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At least 19 recordsLinked to original sources
PubMed2001

Role of brain regional GABA: aldrin-induced stimulation of locomotor activity in rat.

Aldrin, a chlorinated hydrocarbon group of pesticide, is a well known central nervous system (CNS) stimulant. The CNS stimulating effect of aldrin is manifested in the form of an increase in locomotor activity (LA) of animals. Maximum increase in LA was observed at 2 h following aldrin (2-10 mg/kg, p.o.) treatment and this aldrin-induced increase in LA attained a peak at a dose of 10 mg/kg, p.o. Administration of aldrin (2 or 5 mg/kg/day, p.o.) enhanced LA of rats and reached a maxima after 12 consecutive days of treatment following which aldrin-induced LA was gradually reduced and restored to control value after 20 consecutive days of aldrin treatment. A single administration of aldrin (2-10 mg/kg, p.o.) reduced the GABA system in cerebellum, hypothalamus and pons-medulla. The treatment with aldrin (2 mg/kg/day, p.o.) for 12 consecutive days produced more inhibition in those brain regional GABA system than that observed with a single dose of aldrin. These results, thus, suggest that aldrin-induced inhibition of central GABA may be a cause of stimulation of LA with aldrin either at a single dose or for 12 consecutive days.

Aldrin↗
PubMed1978

Bioassays of aldrin and dieldrin for possible carcinogenicity.

Bioassays of technical-grade aldrin and dieldrin for possible carcinogenicity were conducted by administering the test materials in feed to Osborne-Mendel rats and B6C3F1 mice. Aldrin Groups of 50 rats of each sex were administered aldrin at one of two doses, either 30 or 60 ppm. Male rats were treated for 74 weeks, followed by 37-38 weeks of observation; female rats were treated for 80 weeks, followed by 32-33 weeks of observation. Matched controls consisted of groups of 10 untreated rats of each sex; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 58 untreated males and 60 untreated females from similar bioassays of other chemicals. All surviving rats were killed at 111-113 weeks. Groups of 50 mice of each sex were administered aldrin at one of two doses for 80 weeks, then observed for 10-13 weeks. Time-weighted average doses were 4 or 8 ppm for males and 3 or 6 ppm for females. Matched controls consisted of groups of 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with 92 untreated male and 79 untreated female mice from similar bioassays of other chemicals. All surviving mice were killed at 90-93 weeks. Mean body weights attained by the rats and mice fed diets containing aldrin were similar to those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency and severity during the second year. Aldrin produced no significant effect on the mortality of rats or of male mice, but there was a dose-related trend in the mortality of female mice, primarily due to the early deaths in the high-dose groups. There was an increased combined incidence of follicular-cell adenoma and carcinoma of the thyroid both in male rats fed aldrin (matched controls 3/7, pooled controls 4/48, low-dose 14/38, high-dose 8/38) and female rats fed aldrin (matched controls 1/9, pooled controls 3/52, low-dose 10/39, high-dose 7/46). These incidences were significant in the low-dose but not in the high-dose groups both of males (P=0.001) and females (P=0.009) when compared with the pooled controls. Comparisons with matched controls, however, were not significant. Cortical adenoma of the adrenal gland was also observed in aldrin-treated rats in significant proportions (P=0.001) in low-dose (8/45) but not in high-dose (1/48) females when compared with pooled controls (0/55). Because these increased incidences were not consistently significant when compared with matched rather than pooled control groups, it is questionable whether the incidences of any of these adrenal tumors were associated with treatment. In male mice, there was a significant dose-related increase in the incidence of hepatocellular carcinomas (matched controls 3/20, pooled controls 17/92, low-dose 16/49, high-dose 25/45) when compared with either matched controls (P=0.001), or pooled controls (P<0.001). The incidence in the high-dose group was significant when compared with matched controls (P=0.002) or pooled controls (P<0.001). Dieldrin Groups of 50 rats and 50 mice of each sex were administered dieldrin at one of two doses. Low-dose rats and both low-and high-dose mice were treated for 80 weeks, followed by observation periods of 30-31 weeks for rats and 10-13 weeks for mice. Treatment of high-dose rats was terminated after 59 weeks and followed by 51-52 weeks of observation. Time-weighted average doses doses for rats were 29 or 65 ppm; doses for mice were 2.5 or 5 ppm. Matched controls consisted of groups of 10 untreated rats of each sex and 20 untreated male mice and 10 female mice; pooled controls, used for statistical evaluation, consisted of the matched-control groups combined with untreated animals from similar bioassays of other chemicals (58 male and 60 female rats, 92 male and 79 female mice). All surviving rats were killed at 110-111 weeks, and all surviving mice at 90-93 weeks. Mean body weights attained by the rats and mice fed diets containing dieldrin showed little or no differences compared with those of the controls during the first year of the study; however, mean body weights of the treated rats were lower than those of the controls during the second year of the study. Hyperexcitability was observed in all treated groups with increasing frequency during the second year, especially in high-dose rats. There was a marked increase in the mortality rate of rats during the first 90 weeks of the study. However, because of the high rates of mortality in the control groups during the remaining 20 weeks, survival could not be shown to be statistically dose responsive. In rats, there was a significant (P=0.007) difference between the combined incidence of adrenal cortical adenoma or carcinoma in the low-dose females (6/45) and that in the pooled controls (0/55). Although this tumor was also found in animals treated with aldrin, it is not clearly associated with treatment, because the incidence in the high-dose (2/40) was not significant, and the incidences were not significant when matched, rather than pooled, controls were used for comparison. In male mice, there was a significant positive dose-related trend (P=0.020) in the incidence of hepatocellular carcinomas using the pooled controls (pooled controls 17/92, low-dose 12/50, high-dose 16/45). When high-dose males were compared with the pooled controls, the results were also significant (P=0.025). It is concluded that under the conditions of these bioassays, none of the tumors occurring in Osborne-Mendel rats treated with aldrin or dieldrin could clearly be associated treatment. Aldrin was carcinogenic for the liver of male B6C3F1 mice producing hepatocellular carcinomas. With dieldrin, there was a significant increase in the incidence of hepatocellular carcinomas in the high-dose males which may be associated with treatment.

