Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat alpha1beta2gamma2L GABA(A) receptor.

ABSTRACT: Fipronil is the active ingredient in a number of widely used insecticides. Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABA(A) receptors in the brain. In this study, we have examined the modulation of the common brain GABA(A) receptor subtype by fipronil and its major metabolite, fipronil sulphone.Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat alpha1beta2gamma2L GABA(A) receptors.The major effect of fipronil was to increase the rate of current decay in macroscopic recordings. In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance. The alpha1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil. The mode of action of fipronil sulphone was similar to that of its parent compound but the metabolite was less potent at inhibiting the alpha1beta2gamma2L receptor.We conclude that exposure to fipronil induces accumulation of receptors in a novel, long-lived blocked state. This process proceeds in parallel with and independently of, channel desensitization. The lower potency of fipronil sulphone indicates that the conversion serves as a detoxifying process in mammalian brain.

SUBMITTER: Li P

PROVIDER: S-EPMC2584928 | biostudies-other | 2008 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

GABAA Receptor Subunit Composition Drives Its Sensitivity to the Insecticide Fipronil.

Project description:Fipronil (FPN) is a worldwide-used neurotoxic insecticide, targeting, and blocking GABAA receptors (GABAARs). Beyond its efficiency on insect GABAARs, FPN causes neurotoxic effects in humans and mammals. Here, we investigated the mode of action of FPN on mammalian α6-containing GABAARs to understand its inhibitory effects on GABA-induced currents, as a function of the synaptic or extrasynaptic localization of GABAARs. We characterized the effects of FPN by electrophysiology using Xenopus oocytes which were microtransplanted with cerebellum membranes or injected with α6β3, α6β3γ2S (synaptic), and α6β3δ (extrasynaptic) cDNAs. At micromolar concentrations, FPN dose-dependently inhibited cerebellar GABA currents. FPN acts as a non-competitive antagonist on ternary receptors. Surprisingly, the inhibition of GABA-induced currents was partial for extra-synaptic (α6β3δ) and binary (α6β3) receptors, while synaptic α6β3γ2S receptors were fully blocked, indicating that the complementary γ or δ subunit participates in FPN-GABAAR interaction. FPN unexpectedly behaved as a positive modulator on β3 homopentamers. These data show that FPN action is driven by the subunit composition of GABAARs-highlighting the role of the complementary subunit-and thus their localization within a physiological synapse. We built a docking model of FPN on GABAARs, which reveals two putative binding sites. This is consistent with a double binding mode of FPN on GABAARs, possibly one being of high affinity and the other of low affinity. Physiologically, the γ/δ subunit incorporation drives its inhibitory level and has important significance for its toxicity on the mammalian nervous system, especially in acute exposure.

| S-EPMC8668240 | biostudies-literature

New GABA/glutamate receptor target for [³H]isoxazoline insecticide.

Project description:The highly effective and selective isoxazoline insecticide A1443 is known to potently displace [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB) binding to house fly head membranes with an IC50 of 0.2 nM in a manner characteristic of GABA-gated chloride channel antagonists. To further define its mode of action, we prepared phenyl-labeled [(3)H]A1443 as described with a specific activity of 14 Ci/mmol. This new radioligand with an apparent IC50 of about 0.4 nM is poorly displaced by most insecticides acting at the [(3)H]EBOB site. Interestingly, the isoxazoline binding site is directly coupled to the avermectin GABA/glutamate chloride channel activator site. These findings revive interest in the insect GABA/glutamate receptor as an insecticide target.

| S-EPMC3731417 | biostudies-literature

Development of an Immunoassay for the Detection of the Phenylpyrazole Insecticide Fipronil.

Project description:Phenylpyrazole insecticides such as fipronil have been used as replacements for organophosphates. The wide application of fipronil raises concern about environmental contamination and risk for fish, birds, and other nontargeted beings as well as human health. A sensitive, competitive indirect heterologous enzyme-linked immunosorbent assay (ELISA) was developed. Antibodies with different specificities to fipronil and its metabolites were produced. Two ELISAs having IC50 values of 0.58 ± 0.06 and 2.6 ± 0.4 ng/mL were developed. Design of different haptens and coating antigens resulted in two assays with distinct cross-reactivity patterns for structurally related compounds: 96, 38, and 101% versus 39, 1.4, and 25% for fipronil-sulfide, fipronil-detrifluoromethylsulfonyl, and fipronil-desulfinyl, respectively. Performance of the immunoassays was demonstrated by a recovery study from spiked water and human serum and urine matrices, giving recovery values in the range of 85-111% for different concentrations. The assays demonstrated good correlation in fipronil recovery with conventional LC-MS/MS analysis. The generic assay 2265 has the sensitivity to measure fipronil and its analogs in serum at levels relevant for exposure monitoring. The assays were used to analyze human urine samples obtained from exposure studies and serum samples from rats treated with a fipronil-containing diet.

| S-EPMC4605820 | biostudies-literature

Biomineralisation of fipronil and its major metabolite, fipronil sulfone, by Aspergillus glaucus strain AJAG1 with enzymes studies and bioformulation.

