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PubMed2005

Transport and fate of dieldrin in poplar and willow trees analyzed by SPME.

Dieldrin is a hydrophobic organochlorine insecticide that is persistent in the environment. The fate and transport of dieldrin in trees is important both in the context of potential remediation, as well as food chain impacts through dieldrin transport to shoots and leaves. Experiments were conducted to measure the degree of dieldrin partitioning to plant tissue and the potential for biodegradation of dieldrin in the microbe rich tree rhizosphere. Dieldrin was analyzed in water and plant tissue using headspace solid-phase microextraction (SPME) coupled with gas chromatography. Poplar and willow saplings planted in soil and watered with 10 microgl(-1) dieldrin for up to 9 months showed no adverse effects due to dieldrin exposure and no dieldrin was observed in plant shoots with a method detection limit (MDL) of 7 ngg(-1). One-week hydroponic tests of poplar saplings exposed to aqueous dieldrin also showed no detection of dieldrin in shoots, with an average of 66% of the dieldrin partitioned to the plant roots and an overall mass balance recovery of 76% in the plant-water system. The root concentration factor (RCF) was found to be 30+/-3 ml water g(-1) root. Biodegradation of dieldrin was not observed in an aqueous batch bioreactor containing 8 microgl(-1) dieldrin, nutrients and bacteria from the root zone of a poplar sapling that had been exposed to dieldrin for 9 months. These results show that planting trees is likely to be safe and potentially useful at sites containing low-levels of dieldrin in groundwater.

Biodegradation, Environmental↗
PubMed1997

Absorption by sheep of dieldrin from contaminated soil.

OBJECTIVE: To study the accumulation of dieldrin residues in sheep from ingestion of contaminated soils was studied in two experiments. DESIGN: A controlled feeding study of sheep fed contaminated soils of different type at varying intervals. ANIMALS AND PROCEDURE: Thirty-four 2-year-old wethers were divided into four groups (one control sheep only) and fed water-soluble dieldrin or soil contaminated with aldrin and dieldrin at varying intervals in the first study. In a second study 34 similar sheep were divided into four treatments with one being a control. Sheep were fed sandy, high clay or high organic matter soils with similar dieldrin and aldrin concentrations. RESULTS: In the first study the concentration of dieldrin in the body fat of sheep dosed with dieldrin-contaminated soil was about half that in the body fat of sheep dosed with an equivalent amount of water-soluble dieldrin. The concentration of dieldrin was almost the same in sheep fed 500 micrograms of total dieldrin per day as it was in sheep fed 5000 micrograms every tenth day, over a 50-day period. In the second experiment sheep accumulated nearly three times as much pesticide from a soil with a high organic matter content, and about four times as much from a soil with a high clay content, as from a sandy soil with the same dieldrin content, over a 100-day period. The half-life of dieldrin in the fat of all sheep varied between 96 and 116 days after sheep caused ingesting contaminated soil. CONCLUSIONS: Dieldrin concentrations in the fat of sheep that consume dieldrin contaminated soil fall within 10 days of removal from the source of contamination. However, dieldrin accumulates in the wool of sheep that consume dieldrin contaminated soil.

Absorption↗
PubMed1998

Role of oxidative stress in the selective toxicity of dieldrin in the mouse liver.