Journal Article↗
PubMedDate not supplied

Aldrin-induced locomotor activity: possible involvement of the central GABAergic-cholinergic-dopaminergic interaction.

Aldrin (5 mg/kg/day, p.o.) under nontolerant condition, administered either for a single day or for 12 consecutive days, enhanced locomotor activity (LA) of rats. The increase in LA was greater in rats treated with aldrin for 12 consecutive days than that observed with a single dose. The aim of the present study is to evaluate the involvement of possible interactions of central GABAergic, cholinergic and dopaminergic systems using their agonist(s) and antagonist(s) in the regulation of LA in aldrin nontolerant rats. Administration of either L-DOPA along with carbidopa or bicuculline potentiated aldrin-induced increase in LA under nontolerant condition as well as LA of the control rats. Treatment with muscimol, haloperidol, atropine or physostigmine all decreased the LA of both aldrin nontolerant and control rats. Further, the application of (a) haloperidol along with bicuculline, atropine or physostigmine and (b) physostigmine along with bicuculline or L-DOPA + carbidopa significantly reduced LA but L-DOPA + carbidopa along with atropine or bicuculline increased LA of the control rats. These agonist(s)/antagonist(s)-induced decrease or increase in LA of the control rats were attenuated or potentiated, respectively, when those agonist(s)/antagonist(s) under abovementioned condition were administered to aldrin nontolerant rats. The attenuating or potentiating effects of aldrin on agonist(s)/antagonist(s) (either individually or in different combinations)-induced change in LA were greater in rats treated with aldrin for 12 consecutive days than that observed with a single-dose aldrin treatment. These results suggest that aldrin, under nontolerant condition, reduces central GABAergic activity and increases LA by activating dopaminergic system via inhibition of cholinergic activity. The treatment with aldrin for 12 consecutive days produces greater effect than that caused by a single-day treatment.

Aldrin↗
PubMed1984

Relationship between oxidative metabolism of 2-acetylaminofluorene, debrisoquine, bufuralol, and aldrin in human liver microsomes.

