation, behavioral changes, and oxidative stress after neonatal administration of pyrethroids
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
References (54)
The respiratory burst-oxidase
Trends Biochem. Sci.
(1987)- et al.
Chemical, enzymological and permeability properties of human erythrocyte ghosts prepared by hypotonic lysis in media of different osmolarities
Biochim. Biophys. Acta
(1971) - et al.
Behavioral differences between subgroups of rats with high and low threshold to clonic convulsions induced by DMCM, a benzodiazepine inverse agonist
Pharmacol. Biochem. Behav.
(2005) - et al.
Immuno-, neuro-and general toxicologic animal studies on a synthetic pyrethroid: cypermethrin
Ecotoxicol. Environ. Saf.
(1986) - et al.
Pyrethroid pesticide-induced alterations in dopamine transporter function
Toxicol. Appl. Pharmacol.
(2006) - et al.
A neurotoxic effect of two different pyrethroids, bioallethrin and deltamethrin on immature and adult mice
Toxicol. Appl. Pharmacol.
(1991) - et al.
Effects of prenatal stress-induced changes in behaviour and macrophage activity in mice
Physiol. Behav.
(2002) - et al.
Cypermethrin-induced plasma membrane perturbation on erythrocytes from rats: reduction of fluidity in the hydrophobic core and in glutathione peroxidase activity
Toxicology
(2002) - et al.
Lymphocyte DNA damage in rats exposed to pyrethroids: effect of supplementation with Vitamins E and C
Toxicology
(2004) - et al.
Pyrethroid toxicology: protective effects of diazepam and phenobarbital in the mouse and the cockroach
Toxicol. Appl. Pharmacol.
(1982)