Project description:Fipronil is a phenylpryazole insecticide which is extensively used for the protection of agricultural yields. However, this insecticide poses various threats to the environment. Therefore it is essential to develop an effective method to degrade or eliminate this pollutant from the environment. In this present study, a fungal strain AJAG1 capable of degrading fipronil and its metabolite, fipronil sulfone, was isolated through enrichment technique. Isolated fungal strain was identified as Aspergillus glaucus based upon its morphological, and 18S rRNA sequence analysis. Strain AJAG1 could degrade 900 mg L-1 of fipronil efficiently in both aqueous medium and soil. In addition, fipronil degradation was tested with various kinetic models and the results revealed that biodegradation in aqueous medium and soil was ascertained by pseudo-first order and zero order rate kinetics, respectively. The infrared spectrum of fipronil degraded sample confirmed the formation of esters, nitro, and alkanes groups. A tentative degradation pathway of fipronil by strain AJAG1 has been proposed on the basis of gas chromatography-mass spectrometry (GC-MS) analysis. The lignolytic enzymes activities were studied during fipronil degradation by strain AJAG1. Further, scanning electron microscopy (SEM) was used to examine the surface morphology of strain AJAG1 after fipronil degradation. In the present investigation, bioformulation of strain AJAG1 was developed using low cost materials such as groundnut shell powder, molasses, and fly ash to remediate the fipronil from agricultural field. These results highlight A. glaucus strain AJAG1 may have potential for use in bioremediation of fipronil-contaminated environment.

| S-EPMC5493570 | biostudies-literature

Synergistic and compensatory effects of two point mutations conferring target-site resistance to fipronil in the insect GABA receptor RDL.

Project description:Insecticide resistance can arise from a variety of mechanisms, including changes to the target site, but is often associated with substantial fitness costs to insects. Here we describe two resistance-associated target-site mutations that have synergistic and compensatory effects that combine to produce high and persistent levels of resistance to fipronil, an insecticide targeting on ?-aminobytyric acid (GABA) receptors. In Nilaparvata lugens, a major pest of rice crops in many parts of Asia, we have identified a single point mutation (A302S) in the GABA receptor RDL that has been identified previously in other species and which confers low levels of resistance to fipronil (23-fold) in N. lugans. In addition, we have identified a second resistance-associated RDL mutation (R300Q) that, in combination with A302S, is associated with much higher levels of resistance (237-fold). The R300Q mutation has not been detected in the absence of A302S in either laboratory-selected or field populations, presumably due to the high fitness cost associated with this mutation. Significantly, it appears that the A302S mutation is able to compensate for deleterious effects of R300Q mutation on fitness cost. These findings identify a novel resistance mechanism and may have important implications for the spread of insecticide resistance.

| S-EPMC4997714 | biostudies-literature

Parasite-insecticide interactions: a case study of Nosema ceranae and fipronil synergy on honeybee.

Project description:In ecosystems, a variety of biological, chemical and physical stressors may act in combination to induce illness in populations of living organisms. While recent surveys reported that parasite-insecticide interactions can synergistically and negatively affect honeybee survival, the importance of sequence in exposure to stressors has hardly received any attention. In this work, Western honeybees (Apis mellifera) were sequentially or simultaneously infected by the microsporidian parasite Nosema ceranae and chronically exposed to a sublethal dose of the insecticide fipronil, respectively chosen as biological and chemical stressors. Interestingly, every combination tested led to a synergistic effect on honeybee survival, with the most significant impacts when stressors were applied at the emergence of honeybees. Our study presents significant outcomes on beekeeping management but also points out the potential risks incurred by any living organism frequently exposed to both pathogens and insecticides in their habitat.

| S-EPMC3310228 | biostudies-literature

Reprotoxic effects of the systemic insecticide fipronil on the butterfly <i>Pieris brassicae</i>.

Project description:In addition to controlling pest organisms, the systemic neurotoxic pesticide fipronil can also have adverse effects on beneficial insects and other non-target organisms. Here, we report on the sublethal effects of fipronil on the farmland butterfly Pieris brassicae. Caterpillars were reared on plants that had been grown from seeds coated with fipronil or on leaf discs topically treated with a range of fipronil dosages (1-32 µg kg-1 on dry mass basis). Females that had developed on fipronil plants laid ca half the number of eggs than females that had developed on control plants. In the bioassay with leaf discs, longevity and lifetime egg production declined with increasing fipronil dosage. Remarkably, exposure to fipronil during larval development primarily affected the adult stage. Chemical analyses of leaf tissues collected from seed-treated plants revealed concentrations of fipronil and its degradation products close to the analytical limit of detection (less than or equal to 1 µg kg-1). The effective dosage was fivefold higher in the leaf-disc than in the whole-plant experiment. In the whole plant, degradation of fipronil to products that are more toxic than fipronil may explain this discrepancy. Neurotoxicity of insecticides at the level of detection decreases the probability of pinpointing insecticides as the causal agent of harmful effects on non-target organisms.

| S-EPMC7126071 | biostudies-literature

Valerian inhibits rat hepatocarcinogenesis by activating GABA(A) receptor-mediated signaling.

