Effect of acute administration of certain heavy metals and their combinations on the spontaneous and evoked cortical activity in rats

The aim of this study was to see the effect of acutely administered inorganic lead, mercury, manganese, and their combinations, on the electrical activity in the somatosensory system of rats. Male Wistar rats were anaesthetised with urethane, the head was fixed in a stereotaxic frame and the left hemisphere was exposed. Weak electric shocks to the whiskers and the tail served as stimuli. Spontaneous and stimulus-evoked activity was recorded from the primary projection area of the whiskers and the tail. After an hour of control recording, one of the following was given to the rat i.p.: 1000 mg/kg Pb2+, 7 mg/kg Hg2+, 50 mg/kg Mn2+, 500 mg/kg Pb2+ + 25 mg/kg Mn2+, or 500 mg/kg Pb2+ + 3.5 mg/kg Hg2+. Lead caused a massive increase in the cortical response amplitude, starting immediately after administration and developing in the next 40-50 min. Latency showed a minimal increase. The spontaneous activity was moderately shifted to lower frequencies. The effect of Hg2+ on the response amplitude and on the ECoG was similar but stronger than that of Pb 2+. The effect of Mn2+ on the evoked activity was marked but less strong than with Pb2+. The ECoG shift was moderate. With Hg2+ and Mn2+, the response amplitude showed first a decrease than an increase. The effect of the Pb2+ + Mn2+ combination on the activities was not additive but the correlation between the alteration of the ECoG and the evoked potential was stronger than with any of the metals alone. With Pb2+ + Hg2+, the effect of Pb 2+ dominated on the evoked and that of Hg2+ on the spontaneous activity. In the peripheral nerve, action potential amplitude and conduction velocity were decreased. These alterations of the spontaneous and stimulus-evoked cortical activity probably reflected a specific action of the heavy metals on the nervous activity. Š 2004 Elsevier B.V. All rights reserved

Experimental model studies of pesticide exposure

The neurotoxic effects of Dimethoate (Dim), Dichlorvos (DDVP) and Methyl-Parathion (MP) respectively were investigated on the central nervous system (CNS) and peripheral nervous system (PNS) of rats after different treatment schedules at the macro and single unit cell level. At the macro investigations 1/25, 1/50 and 1/100 of the respective LD50 values of each pesticide were administered to different groups by garage daily in the following programs: Pregnancy variation (P) to females from 5th to 15th days of pregnancy; Pregnancy and lactation variation (P+L): to females as above and during lactation for 4 weeks; Pregnancy+lactation+post weaning variation (P+L+P) as above plus to the young male rats (F1 generation) up to 8 weeks. Neurotoxicological investigations were conducted on the F1 rats at the age of 12 weeks. Spontaneous electrocorticograms (ECoG) were recorded on the anesthetized rats from the somatosensory, visual and auditory cortex. Cortical evoked potentials (EP) were recorded from the same areas subsequently. Conduction velocity and refractory periods of the tail nerve was investigated. Treatment by Dim, DDVP and MP during P and P+L of the mothers did not influence the bioelectric activity of the offsprings significantly. The same treatment by the P+L+P programme, resulted in significant changes. Frequency of the spontaneous ECoG waves grew significantly in all dose groups of P+L+P group. Latency time become shorter after somatosensory, light or acoustic stimuli respectively on one hand and the beginning of the of answer of these by the evoked potential (EP) waves on the other hand. Conduction velocity of the tail nerve diminished, refractory periods grew dose dependently and significantly at the P+L+P programs with all the three pesticides. Cortical single unit activity was studied after the i.p administration of 1/5 LD50 of the three organophosphates (OP). The decrease of the firing frequencies was observed. The amplitude of the hippocampal population spikes increased. The changes observed in these studies point toward a higher excitation state of the CNS and a disturbed conduction of the nervous impulses of the peripheral nerves. These results could be taken into consideration when deciding on human contaminations by OP-s

Simultaneous changes of the spontaneous and stimulus-evoked cortical activity in rats acutely treated with mercuric chloride