Dieldrin, an organochlorine insecticide, induces hepatic tumors in mice but not in rats. Although the mechanism(s) responsible for this species specificity is not fully understood, accumulating evidence indicates that oxidative stress may be involved. This study examined the association of dieldrin-induced hepatic DNA synthesis with the modulation of biomarkers of oxidative damage to lipids (malondialdehyde [MDA]) and DNA (8-hydroxy-2-deoxyguanosine [oh8dG]), in male B6C3F1 mice and F344 rats fed dieldrin (0.1, 1.0, or 10 mg/kg diet) for 7, 14, 28, and 90 days. The nonenzymatic components of the antioxidant defense system (ascorbic acid, glutathione, and alpha-tocopherol) were also examined. Increased urinary MDA was observed in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet for 7, 14, 28, and 90 days; while increased hepatic MDA was seen only after 7 days in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet and after 14 days in mice fed 10 mg/kg diet. In rats, dieldrin had no effect on either hepatic MDA or urine MDA levels after 7, 14, and 28 days of treatment. A dose-dependent increase in urinary MDA was observed in rats at the 90-day sampling time. The only significant elevation in urinary or hepatic oh8dG content was limited to urinary oh8dG in mice fed 10 mg/kg dieldrin diet for 14 days. Dietary dieldrin produced sustained decreases in hepatic and serum alpha-tocopherol and sustained elevations in hepatic ascorbic acid in both mice and rats. Rats, however, possessed a three- to four-fold higher content of endogenous or basal (control) hepatic alpha-tocopherol; and, even when fed 10 mg dieldrin/kg diet, the levels of hepatic alpha-tocopherol were maintained at higher levels than those of mice fed control diet. In both rats and mice fed dieldrin, transient (14 and 28 days on diet) elevations in hepatic glutathione were observed. These data support the hypothesis that the species specificity of dieldrin-induced hepatotoxicity may be related to dieldrin's ability to induce oxidative stress in the liver of mice, but not in rats. Only in mice fed dieldrin was a temporal association of increases in hepatic MDA content and hepatic DNA synthesis seen, suggesting that oxidative damage (shown by increased lipid peroxidation) may be involved in early events in dieldrin-induced hepatocarcinogenesis. Rats may be protected from dieldrin-induced oxidative stress by a more effective antioxidant defense system, characterized by higher basal levels of hepatic alpha-tocopherol and ascorbic acid than that seen in the mouse.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1988

Dieldrin activates rat neutrophils in vitro.

Suppression of phagocytic cell function has been proposed as a possible mechanism for the enhanced sensitivity to certain infectious agents exhibited by animals exposed to the organochloride insecticide, dieldrin. In the present study, we examined the effects of dieldrin on superoxide production by glycogen-elicited peritoneal neutrophils (PMNs) from the rat. Dieldrin caused a concentration-dependent increase in superoxide production by PMNs incubated in vitro at 37 degrees C. Superoxide release was increased significantly with 10 microM dieldrin and reached a maximum of 17 nmol/10 min/2.0 X 10(6) PMNs at a dieldrin concentration of 35 microM. Preincubation of PMNs for 5 min at room temperature with a barely suprathreshold concentration of either phorbol 12-myristate 13-acetate (PMA) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) enhanced dieldrin-stimulated superoxide release by as much as ninefold or threefold, respectively. Maximum enhancement was obtained with 10 microM dieldrin for both PMA and FMLP. Time course studies with PMA-pretreated cells revealed that the rate of superoxide release was dependent on the concentration of dieldrin. Extracellular calcium played an important role in dieldrin-stimulated superoxide release, since PMNs treated with dieldrin in the absence of extracellular calcium did not release superoxide. Also, pretreatment with calcium ionophore A23187 greatly enhanced superoxide release from dieldrin-stimulated PMNs. These results show that dieldrin has a stimulatory effect on superoxide release from rat PMNs in vitro and that this stimulation is dependent on extracellular calcium.

Animals↗
PubMed1977

Accumulation and elimination of dieldrin in muscle tissue of channel catfish.