The capacity of human liver microsomes from 28 individuals to metabolize debrisoquine and bufuralol, two drugs oxidized polymorphically in humans, as well as the carcinogen 2-acetylaminofluorene (AAF), was determined. In addition, the cytochrome P-450 content and the capacity of these microsomes to carry out the epoxidation of aldrin were measured. Interindividual differences in debrisoquine 4-hydroxylation, bufuralol 1-hydroxylation, and aldrin epoxidation were 12-, 20-, and 2.4-fold, respectively. The metabolism of debrisoquine was not correlated with cytochrome P-450 content (r = 0.26), whereas both the metabolism of bufuralol (r = 0.45; r2 = 0.20) and the epoxidation of aldrin (r = 0.72; r2 = 0.52) were correlated. Rates of debrisoquine and bufuralol metabolism were significantly correlated (r = 0.73), whereas only weak correlations existed between debrisoquine:aldrin (r = 0.49) and bufuralol:aldrin (r = 0.51). Because biphasic kinetics have been observed in human liver microsomes for the 7- and 5-hydroxylation of AAF, two concentrations of this substrate were used. The disappearance of AAF at either 0.37 or 50 microM was not correlated with debrisoquine, bufuralol, or aldrin metabolism. Similarly, at 0.37 microM AAF, no correlation existed between the formation of N-, 1-, 3-, 5-, 7-, and 9-hydroxylation products of AAF and debrisoquine, bufuralol, or aldrin metabolism. At 50 microM AAF, only the 7-hydroxylation of this substrate correlated with bufuralol metabolism (r = 0.47). This lack of, or weak correlation between pathways leading to metabolic activation (N-hydroxylation) or detoxication (C-hydroxylation) of the carcinogen AAF and debrisoquine, bufuralol, and aldrin metabolism strongly suggests that different forms of cytochrome P-450 are involved in these pathways. In contrast, exceptionally high correlations (r greater than 0.94) existed between N-OH-AAF:1-OH-AAF. N-OH-AAF:7-OH-AAF, and 7-OH-AAF:1-OH-AAF at the low concentration of AAF, and imply that similar forms of cytochrome P-450 produce these metabolites. However, at 50 microM AAF, these correlations are considerably weaker and explain less than 35% of the variance in the data. It is concluded, based on these multiple cross-correlations, that common cytochrome P-450 isoenzymes are involved in the formation of AAF metabolites, while the metabolism of debrisoquine, bufuralol, and aldrin is unrelated to the metabolism of this carcinogen in human liver microsomes.

2-Acetylaminofluorene↗
PubMed1975

Effects of aldrin-transdiol on neuromuscular facilitation and depression.

The effects of aldrin-transdiol, one of the active metabolites of the insecticide dieldrin, on evoked transmitter release, neuromuscular facilitation and neuromuscular depression have been studied in frog sartorius nerve-muscle preparations. Conventional techniques of intracellular recordings were used. Aldrin-transdiol caused a marked increase in end-plate potential amplitude under conditions of low quantal content, i.e., in Mg2+-blocked junctions. The increase in end-plate potential amplitude was less pronounced in curarized junctions, in which the transmitter release was not impaired. Concomitant with the increase in end-plate potential size there was a marked enhancement of facilitation during short trains of stimuli applied to the motor nerve. The decay of facilitation was, however, not seriously affected by aldrin-transdiol. These effects may be explained in terms of the known 'calcium hypothesis' by assuring that aldrin-transdiol increases the amount of calcium which enters the nerve terminal during the nerve impulse. The increase in end-plate potential amplitude and in facilitation by aldrin-transdiol was transient. At later stages of poisoning, end-plate potential and facilitation decreased below control level and neuromuscular depression was significantly enhanced. This latter effect may be the result of a direct inhibitory effect of aldrin-transdiol on transmitter mobilization. As far as the fall in end-plate potential amplitude is concerned the known suppressive action of aldrin-transdiol on the chemical sensitivity of the postsynaptic membrane and on the nerve action potential probably plays a part as well. Finally, neuromuscular transmission was completely blocked by aldrin-transdiol.