In earlier studies of our laboratory and in several other reports, alterations in the electrical activity of the cortex of experimental animals on subchronic mercury (Hg) administration were described. In the present work, simultaneous changes in the spontaneous and stimulus-evoked cortical activity elicited by acute administration of inorganic Hg were evaluated with the aim of finding any correlation of the two, possibly giving insight into the mechanism of the alterations. In young adult male Wistar rats, spontaneous cortical, as well as stimulus-evoked cortical and peripheral nervous activity was recorded, before and after acute administration of 3.5 and 7.0 mg/kg Hg2+ ip. The effects of Hg2+ appeared within 10 min and most became significant over 3 h. On the cortex, slowed spontaneous activity, as well as increased amplitude and latency of the evoked potentials (EPs) was seen, and in the periphery, decreased nerve conduction velocity. These alterations seemed to be consistent with a separate cortical and peripheral axonal effect of Hg. Š 2003 Elsevier Inc. All rights reserved

Stimulus frequency dependence of the central and peripheral somatosensory evoked activity in rats treated with various pesticides

Rats were treated with a combination of insecticide agents in different timing schemes. In acute administration, 1/5 LD50 of the three insecticides: dimethoate, propoxur and cypermethrin, or their combination, was given once by gavage. In the developmental model, female rats received oral doses of 1/25 LD50 of the above insecticides in combination in three timing schemes including pregnancy and lactation. Responses in the somatosensory cortex and in the tail nerve, evoked by peripheral electric stimulation, were recorded in acute preparation under urethane anesthesia. It was tested whether the parameters of the cortical and peripheral evoked response are dependent on the frequency and whether this dependence is different in control and treated animals. The latency increase of the cortical responses with increasing stimulation frequency was significantly stronger in rats treated acutely with cypermethrin and the combination, and in rats receiving the combination during both intra- and extrauterine development. On the duration, the effects were less clear. Frequency dependent increase of the tail nerve action potential latency was significantly intensified by cypermethrin, and the amplitude decrease, by cypermethrin and dimethoate. Fatigue of this response during a stimulation series was also altered by the insecticides. Frequency dependence and fatigue possibly reflect the actual state of the nervous system and may have the potency to be developed to functional biomarkers. Š 2005 AkadÊmiai Kiadó

Effects of 3-nitrpropionic acid in rats: general toxicity and neurotoxicity

Three-nitropropionic acid (3-NP) causes biochemical and morphological alterations in human and animal brain. Young adult male Wistar rats received 3-NP ip. on 5 consecutive days and were investigated four weeks later (subacute treatment). Acute effects were investigated 24 h after one ip. dose. Spontaneous or stimulus-evoked activity was recorded from cortical sensory foci, from subcortical nuclei and from the tail nerve, in urethane anesthesia. The subacutely treated rats were dissected and organ weights measured to study general toxic effects. After subacute treatment, decrease was seen in the theta, and increase in the beta2 and gamma, band of the spontaneous activity, dissimilarly in the cortical vs. subcortical sites. Latency of the sensory evoked potentials increased in all sensory foci after subacute treatment. Following acute treatment, amplitude of the somatosensory evoked potential decreased. The weight of the thymus decreased significantly in the treated rats. Further studies could elucidate the link between biochemical effects of 3-NP and the observed functional neurotoxic changes

Különböző kémiai szerkezetű peszticid hatóanyagok - szerves foszfát, piretroid, karbamát, klórozott szénhidrogén, tercier-aromás-triamin - és kombinációik által kiváltott neuro-, magatartás- és immuntoxikológiai hatások vizsgálata állatkísérletes modellekben = Investigation of neuro-, behavioural and immuntoxicological effects caused by single and combined treatment of pesticides of different chemical structure (organophosphate, pyrethroide, carbamate, chlorinated hydrocarbone, tertial-aromatic-triamine)