Dieldrin accumulation and elimination in muscle tissue of channel catfish (Ictalurus punctatus) from water and food was determined in the laboratory. Twenty-eight-day exposure of fish 150-225 mm and 350-400 mm long to 75 parts per trillion (ng/liter) dieldrin resulted in the larger catfish consistently accumulating more dieldrin than the smaller fish. After 28 days of elimination, dieldrin levels in both size groups were nearly equal. Catfish exposed to 2 ppm (mg/kg) dieldrin through their diets accumulated significantly more dieldrin in muscle than did fish exposed to 75 pptr in water. When fish were exposed to dieldrin both in food and water, dieldrin from both sources contributed to the total dieldrin load. Large catfish accumulated more dieldrin from food and water than did smaller catfish. After 28 days of elimination, levels of dieldrin were not significantly different in muscles of 150-225 mm and 350-440 mm catfish exposed via both food and water.

Animal Feed↗
PubMed1985

The effects of phenobarbital, atropine, L-alpha-methyldopa, and DL-propranolol on dieldrin-induced hyperglycemia in the adult rat.

The hyperglycemic response of adult male Wistar rats given dieldrin (63 mg/kg, po) and either phenobarbital (40 mg/kg, ip), atropine (4 mg/kg, sc), L-alpha-methyldopa (200 mg/kg, ip), or DL-propranolol (8 mg/kg, sc) was studied. The hyperglycemia was maximal (73% above control values) 2 hr after exposure to dieldrin alone. Phenobarbital reduced the hyperglycemia by 41% and abolished dieldrin-induced convulsions. It also prevented the increases that dieldrin causes in hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity. These results suggest that the dieldrin-induced hyperglycemia is mediated via the CNS. Atropine prevented the hyperglycemia for 2 hr and delayed the attainment of maximal glucose concentrations for another 2 hr. However, additional atropine 4, 8, 12, and 18 hr after the dieldrin had no effect. Atropine also increased (125%) the time to the onset of dieldrin-induced convulsions. It did not alter hepatic PEPCK activity. L-alpha-Methyldopa decreased (24%) the hyperglycemic response in the first 2 hr after dieldrin treatment. It caused similar reductions in blood glucose when given during the peak hyperglycemic response. L-alpha-Methyldopa also reduced (49%) the dieldrin-effected increase in hepatic PEPCK activity. DL-Propranolol did not alter the effects of dieldrin. Thus these data suggest that the dieldrin-induced hyperglycemia is mediated by the CNS, primarily via enhanced cholinergic activity and secondarily by increased alpha-adrenergic activity. It is suggested that the pancreas responds to the cholinergic outflow by increasing the secretion of glucagon while simultaneously responding to the alpha-adrenergic outflow by decreasing insulin secretion.

Administration, Oral↗
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↗
PubMed2005

Reductive transformation of dieldrin under anaerobic sediment culture.

A pathway of dieldrin transformation to aldrin by epoxide reduction was found in this study. Investigation of dieldrin degradation under anaerobic conditions was performed with a mixed culture containing indigenous microorganisms obtained from sediment of the Er-Jen River in Taiwan. During the incubation, the transformation of dieldrin to aldrin was analyzed by GC-ECD and GC-MS. Effects of incubation factors including dieldrin concentrations, incubation temperatures and kinds of carbon sources on the degradation of dieldrin were also studied. Original concentrations (from 0.5 to 10 microg ml(-1)) of dieldrin affect the transformation rate of dieldrin, and lower concentrations indicated the higher degradation rates. But once the concentration higher than 100 microg ml(-1), almost no degradation occurred. The optimal temperature for degradation in mixed culture was found at 40 degrees C in this study. Dieldrin transformation rates varied with the type of major carbon sources in the mixed culture and were in order of yeast extract > sodium acetate > glucose. In addition, the denaturing gradient gel electrophoresis (DGGE) fingerprint revealed that four microbials evolved in dieldrin-amended cultures, but not in the dieldrin-free cultures. Partial sequence of 16S rDNA for these four organisms exhibited 94-99% similarity to those of genera Clostridium, Acidaminobacter and an uncultured bacterial group. These results suggest that the four microbials might promote the dieldrin transformation.

Anaerobiosis↗
PubMed2003

Dieldrin induces apoptosis by promoting caspase-3-dependent proteolytic cleavage of protein kinase Cdelta in dopaminergic cells: relevance to oxidative stress and dopaminergic degeneration.

