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Use of chemical probes to explore the toxicological potential of the K/Cl cotransporter (KCC) as a novel insecticide target to control the primary vector of dengue and Zika virus, Aedes aegypti.
Prael FJ, Chen R, Li Z, Reed CW, Lindsley CW, Weaver CD, Swale DR
(2018) Pestic Biochem Physiol 151: 10-17
MeSH Terms: Aedes, Animals, Dengue, Drosophila, Insecticides, Mammals, Mosquito Vectors, Nervous System, Symporters, Zika Virus
Show Abstract · Added April 10, 2019
The majority of commercialized insecticides target the insect nervous system and therefore, neural proteins are well-validated targets for insecticide development. Considering that only a few neural targets are exploited for insecticidal action and the development of insecticide resistance has reduced the efficacy of current insecticidal classes, we sought to test the toxicological potential of the potassium-chloride cotransporter (KCC). In mammals, KCC proteins have seminal roles in shaping GABAergic signaling and inhibitory neurotransmission, thus ion transport through KCC is critical for proper neurotransmission. Therefore, we hypothesized that mosquito KCC represents a putative insecticide target site and that pharmacological inhibition of KCC constructs in Aedes aegypti will be lethal. To test this hypothesis, we developed a robust, cell-based fluorescence assay that enables in vitro characterization of small-molecules against Ae. aegypti KCC and performed a proof-of-concept study employing well characterized mammalian KCC modulators to determine the toxicological potential of Ae. aegypti KCC. The selective inhibitor of mammalian KCC, termed VU0463271, was found to be a potent inhibitor Ae. aegypti KCC and microinjection induced lethality in a concentration-dependent manner to susceptible and pyrethroid resistant strains. Importantly, an analog of VU0463271 was shown to be >40-fold less potent and did not induce toxicity, suggesting that the observed physiological effects and mortality are likely due to KCC inhibition. This proof-of-concept study suggests that Ae. aegypti KCC represents a putative target site for mosquitocide design that can mitigate the current mechanisms of insecticide resistance.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Larval exposure to predator cues alters immune function and response to a fungal pathogen in post-metamorphic wood frogs.
Groner ML, Buck JC, Gervasi S, Blaustein AR, Reinert LK, Rollins-Smith LA, Bier ME, Hempel J, Relyea RA
(2013) Ecol Appl 23: 1443-54
MeSH Terms: Animals, Behavior, Animal, Chytridiomycota, Fungi, Insecticides, Larva, Malathion, Metamorphosis, Biological, Ranidae
Show Abstract · Added May 20, 2014
For the past several decades, amphibian populations have been decreasing around the globe at an unprecedented rate. Batrachochytrium dendrobatidis (Bd), the fungal pathogen that causes chytridiomycosis in amphibians, is contributing to amphibian declines. Natural and anthropogenic environmental factors are hypothesized to contribute to these declines by reducing the immunocompetence of amphibian hosts, making them more susceptible to infection. Antimicrobial peptides (AMPs) produced in the granular glands of a frog's skin are thought to be a key defense against Bd infection. These peptides may be a critical immune defense during metamorphosis because many acquired immune functions are suppressed during this time. To test if stressors alter AMP production and survival of frogs exposed to Bd, we exposed wood frog (Lithobates sylvaticus) tadpoles to the presence or absence of dragonfly predator cues crossed with a single exposure to three nominal concentrations of the insecticide malathion (0, 10, or 100 parts per billion [ppb]). We then exposed a subset of post-metamorphic frogs to the presence or absence of Bd zoospores and measured frog survival. Although predator cues and malathion had no effect on survival or size at metamorphosis, predator cues increased the time to metamorphosis by 1.5 days and caused a trend of a 20% decrease in hydrophobic skin peptides. Despite this decrease in peptides determined shortly after metamorphosis, previous exposure to predator cues increased survival in both Bd-exposed and unexposed frogs several weeks after metamorphosis. These results suggest that exposing tadpoles to predator cues confers fitness benefits later in life.