Inszekticidek (dimetoát, propoxur, cipermetrin, amitraz) önálló ill. kombinált szubkrónikus bevitelével vizsgáltuk felnőtt patkányok immunrendszerének ill. idegrendszerének; valamint akut ill. az intra- és extrauterin egyedfejlődés során való adást követően az idegrendszer működését. Az anyagok jellemzői és alkalmazása valószínűsítik egyidejű jelenlétüket és hatásukat az emberi szervezetben. Neurotoxicitás: Az amitráz esetében igazoltuk a neurotoxicitást. A dimetoát és az amitráz hatásai eltérő hatásmechanizmus mellett hasonlóak, a dimetoát és propoxur hatásai hasonló hatásmechanizmus mellett eltérőek voltak. A dimetoát és az amitráz kombinációs kezelésekben is dominált. A spontán kérgi aktivitás változásai több hatóanyag esetében ellentétesek voltak pre- ill. pre- és posztnatális adagolásnál; a kérgi kiváltott válaszok változásai a pre- és posztnatális expozíció összeadódó hatását jelezték. A kiváltott aktivitás változásai voltak pontosabban értékelhetők. Általános és immuntoxikus hatások: A hatások közül a relatív szervtömegek és egyes hematológiai paraméterek voltak legérzékenyebbek az inszekticidekre. A kezelés időtartamának hatása itt is jelentős volt. Az általános, neuro- ill. immuntoxikológiai eredmények között nem volt minden hatást és kölcsönhatást jól jelző paraméter. Az eredmények hozzájárulhatnak az expozíciós határértékek finomításához. Egyes funkcionális eltérések eléggé érzékenyek és specifikusak ahhoz, hogy a későbbiekben biomarkerré váljanak. | Effects of insecticides (dimethoate, prpopxur, cypermethrin, amitraz) was studied, alone or combined, on the nervous and immune system of adult rats in subchronic exposure, and on the nervous system in acute dosage or in exposure including pre- and postnatal development. The agents' characteristics and usage make their simultaneous presence and effects in humans likely. Neurotoxic effects: Neurotoxicity of amitraz was verified. Effects of dimethoate and amitraz were like, despite different way of action, and those of dimethoate and propoxur were unlike, despite similar way of action. Effects of combinations were dominated by dimethoate or amitraz. Changes of spontaneous cortical activity were with several agents opposite when given only in the prenatal, than when in the pre- and postnatal period. Evoked responses, however, indicated an additive effect of pre- and postnatal exposure. The changes of the evoked activity were to evaluate more accurately. General and immuntoxicological parameters: Of all effects, the changes of relative organ weights and certain haematological parameters were the most sensitive to the insecticides. The length of exposure had a major effect also here. None the general, neuro- and immuntoxicological outcomes indicated all effects and interactions. The results can contribute to refining exposure limit values. Some functional alterations were sensitive and specific enough to be developed to biomarkers

Functional neurotoxic effects in rats acutely exposed to insecticide combinations

The aim of the present study was to analyse the alterations in the cortical and peripheral electrophysiological activity of rats acutely treated with combinations of insecticides. Young adult male Wistar rats were treated with 1/5 and 1/25 LD50 of the insecticides dimethoate, propoxur, cypermethrin and amitraz, given alone or in triple or quadruple combinations. After 24 h, spontaneous cortical activity, and stimulus-evoked cortical and peripheral responses, was recorded and analysed. All treatments changed the cortical activity spectrum. The effect of the 1/5 LD50 combinations indicated non-additive interactions. In the cortical-evoked responses, dimethoate and its combinations gave the strongest change in the latency, while amitraz and its combinations, in the response duration. In the tail nerve, relative refractory period was the most sensitive parameter. The frequency dependence of the cortical responses was the most strongly altered by propoxur, and the least, by amitraz. Our results indicate that simultaneous exposure by various pesticide agents, which happens possibly also in humans, deserves further investigation in, among others, neurotoxicological points of view. Š 2006 Elsevier Inc. All rights reserved

Behavioral effects of subchronic inorganic manganese exposure in rats

Background: Manganese, an essential micronutrient, is a potential neurotoxicant in prolonged overexposure. Parkinson- like syndrome, motor deficit, disturbed psychomotor development are typical signs of neuropathological alterations due to Mn in humans. Methods: Young adult rats, in three groups of 16 each, received 15 and 59 mg/kg b.w. MnCl2, (control: distilled water) via gavage for 10 weeks, and were kept for further 12 weeks. Correlation of MnCl2 exposure to body and organ weights, neurobehavioral effects (spatial memory, exploratory activity, psychomotor performance, pre-pulse inhibition), and histopathological changes (gliosis) was sought. Results: By the end of treatment, Mn accumulated in blood, cortex, hippocampus, and parenchymal tissues. Body and organ weights were reduced in high dose rats. All treated rats showed hypoactivity, decreased memory performance, and diminished sensorimotor reaction. In the dentate gyrus of these, GFAP immunoreactivity increased. During the post-treatment period, body weight of the high dose group remained decreased, locomotor activity returned to control, but the lasting effect of MnCl2 could be revealed by amphetamine. Conclusion: Using complex methodology, new data were obtained regarding the relationship between the long-term effects of MnCl2 at neuronal and behavioral level. Š 2007 Wiley-Liss, Inc