We previously reported that dieldrin, one of the potential environmental risk factors for development of Parkinson's disease, induces apoptosis in dopaminergic cells by generating oxidative stress. Here, we demonstrate that the caspase-3-dependent proteolytic activation of protein kinase Cdelta (PKCdelta) mediates as well as regulates the dieldrin-induced apoptotic cascade in dopaminergic cells. Exposure of PC12 cells to dieldrin (100-300 microM) results in the rapid release of cytochrome C, followed by the activation of caspase-9 and caspase-3 in a time- and dose-dependent manner. The superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid)porphyrin chloride significantly attenuates dieldrin-induced cytochrome C release, indicating that reactive oxygen species may contribute to the activation of pro-apoptotic factors. Interestingly, dieldrin proteolytically cleaves native PKCdelta into a 41 kDa catalytic subunit and a 38 kDa regulatory subunit to activate the kinase. The dieldrin-induced proteolytic cleavage of PKCdelta and induction of kinase activity are completely inhibited by pretreatment with 50-100 microM concentrations of the caspase inhibitors benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) and benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK), indicating that the proteolytic activation of PKCdelta is caspase-3-dependent. Additionally, Z-VAD-FMK, Z-DEVD-FMK or the PKCdelta specific inhibitor rottlerin almost completely block dieldrin-induced DNA fragmentation. Because dieldrin dramatically increases (40-80-fold) caspase-3 activity, we examined whether proteolytically activated PKCdelta amplifies caspase-3 via positive feedback activation. The PKCdelta inhibitor rottlerin (3-20 microM) dose-dependently attenuates dieldrin-induced caspase-3 activity, suggesting positive feedback activation of caspase-3 by PKCdelta. Indeed, delivery of catalytically active recombinant PKCdelta via a protein delivery system significantly activates caspase-3 in PC12 cells. Finally, overexpression of the kinase-inactive PKCdelta(K376R) mutant in rat mesencephalic dopaminergic neuronal cells attenuates dieldrin-induced caspase-3 activity and DNA fragmentation, further confirming the pro-apoptotic function of PKCdelta in dopaminergic cells. Together, we conclude that caspase-3-dependent proteolytic activation of PKCdelta is a critical event in dieldrin-induced apoptotic cell death in dopaminergic cells.

Animals↗
PubMed2005

Cross-resistance between dieldrin and fipronil in German cockroach (Dictyoptera: Blattellidae).

The toxicity of fipronil and dieldrin was determined in one susceptible laboratory strain and seven insecticide-resistant field-collected strains of Blattella germanica (L). The Zo960302 and Ga021001 strains were 1,270- and 2,030-fold resistant to dieldrin and 15- and 14-fold resistant to fipronil. The Su960304 and Od010803 strains were 15- and 13-fold resistant to dieldrin and two- and four-fold resistant to fipronil. Three strains showed no or a low level of resistance to dieldrin and fipronil. Crosses were performed between the susceptible strain Danish Pest Infestation Laboratory (DPIL)-SUS and the resistant strains Zo960302 and Su960304 and resistance to dieldrin and fipronil were intermediate compared with the susceptible and the resistant strains. Backcrosses to both of the parental strains showed cosegregation of dieldrin and fipronil resistance. The toxicity of dieldrin and fipronil was correlated when compared at LD50, and 93% of the observed variation in LD50 of fipronil can be ascribed to variation among predictions based on the value of LD50 of dieldrin. The frequency of the A302S substitution in the resistance to dieldrin (Rdl) gene in the highly dieldrin- and fipronil-resistant strains Zo960302 and Ga021001 and the moderately resistant Su960304 was 0.97, 1.0, and 0.38, respectively. We consider the connection between the frequency of the Rdl mutation and dieldrin and fipronil resistance a causal connection and not merely a coincidence.

