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The effects of dieldrin and chlordimeform on learning and memory in the cockroach, Periplaneta americana: a study in behavioral toxicology.

A one-session T-maze training procedure for cockroaches in which animals were trained to turn right or left to avoid a shock was utilized to investigate the effects of dieldrin and chlordimeform (two neurotoxic pesticides) on learning and memory. These animals were trained and then tested for retention 5 h later. Three behavioral measures were recorded: choice behavior or direction turned, the time taken to proceed down the runway (runway time), and the time taken to proceed from the runway to either choice arm (choice point time). In control animals the number of correct choices, the runway time, and the choice point time increased with succeeding trials during training. Furthermore, control animals showed retention of correct choice behavior from training to testing. A nontoxic dose (no overt behavioral signs) of dieldrin was injected 2 h before training or 15 min after training. Pretraining injections of dieldrin eliminated correct-choice learning but did not alter the increase with training in runway or choice point times. Posttraining dieldrin administration did not interfere with retention of correct-choice behavior upon testing. These findings indicate that dieldrin induces behavioral alterations in a low acute dose and that detrimental effects are more likely with more complex behavior. Furthermore, behavioral disruption is more likely the closer exposure is to the initial learning of a task. Nontoxic doses of chlordimeform injected 1 h before training eliminated correct-choice learning and facilitated an increase in runway times during training.

Amidines↗

Comparison of gas chromatography and immunoassay methods in measuring the distribution of dieldrin in rainbow trout tissues.

Studies have been conducted to determine the distribution of dieldrin in various tissues of rainbow trout when exposed to several dieldrin concentrations. Medium sized fish with an average weight and length of 195.4 +/- 30.5 g and 25.7 +/- 1.4 cm, respectively, were placed in groups of 6 in 300 L tanks containing purified and aerated water and maintained at 10 degrees C. Following an acclimatization period of 10 days, each group of fish was exposed to one of four dieldrin concentrations ranging from 50 to 80 ppb. After 24 hours, the fish were taken out of the tanks and sacrificed. The brain, gills, liver, muscles and skin were collected from each fish. Dieldrin was extracted from each tissue using SPE techniques and analyzed by both gas chromatography (GC) and enzyme linked immunosorbent assay (ELISA). Results of analyses by the two techniques were highly correlated. The results also showed that liver and skin tissues had the highest level of dieldrin residues. In comparing the means of the six fish samples, it was found that liver or skin contained about 1.5-fold the level in brain, about 4.0 fold the level in muscles and about 6.5 fold the level in gills. Immunoassay proved to be as reliable an analytical tool as gas chromatography in this case.

Animals↗

Selective dieldrin promotion of hepatic focal lesions in mice.

Chronic exposure to a number of chlorinated pesticides, including dieldrin, results in an increased incidence and/or multiplicity of hepatocellular neoplasia in mice, with no such effect in similarly treated rats. One possible explanation of this observed selective carcinogenicity is species-specific hepatic tumor promotion. In the present study we examined the dose-response effect of dieldrin (at several doses) on focal lesion growth (tumor promotion), hepatocyte apoptosis and DNA synthesis in rat and mouse liver. Preneoplastic focal hepatic lesions were produced by diethylnitrosamine (DEN). After the lesions developed, mice and rats were placed into one of the following dose groups: control (NIH-07 diet) or 0.1, 1.0 or 10.0 mg dieldrin/kg diet. Increased focal lesion volume, number of foci per liver and focal DNA synthetic labeling index were observed in 10 mg dieldrin/kg diet-treated mice, but not in similarly treated rats. Dieldrin at dietary concentrations of 0.1 and 1.0 mg/kg diet produced an increase in the number of preneoplastic lesions (0.1 mg/kg diet at 7 days only) and focal volume (0.1 mg/kg diet at 7 and 30 days, 1.0 mg/kg diet at 30 days), but these concentrations did not increase focal DNA labeling index. At dietary concentrations of 0.1, 1.0 and 10 mg dieldrin/kg diet no significant change in lesion percent volume, number of preneoplastic lesions per liver or preneoplastic lesion DNA labeling index was seen in treated rats compared with control rats. Apoptosis, a form of programed cell death, was not decreased in foci by any concentration of dieldrin in either rats or mice. Thus our results suggest that dieldrin may function as a mouse-specific tumor promoter through increased lesion DNA synthesis.

Animals↗

Dose-response analysis of the enhancement of liver tumour formation in CF-1 mice by dieldrin.