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9 MeSH Terms
NMDA-induced seizure intensity is enhanced in COX-2 deficient mice.
Toscano CD, Kingsley PJ, Marnett LJ, Bosetti F
(2008) Neurotoxicology 29: 1114-20
MeSH Terms: Animals, Cyclooxygenase 2, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists, Fluoresceins, Gas Chromatography-Mass Spectrometry, Hexachlorocyclohexane, Insecticides, Kainic Acid, Male, Mice, Mice, Knockout, N-Methylaspartate, Organic Chemicals, Prostaglandins, Seizures
Show Abstract · Added June 1, 2014
Pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not COX-1, has been shown to increase susceptibility to kainic acid (KA)-induced excitotoxicity. However, it is unclear if susceptibility to excitotoxins that act through other neurotransmitter receptors is altered by COX-2 inhibition. To further understand the involvement of COX-2 in regulating susceptibility to excitotoxicity, we investigated the effect of COX-2 deletion on excitotoxicity induced by peripheral injection of N-methyl-d-aspartate (NMDA, a specific agonist of the NMDA receptors) or lindane (a GABA(A) receptor antagonist). COX-2(-/-) mice injected intraperitoneally with NMDA (50-100mg/kg) exhibited significantly increased median seizure intensity when compared to COX-2(+/+) mice. Further, COX-2(-/-) mice exposed to NMDA showed neuronal damage, detected by Fluoro Jade B (FJB) staining, in the CA3 region of the hippocampus. There was no FJB staining nor any significant difference in median or maximal seizure intensity in COX-2(+/+) and COX-2(-/-) mice exposed to lindane. LC-MS/MS analysis of brain prostaglandin profile in COX-2(-/-) mice demonstrated a significant increase in PGF(2alpha), TXB(2), PGE(2) and PGD(2) expression 1h after administration of an excitotoxic dose of KA, but not of NMDA. Our findings demonstrate that COX-2 regulates susceptibility to KA and NMDA excitotoxicity, which directly activate glutamatergic neurotransmission, but not to lindane, which indirectly alters glutamatergic neurotransmission. Furthermore, increased levels of prostaglandins after seizures are associated with consistent manifestation of neuronal damage.
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16 MeSH Terms
Use of permethrin eradicated the tropical rat mite (Ornithonyssus bacoti) from a colony of mutagenized and transgenic mice.
Hill WA, Randolph MM, Boyd KL, Mandrell TD
(2005) Contemp Top Lab Anim Sci 44: 31-4
MeSH Terms: Animals, Dermatitis, Housing, Animal, Humans, Insect Bites and Stings, Insect Control, Insecticides, Mice, Mice, Transgenic, Mite Infestations, Mites, Mutation, Permethrin, Research Personnel
Show Abstract · Added March 20, 2014
The tropical rat mite, Ornithonyssus bacoti, was identified in a colony of mutagenized and transgenic mice at a large academic institution. O. bacoti is an obligate, blood-feeding ectoparasite with an extensive host range. Although the source of the infestation was likely feral rodents, none were found in the room housing infested mice. We hypothesize that construction on the floor above the vivarium and compromised ceiling integrity within the animal room provided for vermin entry and subsequent O. bacoti infestation. O. bacoti infestation was eliminated by environmental decontamination with synthetic pyrethroids and weekly application of 7.4% permethrin-impregnated cotton balls to mouse caging for five consecutive weeks. Visual examination of the macroenvironment, microenvironment, and colony for 38 days confirmed the efficacy of treatment. We noted no treatment-related toxicities or effects on colony production.
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14 MeSH Terms
The prevalence of serum antibodies to tick-borne infections in Mbale District, Uganda: the effect of agro-ecological zone, grazing management and age of cattle.