Animals↗
PubMed2001

Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells.

We examined the acute toxicity of dieldrin, a possible environmental risk factor of Parkinson's disease, in a dopaminergic cell model, PC12 cells, to determine early cellular events underlying the pesticide-induced degenerative processes. EC(50) for 1 h dieldrin exposure was 143 microM for PC12 cells, whereas EC(50) for non-dopaminergic cells was 292-351 microM, indicating that dieldrin is more toxic to dopaminergic cells. Dieldrin also induced rapid, dose-dependent releases of dopamine and its metabolite, DOPAC, resulting in depletion of intracellular dopamine. Additionally, dieldrin exposure caused depolarization of mitochondrial membrane potential in a dose-dependent manner. Flow cytometric analysis showed generation of reactive oxygen species (ROS) within 5 min of dieldrin treatment, and significant increases in lipid peroxidation were also detected following 1 h exposure. ROS generation was remarkably inhibited in the presence of SOD. Dieldrin-induced apoptosis was significantly attenuated by both SOD and MnTBAP (SOD mimetic), suggesting that dieldrin-induced superoxide radicals serve as important signals in initiation of apoptosis. Furthermore, pretreatment with deprenyl (MAO-inhibitor) or alpha-methyl-L-p-tyrosine (TH-inhibitor) also suppressed dieldrin-induced ROS generation and DNA fragmentation. Taken together, these results suggest that rapid release of dopamine and generation of ROS are early cellular events that may account for dieldrin-induced apoptotic cell death in dopaminergic cells.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Overview of human exposure to dieldrin residues in the environment and current trends of residue levels in tissue.

An overview of available literature indicates that dieldrin residues are still found routinely in soil, air, water, and food, despite the 1974 U.S. Environmental Protection Agency ban on the use of aldrin and dieldrin. Dieldrin residue levels in environmental substrates, which are indicative of aldrin or dieldrin use, have decreased significantly since the mid-1960s, the peak usage years. However, human tissue studies do not show a corresponding decline in dieldrin residue levels. Thirteen studies, conducted between 1963 and 1976, show that average dieldrin levels in human adipose tissue and human milk fat remain between 0.160 ppm and 0.220 ppm. Other studies suggest that an equilibrium exists in the distribution of dieldrin among various tissues in humans, including blood, fat, brain, and liver. This relationship indicates that the concentration of dieldrin in any tissue may be used as an index of total body burden. Thus it appears that the concentration of dieldrin in the human body has reached a constant level at which the amount ingested and absorbed equals the amount metabolized and excreted. The mechanism of the stable concentrations is unknown, as are the possible health effects of chronic, low-level exposure to dieldrin.

Adipose Tissue↗
PubMed1991

Teratogenesis, toxicity, and bioconcentration in frogs exposed to dieldrin.