The current study was undertaken to investigate the dose-response characteristics of dieldrin-mediated enhancement of liver tumour formation in CF-1 mice. The median time to tumour development was established in controls, and in dieldrin-treated animals at six levels of continuous exposure (0.1, 1, 2.5, 5, 10 and 20 p.p.m.). The results of the analysis, which was based on liver tumour data from two parallel chronic feeding studies involving 1800 mice, are at variance with those reported by Druckrey for various established chemical carcinogens. In a double-logarithmic system of coordinates there was no linear relationship between the median total dose or the median time to tumour formation and the daily dieldrin exposure level. These results suggest that the tumourigenicity of this compound in CF-1 mouse liver is determined not by the sum of all consecutive doses, but rather by the level of daily exposure, and, presumably, the duration of treatment. This concept is consistent with the observed dose-dependency and reversible nature of dieldrin-induced subcellular changes in mouse liver. These considerations, together with evidence that dieldrin and its mammalian metabolites possess neither genotoxic activity nor potential, are not inconsistent with the concept that this compound is devoid of initiating potential, and operates by enhancing the effect of a genetically linked oncogenic factor in CF-1 mouse liver.

Adenoma↗

Quantitative aspects of enhanced liver tumour formation in CF-1 mice by dieldrin.

The dose-response characteristics of dieldrin-mediated enhancement of liver tumour formation in CF-1 mice were analysed, using existing tumour data from chronic feeding studies at six levels of continuous exposure, involving a total of greater than 1500 animals. The dose-response relationship can be expressed as: Dx X Tx = D0 X T0 = constant, where T0 = the median liver tumour induction period in control CF-1 mice, Tx = the median liver tumour induction period in dieldrin-treated mice at a dose level Dx, D0 = the background dose equivalent for the induction of 'spontaneous' liver tumours, Dx = the sum of background dose (D0) and actual dieldrin dose (delta x). The relationship, which is a Druckrey equation (D X Tn = constant) where n = 1, indicates that: (i) the velocity of liver tumour development is proportional to the daily dose level (Dx), (ii) the total tumourigenic dose is constant across all doses, (iii) the effects of dieldrin on the neoplastic process in mouse liver are essentially irreversible and cumulative, and (iv) there is no evidence for a threshold level. However, when delta x much less than D0, the actual contribution of dieldrin to tumour formation is expected to be negligible.

Animals↗

Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease.

Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Heme oxygenase-1 induction by dieldrin in dopaminergic cells.

We investigated the transcriptional events and signaling pathways involved in the induction of heme oxygenase-1 (HO-1) by dieldrin, an environmental risk factor of Parkinson's disease, in a dopaminergic neuronal cells (SN4741). Dieldrin exposure caused dose-dependent and time-dependent induction of heme oxygenase activity and HO-1 protein expression. Deletional and mutational analyses showed that the 5' distal enhancers, E1 and E2, mediate dieldrin-induced HO-1 gene transcription, and the AP-1 DNA binding sites in the E2 enhancer are critical for E2-mediated HO-1 gene activation. Furthermore, both the p38 and JNK mitogen-activated protein kinase pathways are utilized for HO-1 transcriptional activation by dieldrin. HO-1 inhibitor, ZnPP IX reduced the expression of HO-1 but enhanced the cytotoxicity induced by dieldrin.

Animals↗

Fatal association between dieldrin-resistant and susceptible Australian sheep blowflies, Lucilia cuprina.

A novel phenomenon of interactions between genotypes of the dieldrin-resistance (Rdl) locus of the Australian sheep blowfly (Lucilia cuprina) is described. Susceptible adult flies exposed to dieldrin-resistant (Rdl/Rdl or Rdl/S) adults, raised from larvae grown on media containing sublethal concentrations of dieldrin, display mortality related to the concentration on which the resistant flies developed. The resistant flies excrete quantities of dieldrin that are toxic to susceptible flies. These observations provide an additional mechanism to those previously identified for the rapid evolution of resistance to dieldrin by L. cuprina.

Animals↗

Aldrin and dieldrin residues in human fat, milk and blood serum collected from Delhi.

1. Aldrin and dieldrin residues were monitored in the fat, breast milk and blood serum from female residents of Delhi. 2. The average aldrin and dieldrin contents were 0.048 and 0.099 ppb in adipose tissue, 0.003 and 0.060 ppb in breast milk and 0.004 and 0.002 ppb in blood serum, respectively. 3. The older donors contained higher levels of aldrin and dieldrin in their adipose tissue. 4. Primagravidae contained more of these chemicals in their breast milk. 5. A positive correlation was observed between the aldrin concentration in adipose tissue and breast milk, and that in adipose tissue and blood serum. Similarly, a significant correlation was found between dieldrin in adipose tissue and blood serum. 6. The levels of aldrin and dieldrin were low in samples from residents of Delhi when compared to those in developed countries.