Aldrin↗
PubMed1991

Metabolism of aldrin to dieldrin by rat skin following topical application.

Metabolism of the pesticide aldrin to dieldrin in the rat was studied following topical and ip administration of 0.1-10 mg aldrin/kg body weight. When aldrin was applied topically to the dorsal skin at a dose of 10 mg/kg body weight, absorption was less efficient than after ip administration; lower blood levels of aldrin and dieldrin were seen and peak dieldrin levels were delayed. After ip administration of 1 or 10 mg aldrin/kg body weight, dieldrin was found at similar concentrations in the dorsal and ventral skin 7 hr later, whereas 7 hr after topical administration of 10 mg aldrin/kg, the dieldrin concentration in the skin at the dorsal site of application was four times higher than that at a ventral skin site. Similar differences in dieldrin concentrations between dorsal and ventral skin persisted throughout the 7-hr period following topical application. The results indicate that topically applied aldrin is metabolized to dieldrin in the skin during absorption, but the overall proportion of metabolism that takes place in the skin is small compared with the contribution of the liver. Dieldrin was not detected in the ventral skin remote from the application site 1 hr after topical application of aldrin, whereas a dieldrin concentration of 2.2 nmol/g was detected in the skin of the application site at this time; more than 99% of this dieldrin was probably formed locally by dermal metabolism of percutaneously absorbed aldrin. The efficiency of conversion of applied aldrin to dieldrin decreased with increasing aldrin dose in the range 0.1 to 10 mg/kg.

Administration, Topical↗
PubMed1992

Evaluation of prenatal aldrin intoxication in rats.

The aim of the present study was to evaluate the impact of prenatal exposure to low doses of aldrin on physical and behavioral developments of rats (1-21 days old). To detect the possible persistent adversities produced by this exposure, the animals were also tested when adults (90 days old). Plasma determinations of both aldrin and its metabolite dieldrin and histopathological evaluations of brain slices were also performed in adult animals. Pregnant female rats were subcutaneously (s.c.) treated with aldrin (1.0 mg/kg) or with its vehicle (0.9% NaCl solution plus Tween-80) from day 1 of pregnancy until delivery. Results show that prenatal aldrin administration was able to decrease the median effective time (TE50) for incisor teeth eruption and to increase the TE50 for testes descent; other parameters indicative of physical development were not modified. Aldrin and dieldrin were not found in plasma of the adult rats; no differences were observed between control and experimental rats in the cellular and structural organization of the cerebral cortex neurones. Prenatal aldrin administration produced no impairment of adult animal's behavior in an avoidance learning test; nevertheless, the locomotor frequency of the experimental rats was higher than that of controls at 21 and 90 days old. When adults, these experimental rats had their performance in a hole-board apparatus (total number and duration of head-dips) also higher than that of the control ones. It was concluded that prenatal aldrin exposure induced not only developmental changes in the rat pups but also persistent behavioral alterations in adulthood, when the pesticide was not present in these animals.

Aldrin↗
PubMed2001

Aldrin-induced stimulation of locomotor activity and brain regional glutamate.

Single administration of aldrin (2-10 mg/kg) to adult male albino rats (120-130 g) enhanced locomotor activity (LA), with the maximum effect reached 2 h after treatment. The measurement of steady state levels of glutamate, glutamine and the activities of their metabolizing enzymes in different regions of the brains of rats treated with aldrin under its nontolerant condition showed that aldrin enhanced the activity of the neuronal glutamate system in the cerebral cortex, cerebellum and hypothalamus. Moreover, treatment with the glutamatergic NMDA receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid, in the absence and presence of aldrin, reduced the LA of control rats and attenuated the aldrin-induced increase in LA of treated rats. These results suggest that aldrin-induced activation of the central glutamate system may be a cause of stimulation of LA with aldrin under its nontolerant condition.

2-Amino-5-phosphonovalerate↗
PubMed1987

Rat liver cytochrome P-450 isozymes as catalysts of aldrin epoxidation in reconstituted monooxygenase systems and microsomes.