Rubaire-Akiiki C, Okello-Onen J, Nasinyama GW, Vaarst M, Kabagambe EK, Mwayi W, Musunga D, Wandukwa W
(2004) J Insect Sci 4: 8
MeSH Terms: Aging, Anaplasma marginale, Animal Husbandry, Animals, Antibodies, Bacterial, Antibodies, Protozoan, Babesia, Cattle, Cattle Diseases, Cross-Sectional Studies, Environmental Pollution, Insecticides, Risk Factors, Seroepidemiologic Studies, Theileria parva, Tick-Borne Diseases, Ticks, Uganda
Show Abstract · Added April 24, 2015
Between August and October 2000, a cross-sectional study was conducted in smallholder dairy farms in Mbale District, Uganda to assess the prevalence of ticks and tick-borne diseases under different grazing systems and agro-ecological zones and understand the circumstances under which farmers operated. A questionnaire was administered to obtain information on dairy farm circumstances and practices. A total of 102 farms were visited and sera and ticks were collected from 478 animals. Sero-prevalence of tick-borne diseases was determined using an enzyme-linked immunoassay. Acaricides were used indiscriminately but the intensity of their use varied with the grazing system and zone. Cattle from different farms mixed for various reasons. During the dry seasons farmers have to get additional fodder from outside their farms that can result in importation of ticks. The prevalence of ticks and serum antibodies to tick-borne infections differed across the grazing systems and zones. The highest serum antibody prevalence (>60%) was recorded in the lowland zone under the free range and tethering grazing systems. The lowest tick challenge and serum antibody levels (<50%) were recorded in the midland and upland zones under a zero-grazing system. These findings suggest that endemic stability to East Coast Fever, babesiosis and anaplasmosis is most likely to have existed in the lowland zone, particularly, under the tethering and free-range grazing systems. Also, endemic stability for babesiosis existed in the upland zones. Endemic instability for East Coast Fever existed in the midland and upland zones. These structured observational studies are instrumental in planning of control strategies for ticks and tick borne diseases since production systems and the cattle population at high risk of the diseases in the district have been identified.
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18 MeSH Terms
K-ras and p53 in pancreatic cancer: association with medical history, histopathology, and environmental exposures in a population-based study.
Slebos RJ, Hoppin JA, Tolbert PE, Holly EA, Brock JW, Zhang RH, Bracci PM, Foley J, Stockton P, McGregor LM, Flake GP, Taylor JA
(2000) Cancer Epidemiol Biomarkers Prev 9: 1223-32
MeSH Terms: Aged, Carcinogens, Case-Control Studies, DNA Mutational Analysis, Diabetes Complications, Dichlorodiphenyl Dichloroethylene, Environmental Exposure, Female, Genes, p53, Genes, ras, Humans, Immunohistochemistry, Insecticides, Male, Medical History Taking, Middle Aged, Pancreatic Neoplasms, Risk Factors
Show Abstract · Added March 5, 2014
Pancreatic cancer is a highly fatal cancer with few identified risk factors. Increased risk of pancreatic cancer in tobacco smokers and among diabetic patients is well established, and some reports have suggested associations with coffee consumption and occupational exposure to organochlorines. At present, there is little information regarding the possible association of these risk factors with the known genetic alterations found in pancreatic cancers, such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor gene. Knowledge of such relationships may help to understand the molecular pathways of pancreatic tumorigenesis. We investigated the association between these molecular defects and risk factors for pancreatic cancer in 61 newly diagnosed patients identified through an ongoing study of pancreatic cancer in the San Francisco Bay Area. Interview information was obtained regarding environmental exposures, medical history, and demographic factors. Serum levels of dichlorodiphenyltrichloroethylene (DDE) and polychlorinated biphenyls were available on a subset of 24 patients. Tumor blocks were located from local hospitals and used for K-ras mutational analysis at codon 12 and for p53 protein immunohistochemistry. The molecular analyses were facilitated through the use of laser capture microdissection, which provides a reliable method to obtain almost pure populations of tumor cells. Mutations in K-ras codon 12 were found in 46 (75%) of 61 pancreatic cancers. A prior diagnosis of diabetes was significantly associated with K-ras negative tumors (P = 0.002, Fisher's exact test). The absence of this mutation was also associated with increased serum levels of DDE, although this association was not statistically significant (P = 0.16, Wilcoxon's test). There was no difference in polychlorinated biphenyl levels between the K-ras wild-type and mutant groups. Immunohistochemical staining for p53 protein did not differ by patient characteristics or clinical history, but significant associations were found with poor glandular differentiation (P = 0.002, chi2 trend test), severe nuclear atypia (P = 0.0007, chi2 trend test), and high tumor grade (P = 0.004, chi2 trend test). Our results are suggestive of the presence of K-ras codon 12 mutation-independent tumorigenesis pathways in patients with prior diabetes and possibly in patients with higher serum levels of DDE. Our results also support a role for the p53 tumor suppressor protein in the maintenance of genomic integrity.