Adipose Tissue↗

Dieldrin reduces male production and sex ratio in Daphnia galeata mendotae.

We used the sex ratio of neonate Daphnia, as well as the more standard endpoints of adult survivorship and fecundity and neonatal morphology, as an assay for detecting the effects of the insecticides endosulfan and dieldrin. Dieldrin caused a decrease in sex ratio (number of males/number of males plus females); we observed no endosulfan effect. We estimated (by extrapolation) that the sex ratio was reduced by dieldrin from concentrations of about 30 ppb and higher, based on a linear decrease in sex ratio with log dieldrin concentrations from 50 to 600 ppb. Neither insecticide significantly affected adult survival or clutch size. Because sex ratio changed but total neonate production did not change, the data suggest that the effect of dieldrin was on the sex-determining system during embryogenesis. Neither insecticide caused morphological abnormalities. Mixtures of the two pesticides produced only additive effects.

Animals↗

Study on the absorption and protein binding of carbaryl, dieldrin and paraquat in rats fed on protein diet.

Carbaryl was well absorbed from the small intestine of rats. In the cytosol fraction of intestinal mucosa, it was bound to a smallmolecular component (M. W. 2,200 daltons). In serum, carbaryl was bound mainly to albumin and partly to globulins. Dieldrin was slowly absorbed from small intestine. The peak of dieldrin concentration in blood was observed 2.5 hr after the administration. Binding of dieldrin to mucosal protein in cytosol was not detectable. In serum, dieldrin was bound to lipoproteins, globulins and partly to albumin. Absorption of paraquat from the small intestine was more rapid than that of dieldrin in situ study. However, in vivo study, the absorption of paraquat was the lowest among these three chemicals. In the cytosol fraction of intestinal mucosa, paraquat was bound to a small-molecular component (M. W. 3,100 daltons). In serum, it was present in unbound fraction. In the comparative studies with protein diets, absorption of paraquat from small intestine in situ was higher in low protein diet rats than that in high protein diet rats. However, difference in absorption in vitro and in histopathological study was not noted between low protein diet rats and high protein diet rats.

Animals↗

Effect of sex hormones on the retention of dieldrin in the fat of growing chickens.

The effects of the bird's sex, castration, and sex hormone replacement on the retention of dieldrin in the carcass fat of growing chickens given low levels of dieldrin in the feed (1 mg/kg) were investigated. Confirmed were previous results that "best-fit" curves for depletion after noncontaminated feed was provided were represented by an equation of the form, y = aX-b, and that, with the approach of sexual maturity, males tend to retain greater concentrations of dieldrin in the carcass fat than females. This sex difference was partly a diluting effect of higher carcass fat deposition in females as compared to males. Additionally, when dieldrin feeding was discontinued after 10 weeks of age, androgen replacement in castrates restricted the clearance of dieldrin from the fatty tissue, and estrogen replacement did not further increase clearance over that of nontreated castrates.

Adipose Tissue↗

The effect of dieldrin-contaminated feed on rat hepatic microsomal epoxide hydrase and aryl hydrocarbon hydroxylase.

Adult male rats were exposed to dieldrin-contaminated rations. The hydroxylation of benzpyrene (AHH) and hydration of styrene oxide (EH) by the hepatic microsomal fraction were followed. At dieldrin levels of 5 to 25 ppm for one week, the EH activity increased from 19% to 115% above control levels respectively. Animals exposed to 25 ppm developed elevated EH activities after a few days, with a maximum increase of 2.5 times control levels after two weeks. AHH activity was not elevated over control levels at any dose or time studied. Slight but significant increases in levels of cytochrome P-450 were observed. Pentobartibal sleeping time was decreased to 61% of control levels after exposure to 20 ppm dieldrin-contaminated food for 7 days. Two days of intraperitoneal administration of technical grade dieldrin, analytical grade dieldrin and analytical grade aldrin gave similar increases in EH activity within this group. Again, no changes in AHH activity were seen.

Aldrin↗

The toxicity of dieldrin to man: report on a survey.

Increased use of dieldrin for malaria control has been caused by several factors, including sporadic resistance of some vectors to DDT. Poisoning of spray-men by dieldrin has been recognized in five widely separated countries and reported informally from several others. In some cases illness has recurred months after the last exposure. Observations of antimalaria programmes in Kenya, Tanganyika, Indonesia, India (Bombay State), and Iran and a review of the relevant literature have shown that the hazard associated with dieldrin is proportional to the degree of workers' exposure as determined by concentration of spray, area of bare skin, duration of contact, and lack of hygiene. Measurements of workers' exposure and a review of toxicity by different routes incriminates skin contamination as the greatest hazard under practical conditions. It is considered that dieldrin should not be used without justification; if it is required, then certain individual and group protective measures listed in this paper may minimize, but not necessarily eliminate, the risk. The author enumerates certain features of the toxicology of dieldrin which require intensive research.