Teratogenesis, acute and chronic toxicity, growth and bioconcentration were investigated in various life stages (embryos, tadpoles, juveniles, adults) of the frogs Xenopus laevis (African clawed frog), Rana catesbeiana (bullfrog) and Rana pipiens (leopard frog) exposed to aqueous dieldrin in static-renewal and flow-through systems in a study on the development of wildlife-based water quality criteria. R. catesbeiana was the most sensitive tadpole in acute tests; X. laevis was the most sensitive in embryo-larval and chronic tadpole tests. Tadpole 96-h LC50s ranged from 40.4 to 49.5 micrograms/L dieldrin for X. laevis, from 8.7 to 30.3 micrograms/L for R. catesbeiana and was 71.3 micrograms/L for R. pipiens. The 24-day LC50 for X. laevis tadpoles was 5.5 micrograms/L dieldrin; the 28-day LC50 for R. pipiens tadpoles was 8.3 micrograms/L. Adult R. pipiens had a 28-day LC50 of 53.4 micrograms/L dieldrin. Gross spinal deformities in embryo-larval tests were observed at dieldrin concentrations as low as 1.3 micrograms/L after 10-days exposure to X. laevis and at 25.4 micrograms/L for a 21-day exposure to R. catesbeiana. Mean X. laevis 14 to 21-day LOAEL (Lowest Observed Adverse Effect Level) and NOAEL (No Observed Adverse Effect Level) values for embryo-larval tests (25.5 and 11.0 micrograms/L dieldrin, respectively) were virtually the same as the 21-day single test values obtained for R. catesbeiana (25.1 and 11.0 micrograms/L dieldrin). Mean 14 to 24-day X. laevis LOAEL and NOAEL values for tadpole chronic tests (1.6 and less than 1.4 micrograms/L dieldrin, respectively) were lower than the 28-day single test values obtained for R. pipiens (4.1 and 1.9 micrograms/L, respectively). Tissue dieldrin levels at the LC50, LOAEL and NOAEL in the tadpole acute tests were fairly similar between X. laevis (11, 24 and 7 micrograms/g, respectively) and R. catesbeiana (means of 8.6, 12.0 and 1.2 micrograms/g, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Dieldrin stimulates biliary excretion of 14C-benzo[a]pyrene polar metabolites but does not change the biliary metabolite profile in rainbow trout (Oncorhyncus mykiss).

Activities of hepatic microsomal and cytosolic epoxide hydrolases, accumulation of dieldrin in liver, and in vivo metabolism and disposition of the polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BP), were examined in rainbow trout pretreated with dieldrin, a chlorinated cyclodiene insecticide. Rainbow trout were fed 0.3 mg dieldrin/kg/day for 9 weeks and the same dose of dieldrin for 9 weeks, followed by 3 weeks on control diet (12 weeks). Fish then received an intraperitoneal (ip) challenge dose of 14C-BP (10 micromol/kg). Dieldrin pretreatment significantly elevated the concentration of 14C-BP in bile (142% and 200% at 9 and 12 weeks, respectively), but not liver or fat. Extraction of bile subsamples confirmed dieldrin pretreatment significantly stimulated total biliary excretion of 14C-BP polar metabolites (244% and 221% at week 9 and 12, respectively). The complex metabolism of BP characterized the in vivo state of the CYP system, UDP-glucuronyltransferases, and sulfotransferases. Bile was extracted and then hydrolyzed by beta-glucuronidase and arylsulfatase to regenerate BP metabolites conjugated by phase II enzymes. Evaluation of biliary polar metabolite profiles of 14C-BP revealed no significant differences between control and dieldrin-fed fish. There was no selective enhancement of any particular metabolite, or formation of a novel metabolite with dieldrin pretreatment. This research confirmed that enhanced biliary excretion, following chronic dieldrin exposure, was not explained by induction of xenobiotic metabolizing enzymes. The results are consistent with induction of hepatic intracellular trafficking proteins in dieldrin-fed fish.

Animals↗
PubMed2003

Differential actions of fipronil and dieldrin insecticides on GABA-gated chloride channels in cockroach neurons.

Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to fipronil and dieldrin. We examined differential actions of fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.

Animals↗
PubMed2005

Dieldrin induces ubiquitin-proteasome dysfunction in alpha-synuclein overexpressing dopaminergic neuronal cells and enhances susceptibility to apoptotic cell death.

Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein. Overexpression of wild-type alpha-synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0-70 microM) decreased proteasomal activity, and 30 microM dieldrin inhibited activity by more than 60% in alpha-synuclein cells. Confocal microscopic analysis of dieldrin-treated alpha-synuclein cells revealed that alpha-synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The dieldrin-induced proteasomal dysfunction in alpha-synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after dieldrin treatment and that alpha-synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of alpha-synuclein cells to dieldrin-induced apoptosis. Together, our results suggest that increased expression of alpha-synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as dieldrin.