Project description:Valerian is widely used as a traditional medicine to improve the quality of sleep due to interaction of several active components with the ?-aminobutyric acid (GABA) A receptor (GABA(A)R) system. Recently, activation of GABA signaling in stem cells has been reported to suppress cell cycle progression in vivo. Furthermore, possible inhibitory effects of GABA(A)R agonists on hepatocarcinogenesis have been reported. The present study was performed to investigate modulating effects of Valerian on hepatocarcinogenesis using a medium-term rat liver bioassay. Male F344 rats were treated with one of the most powerful Valerian species (Valeriana sitchensis) at doses of 0, 50, 500 and 5000 ppm in their drinking water after initiation of hepatocarcinogenesis with diethylnitrosamine (DEN). Formation of glutathione S-transferase placental form positive (GST-P(+)) foci was significantly inhibited by Valerian at all applied doses compared with DEN initiation control rats. Generation of 8-hydroxy-2'-deoxyguanosine in the rat liver was significantly suppressed by all doses of Valerian, likely due to suppression of Nrf2, CYP7A1 and induction of catalase expression. Cell proliferation was significantly inhibited, while apoptosis was induced in areas of GST-P(+) foci of Valerian groups associated with suppression of c-myc, Mafb, cyclin D1 and induction of p21(Waf1/Cip1), p53 and Bax mRNA expression. Interestingly, expression of the GABA(A)R alpha 1 subunit was observed in GST-P(+) foci of DEN control rats, with significant elevation associated with Valerian treatment. These results indicate that Valerian exhibits inhibitory effects on rat hepatocarcinogenesis by inhibiting oxidative DNA damage, suppressing cell proliferation and inducing apoptosis in GST-P(+) foci by activating GABA(A)R-mediated signaling.

| S-EPMC4242630 | biostudies-literature

Lethal and sub-lethal effects of the insecticide fipronil on juvenile brown shrimp Farfantepenaeus aztecus.

Project description:Chemical pesticides are widely used around the world, but at the same time, they may cause direct or indirect risks to many non-target organisms. Recent increased use of insecticides in coastal areas, for example to control invasive tawny crazy ants, raises concern that insecticides may affect ecologically and/or commercially important species found in estuaries. Here, we investigated the lethal and sub-lethal effects of fipronil on juvenile brown shrimp Farfantepenaeus aztecus over 29 days at five different nominal concentrations (0.1, 1.0, 3.0, 6.4, and 10.0?µg/L) in a laboratory experiment. Exposure to all of the fipronil treatments resulted in all individuals dying before the end of the experiment; whereas, no individual died in the control (0.0?µg/L). The 96-hour LC50 was determined to be 1.3?µg/L. Shrimp also experienced weight loss under all of the fipronil treatments. Inter-moult interval was increased from 12.2?±?1.64?day in the control group to 15.5?±?0.53?day in the 1.0??g/L treatment. Lipid content of shrimp increased significantly in a concentration-dependent manner. Finally, behavioral and body color changes were also observed under the fipronil treatments. We conclude F. aztecus is very sensitive to fipronil and monitoring is needed in coastal areas.

| S-EPMC6050305 | biostudies-literature

Garlic and allopurinol alleviate the apoptotic pathway in rats' brain following exposure to fipronil insecticide.

Project description:Fipronil can cause oxidative tissue damage and apoptosis. Our goal is to evaluate the antiapoptotic impact of garlic or allopurinol against fipronil neurotoxicity. Thirty-six mature male albino rats were separated into control, garlic aqueous extract (500 mg/kg), allopurinol (150 mg/L in their drinking water), fipronil (13.277 mg/kg), garlic+fipronil, and allopurinol+fipronil. Our results revealed that fipronil induced a significant increase in brain malondialdehyde, protein carbonyl levels as well as enzymatic antioxidant activities (superoxide dismutase, catalase, glutathione peroxidase, and xanthine oxidase), but glutathione-S-transferase recorded a significant decrease as compared to the control. In addition, fipronil significantly up-regulated the brain pro-apoptotic (Bax) and caspase -3 mRNA gene expression and induced DNA fragmentation but caused down-regulation in anti-apoptotic (Bcl-2) mRNA genes expression. Interestingly, co-administration with garlic or allopurinol improved the lipid peroxidation, antioxidant disturbance, and apoptosis induced by fipronil in the brain tissues. In conclusion, garlic or allopurinol reduced fipronil-induced apoptosis and reduced oxidative tissue damage, most likely through enhancing the tissue antioxidant defense system.

| S-EPMC10014746 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data