Dieldrin↗

Dieldrin residues in soybeans in Illinois, 1965, 1966, 1967, 1971, and 1974.

The Illinois soybean crop was monitored in 1965, 1966, 1967, 1971, and 1974 for dieldrin residues resulting from aldrin applied to corn in the years before soybean cultivation. Residue levels of dieldrin in soybeans increased between 1965 and 1974. The percent of fields which had soybeans with a dieldrin level above 0.03 ppm increased between 1965 and 1974. Dieldrin residue levels in soybeans grown in Illinois are expected to decline now that the use of aldrin has diminished and will soon cease. No significant correlation was evident between the dieldrin levels in soybeans and the area of the State where they had grown, the date of planting, or the variety.

Acetonitriles↗

Reduced neuronal sensitivity to dieldrin and picrotoxinin in a cyclodiene-resistant strain of Drosophila melanogaster (Meigen).

Toxicological and neurophysiological studies were performed to characterize the resistance mechanism in a cyclodiene-resistant strain of Drosophila melanogaster (Maryland strain). Dieldrin had an LC50 of 0.058 ppm against the larvae of susceptible D. melanogaster (Oregon-R wild type) when formulated in the rearing media. The LC50 of the resistant Maryland strain was 10.8 ppm, giving a resistance ratio (LC50-Maryland/LC50-susceptible) of 186-fold. Suction electrode recordings were made from peripheral nerves of the larval central nervous system to test whether reduced nerve sensitivity played any role in the observed resistance. In susceptible preparations (n = 5), inhibition of nerve firing by 1 mM gamma-aminobutyric acid (GABA) was effectively antagonized within 3-10 min by 10 microM dieldrin. In contrast, 30 min incubations with 10 microM dieldrin had no effect on preparations from cyclodiene-resistant individuals (n = 5). Similarly, 10 microM picrotoxinin blocked GABA-dependent inhibition in susceptible nerve preparations (n = 3). In recordings from resistant insects (n = 4), picrotoxinin displayed either weak antagonism of GABA or hyperexcitation indistinguishable from susceptible preparations. These results demonstrate that cyclodiene resistance in the Maryland strain of D. melanogaster 1) is expressed in immature stages, 2) is present at the level of the nerve, and 3) extends to picrotoxinin, albeit at a reduced level compared with dieldrin. The possible role of an altered GABA receptor in this resistance is discussed.

Animals↗

Effects of L-ascorbic acid supplementation on dieldrin toxicity in rats.

Chronic dieldrin administration to rats (5 mg/kg/day) produced pathological changes in liver and kidney tissues. Dieldrin treated rats showed high levels of liver ascorbic acid and increased activities of inorganic pyrophosphatase in brain and glucose-6-phosphatase in liver. The activities of Mg2+-ATPase in liver and acetylcholinesterase in brain were decreased under toxic doses of dieldrin. L-Ascorbic acid supplements in treated animals could partially prevent the pathological alterations, as observed histologically in liver and kidney tissues. Administration of this vitamin could also prevent alterations in some enzyme activities produced by toxic dieldrin doses.

Animals↗

Toxic, neurochemical and behavioral effects of dieldrin exposure in mallard ducks.

Toxic, neurochemical and behavioral alterations were evaluated in ducks fed various dietary levels of dieldrin. Increasing amounts of dieldrin in the diet caused an appreciable decrease in the levels of three biogenic amines in whole brain, i.e. serotonin, norepinephrine and dopamine. No effect was noted in whole brain gamma aminobutyric acid contents. Hepatic microsomal enzymes were assayed in these birds using p-nitroanisol and O-ethyl-O-p-nitrophenyl benzenethionophosphate as substrates. Sublethal amounts of dieldrin caused an increase in hepatic drug metabolizing enzymes. Similar alterations were noted in liver protein, deoxyribonucleic acid and ribonucleic acid contents. Studies involving encounters between mallard drakes indicated a decline in the tendency for dieldrin exposed drakes to take the initiative and establish rights of access in approach confrontations. Although many of these changes are compatible with life processes, their significance is not well understood, especially in terms of lifelong exposure to persistent pesticides. The possible relationship between neurochemical alterations and the mechanisms of insecticide neurotoxicity is discussed.

Animals↗