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18 MeSH Terms
The effect of fish consumption on DDT and DDE levels in breast milk among Hispanic immigrants.
Mariën K, Conseur A, Sanderson M
(1998) J Hum Lact 14: 237-42
MeSH Terms: Adult, Body Burden, DDT, Dichlorodiphenyl Dichloroethylene, Diet, Emigration and Immigration, Female, Fish Products, Food Contamination, Hispanic Americans, Humans, Infant, Insecticides, Milk, Human, Residence Characteristics, Washington
Show Abstract · Added March 11, 2014
A study was conducted to (1) determine the concentration of DDT/DDE in the breast milk of mothers residing in the Yakima river basin (WA, USA), (2) assess the relative impact of fish consumption on the total DDT/DDE body burden, and (3) determine if the amount of DDT/DDE received by their breastfed infants exceeds levels that could produce deleterious effects. Results indicate that fish consumption did not significantly increase DDT/DDE breast milk concentrations. Subjects born in Mexico had elevated levels of DDT/DDE in breast milk compared to levels found in US born subjects regardless of fish consumption. Infant daily intake levels for the various subject groups were determined and compared to acceptable and tolerable daily intake levels. With benefits of breast milk well understood, breastfeeding should still be strongly recommended for these mothers.
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16 MeSH Terms
Enhancement of bacterial mutagenicity of bifunctional alkylating agents by expression of mammalian glutathione S-transferase.
Thier R, Müller M, Taylor JB, Pemble SE, Ketterer B, Guengerich FP
(1995) Chem Res Toxicol 8: 465-72
MeSH Terms: Alkylating Agents, Animals, Drug Synergism, Glutathione, Glutathione Transferase, Insecticides, Mutagenicity Tests, Mutagens, Propane, Rats, Salmonella typhimurium
Show Abstract · Added March 5, 2014
Recently, we inserted the plasmid vector pKK233-2 containing rat GSH S-transferase (GST) 5-5 cDNA into Salmonella typhimurium TA1535 and found that these bacteria [GST 5-5(+)] expressed the protein and produced mutations when ethylene or methylene dihalides were added [Thier, R., Taylor, J. B., Pemble, S. E., Ketterer, B., Persmark, M., Humphreys, W. G., and Guengerich, F. P. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8576-8580]. After exposure to the known GST 5-5 substrate 1,2-epoxy-3-(4'-nitrophenoxy)propane, the GST 5-5(+) strain showed fewer mutants than the bacteria transfected with the cDNA clone in a reverse orientation [GST 5-5(-)], suggesting a protective role of GST 5-5. However, mutations were considerably enhanced in the GST 5-5(+) strain [as compared to GST 5-5(-)] when 1,2,3,4-diepoxybutane (butadiene diepoxide) or 1,2-epoxy-4-bromobutane was added. The GST 5-5(+) and GST 5-5(-) bacterial stains showed similar responses to 1,2-epoxypropane, 3,4-epoxy-1-butene, and 1,4-dibromobutane. The results suggest that some bifunctional activated butanes are transformed to mutagenic products through GSH conjugation. We also found that the GST 5-5(+) strain showed enhanced mutagenicity with 1,4-dibromo-2,3-epoxybutane, 1,2-epoxy-3-bromopropane (epibromohydrin), and (+/-)-1,4-dibromo-2,3-dihydroxybutane.(ABSTRACT TRUNCATED AT 250 WORDS)
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11 MeSH Terms
Isolation and characterization of N7-guanyl adducts derived from 1,2-dibromo-3-chloropropane.