To explore which rat liver cytochrome P-450 species are involved in aldrin epoxidation, we have studied the catalytic activities of a series of cytochrome P-450 isozymes purified from untreated and inducer-treated Sprague-Dawley rats. Of ten cytochrome P-450 forms analyzed, seven isozymes, listed in order of decreasing activity, catalyzed aldrin epoxidation: P-450UT-A, P-450PB-C, P-450UT-H, P-450PB-B, P-450PCN-E, P-450UT-F, and P-450PB-D. P-450UT-I, P-450BNF-B, and P-450ISF-G were not very active at all. A novel aldrin metabolite, endo-dieldrin, was formed by cytochrome P-450UT-F in a 6-fold excess over dieldrin, which is the exo-isomer. The activity of aldrin epoxidase furthermore was assayed in liver microsomes from Sprague-Dawley rats of diverse physiological status and after pretreatment with various inducers resulting in a peculiar pattern of cytochrome P-450 isozymes. Untreated animals, at an age of 3 weeks, showed similar enzyme activities in both genders. During maturation, the activity of males increased by 3-fold, while the activity in females did not significantly change during this period. Pretreatment with pregnenolone-16-alpha-carbonitrile or dexamethasone strongly increased the activity in females. Pretreatment with dexamethasone did not increase the activity of males. A 50% depression of epoxidase activity was noted for males pretreated with 5,6-benzoflavone. Phenobarbital pretreatment increased the activity of females by 12-fold and of males by 2-fold. Males responded to pretreatment with polychlorinated biphenyls in a strain dependent fashion: enzyme activity was increased 2-fold in Sprague-Dawley rats but was not altered in Wistar rats. "Theoretical" values of microsomal epoxidase activity were calculated for weanling and adult Sprague-Dawley rats from turnover numbers and published data on the relative abundance of aldrin epoxidizing P-450 isozymes (Waxmann et al., Biochemistry 24, 4409, 1985). These values agreed with the activities determined. A similar statement can be made for male rats of both strains pretreated with inducers, when the ratio of enzyme activity of pretreated to control animals was used as a basis of comparison. The activity ratio of females pretreated with pregnenolone-16-alpha-carbonitrile, dexamethasone and phenobarbital, however, was much higher than the ratio calculated. Our results reveal that aldrin epoxidation is a reaction indicative of male specific and of phenobarbital-inducible cytochrome P-450 isozymes in rat liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Aldrin↗
PubMed1990

In vivo and in vitro effects of aldrin on rat brain synaptosomal Mg2+ and Na+,K(+)-adenosine triphosphatase.

Aldrin, a chlorinated hydrocarbon, inhibited rat brain synaptosomal membrane-bound Na+,K(+)-adenosine triphosphatase (ATPase) and Mg2(+)-ATPase activities under in vivo and in vitro conditions. Na+,K(+)-ATPase was non-competitively inhibited whereas Mg2(+)-ATPase was inhibited uncompetitively. Arrhenius plots of both these ATPases without aldrin under in vivo and in vitro conditions were found to be linear. In the presence of aldrin, on the other hand, Arrhenius plots of the same ATPases were nonlinear. Slopes of Arrhenius plots of both ATPases under in vivo and in vitro condition were changed with change in temperature with aldrin. The activation energy (AE) of Na+,K(+)-ATPase and Mg2(+)-ATPase activities were changed over the temperature range 15-40 degrees in the presence of aldrin. These results thus suggest that aldrin increases the lipid fluidity of the synaptosomal membrane which may be a cause of inhibition of neuronal membrane-bound Na+,K+ and Mg2(+)-ATPase activities.

Aldrin↗
PubMed1985

Persistence of aldrin in flooded soil under the cover of rice.