Animals↗
PubMed1994

Dual action of the cyclodiene insecticide dieldrin on the gamma-aminobutyric acid receptor-chloride channel complex of rat dorsal root ganglion neurons.

The gamma-aminobutyric acidA (GABAA) receptor-chloride channel complex is known to be the target site of dieldrin, a cyclodiene insecticide, and lindane. In order to elucidate the mechanisms of dieldrin interaction with the GABA system, whole-cell patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. When co-applied with GABA, dieldrin exerted a dual effect on the GABA-induced chloride current. The chloride current induced by 10 microM GABA was greatly enhanced by the first 20-sec co-application with 1 microM dieldrin, but the enhancement subsided during repeated co-applications, and the current was eventually suppressed below the control level. No recovery occurred after a prolonged washing with dieldrin-free solution. Desensitization of the chloride current was accelerated by dieldrin. However, when the period of co-application was limited to 2 sec, which was short enought to avoid desensitization, no suppression of current was observed during repeated co-applications and recovery occurred after washing. The desensitization and suppression occurred with an EC50 of 92 nM, whereas the enhancement required a higher EC50 at 754 nM. The GABA-induced chloride current comprised two components, one with a high sensitivity to dieldrin suppression with an EC50 of 5 nM and the other with a lower sensitivity with an EC50 of 92 nM. Dieldrin exerted its inhibitory effect on the GABA-induced current regardless of the presence or absence of pentobarbital and chlordiazepoxide. However, its effect was attenuated by the presence of picrotoxin. Furthermore, dieldrin suppressed the GABA-induced chloride current in a noncompetitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Regulation of GABA(A) receptor subunit mRNA expression by the pesticide dieldrin in embryonic brainstem cultures: a quantitative, competitive reverse transcription-polymerase chain reaction study.

Cyclodiene organochlorine pesticides, such as dieldrin, inhibit gamma-aminobutyric acid (GABA)ergic neurotransmission by blocking the Cl- channel of GABA(A) receptors. This action may make the developing nervous system especially vulnerable to these neurotoxins, which could interfere with the trophic actions of GABA on developing neurons and alter expression of GABA(A) receptors. We have used an in vitro model to determine whether exposure to dieldrin alters developmental expression of GABA(A) receptor subunit mRNA transcripts. Dissociated cell cultures were prepared from embryonic day 14 (E14) brainstem and cultured in serum-containing medium for 1 day in vitro (DIV), then treated for 2 DIV with 10 microM dieldrin in serum-free medium. This dose was based on preliminary experiments and previous studies (Nagata et al.: Brain Res 645:19-26, 1994; Pomes et al.: J Pharmacol Exp Ther 271:1616-1623, 1994). Absolute amounts of alpha1, beta3, gamma1, gamma2S and gamma2L mRNA transcripts were quantified in these cultures by quantitative, competitive reverse transcription-polymerase chain reaction (RT-PCR) using subunit-selective internal standards. The most abundant GABA(A) subunit transcript was beta3, which was much more highly expressed than gamma2S, gamma1, gamma2L, or alpha1 subunit mRNAs. Dieldrin differentially regulated expression of these transcripts. Levels of beta3 subunit transcripts were significantly increased (by 300%) by dieldrin, whereas expression of gamma2S and gamma2L transcripts were decreased (by 50% and 40%, respectively). However, dieldrin did not alter the ratio of gamma2S to gamma2L transcripts, indicating that it did not affect alternative splicing of gamma2 transcripts. Dieldrin appeared to increase expression of alpha1 subunit transcripts, but this effect was not statistically significant. Dieldrin did not significantly alter expression of gamma1 subunit transcripts. These results support the hypothesis that in utero exposure to cyclodiene pesticides could pose a risk to the developing brain by virtue of their ability to alter gene expression of GABA(A) receptor subunits, which could produce GABA(A) receptors with altered functional properties.

Animals↗