Humphreys WG, Kim DH, Guengerich FP
(1991) Chem Res Toxicol 4: 445-53
MeSH Terms: Animals, DNA, Electrophoresis, Agar Gel, Glutathione, Insecticides, Male, Propane, Rats, Rats, Inbred Strains
Show Abstract · Added March 5, 2014
1,2-Dibromo-3-chloropropane is a potent renal and testicular toxicant and has been shown to induce tumor formation in laboratory animals. The toxic effects of the compound are thought to be a result of a bioactivation step in which a glutathione conjugate is formed and subsequently reacts with cellular DNA. The L-glutathione conjugate of 1,2-dibromo-3-chloropropane was chemically synthesized and used to alkylate DNA: following incubations of the conjugate with calf thymus DNA and neutral thermal hydrolysis (to release N7-guanyl adducts) four major fluorescent products were observed. Three of these were isolated and characterized, the structures being determined as S-[bis(N7-guanylmethyl)methyl]glutathione and the two diastereomers of S-[1-(hydroxymethyl)-2-(N7-guanyl)ethyl]glutathione. The fourth fluorescent product was unstable and formed in low yield and thus could not be characterized. The formation of these N7-guanyl adducts can be explained by a mechanism that includes the formation of two consecutive episulfonium ion intermediates followed by nucleophilic attack at the unsubstituted methylene carbon. These adducts bear structural and mechanistic similarities to the major adduct derived from 1,2-dibromoethane, S-[2-(N7-guanyl)ethyl]glutathione. The same adducts were also formed when DBCP was incubated with rat liver cytosol, GSH, and DNA. In vivo experiments with DBCP yielded very low levels of the N7-guanyl adducts formed in rat liver compared to the levels seen after treatments with 1,2-dibromoethane. The bis-guanyl adduct represents a cross-linked structure that may be important in the toxicity of this compound. The conjugate was not found to be mutagenic to Salmonella typhimurium TA100 but rather showed a toxic effect toward the bacteria.
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Molecular cloning and transformation of cyclodiene resistance in Drosophila: an invertebrate gamma-aminobutyric acid subtype A receptor locus.
Ffrench-Constant RH, Mortlock DP, Shaffer CD, MacIntyre RJ, Roush RT
(1991) Proc Natl Acad Sci U S A 88: 7209-13
MeSH Terms: Amino Acid Sequence, Animals, Cattle, Chromosome Walking, Cloning, Molecular, Cosmids, Crosses, Genetic, DNA, DNA Transposable Elements, Dieldrin, Drosophila, Drug Resistance, Female, Gene Rearrangement, Insecticides, Macromolecular Substances, Male, Molecular Sequence Data, Phenotype, Protein Conformation, Rats, Receptors, GABA-A, Restriction Mapping, Sequence Homology, Nucleic Acid, Transformation, Genetic
Show Abstract · Added June 9, 2010
Cyclodiene resistance represents 60% of the reported cases of insecticide resistance and is also present in vertebrates. Resistance is due to insensitivity of the cyclodiene/picrotoxinin binding site on the gamma-aminobutyric acid subtype A (GABAA) receptor-chloride ionophore complex. Following isolation of cyclodiene-resistant Drosophila mutants, we report the cloning of the locus conferring resistance via a "chromosomal walk" and rescue of the susceptible phenotype by P-element-mediated germ-line transformation. Amino acid sequence analysis of a cDNA from the locus reveals homology with vertebrate GABAA subunits. To our knowledge, this represents the first cloning of an invertebrate GABA receptor and also allows us to manipulate the resistance status of an insect via germ-line transformation. This gene may be useful as a selectable marker in other insect systems.
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25 MeSH Terms