The persistence of aldrin in soil and its translocation into rice plants and grains were tested under two different field conditions. Treatment T1, which consisted of aldrin application at the rate of 1.5 kg active ingredient/ha at nursery sowing, did not leave aldrin residues in rice plants 40 days after application (10 days after transplanting). Dieldrin was present in plants to the extent of 0.04 ppm at this stage but completely disappeared (below detectable limit) within 70 days (30 days after transplanting). Treatment T2 involved aldrin application 10 days after transplanting in flooded soil at the same rate and left 0.518 ppm residues in soil just after application. These residues dissipated to their half in 90 days. At this stage its conversion to dieldrin was also observed. Remaining residues dwindled to below the detectable limit in 270 days. Plant samples analyzed from this treatment at 7 and 30 days contained 0.079 and 0.169 ppm aldrin and 0.025 and 0.08 ppm dieldrin, respectively. Rice grains also had aldrin and dieldrin residues (each at 0.001 ppm level) at harvest time but these were below the Maximum Tolerance Limits. Both the treatments were found safe from the toxic residue point of view.

Aldrin↗
PubMed1980

Aldrin epoxidation catalyzed by purified rat-liver cytochromes P-450 and P-448. High selectivity for cytochrome P-450.

Aldrin epoxidation was studied in monooxygenase systems reconstituted from purified rat liver microsomal cytochrome P-450 or P-448, NADPH-cytochrome c reductase, dilauroylphosphatidylcholine and sodium cholate. Cytochrome P-450, purified from hepatic microsomes of phenobarbital-treated rats, exhibited a high rate of dieldrin formation. The low enzyme activity observed in the absence of the lipid and sodium cholate was increased threefold by addition of dilauroylphosphatidylcholine and was further stimulated twofold by addition of sodium cholate. The apparent Km for aldrin in the complete system was 7 +/- 2 microM. SKF 525-A, at a concentration of 250 microM, inhibited aldrin epoxidation by 65%, whereas 7,8-benzoflavone had no inhibitory effect at concentrations up to 250 microM. Addition of ethanol markedly increased epoxidase activity. The increase was threefold in the presence of 5% ethanol. When cytochrome P-448 purified from hepatic microsomes of 3-methylcholanthrene-treated rats was used, a very low rate of epoxidation was observed which was less than 3% of the activity mediated by cytochrome P-450 under similar assay conditions. Enzyme activity was independent of the lipid factor dilauroylphosphatidylcholine. The apparent Km for aldrin was 27 +/- 7 microM. The modifiers of monooxygenase reactions, 7,8-benzoflavone, SKF 525-A and ethanol, inhibited the activity mediated by cytochrome P-448. The I50 was 0.05, 0.2 and 800 mM, respectively. These results indicate that aldrin is a highly selective substrate for cytochrome P-450 species present in microsomes of phenobarbital-treated animals and is a poor substrate for cytochrome P-448. The two forms of aldrin epoxidase can be characterised by their turnover number, their apparent Km and their sensitivity to modifiers, like 7,8-benzoflavone and ethanol.

Aldrin↗
PubMed1990

[Acute poisoning by aldrin: relationship between serum levels and toxic effects in humans].

In the attempt to correlate clinical findings with serum levels of aldrin, sixteen patients were followed-up after acute intoxication by this agent. Eight of them, males and females, aged from 1 to 37 years, presented no or light symptoms (some discomfort and nausea). The serum of one of these patients was found to contain 16.6 ppb of aldrin and that of another, 1.41 ppb of dieldrin. A group of five patients, aged from two to 30 years, showed symptoms of moderate severity, reporting nausea, vomiting, drowsiness, dyspnea, sweating, mild jerking, rise in blood pressure and convulsions. Of these cases, two were accidental and three were attempted suicides, the majority achieving complete recovery within 24 hours. Serum levels of aldrin were between 6.98 ppb and 26.3 ppb and of dieldrin between 82.00 and 314.18 ppb. We found three severe cases, aged from 21 to 35 years, two attempted suicides and one occupational case. Two of these patients died and one of them presented hypothermia, coma, absence of reflexes and generalized convulsions, and another presented abdominal pain, paleness, sweating, cold extremities, dyspnea, hyperthermia and generalized convulsions. In the first one that died the serum levels were: of aldrin 30.00 ppb and of dieldrin 720 ppb. In the other levels of 747.3 ppb of aldrin and 1,314.00 ppb of dieldrin were found. The third had less serious symptoms and presented serum levels of aldrin of 31.05 ppb and of dieldrin 147.11 ppb.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