Dataset Information

Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.

ABSTRACT: Pyrethroid insecticides exert toxic effects by prolonging the opening of voltage-gated sodium channels. More than 20 sodium channel mutations from arthropod pests and disease vectors have been confirmed to confer pyrethroid resistance. These mutations have been valuable in elucidating the molecular interaction between pyrethroids and sodium channels, including identification of two pyrethroid receptor sites. Previously, two alanine to valine substitutions, one in the pore helix IIIP1 and the other in the linker-helix connecting S4 and S5 in domain III (IIIL45), were found in Drosophila melanogaster mutants that are resistant to DDT and deltamethrin (a type II pyrethroid with an ?-cyano group at the phenylbenzyl alcohol position, which is lacking in type I pyrethroids), but their role in target-site-mediated insecticide resistance has not been functionally confirmed. In this study, we functionally examined the two mutations in cockroach sodium channels expressed in Xenopus laevis oocytes. Both mutations caused depolarizing shifts in the voltage dependence of activation, conferred DDT resistance and also resistance to two Type I pyrethroids by almost abolishing the tail currents induced by Type I pyrethroids. In contrast, neither mutation reduced the amplitude of tail currents induced by the Type II pyrethroids, deltamethrin or cypermethrin. However, both mutations accelerated the decay of Type II pyrethroid-induced tail currents, which normally decay extremely slowly. These results provided new insight into the molecular basis of different actions of Type I and Type II pyrethroids on sodium channels. Computer modeling predicts that both mutations may allosterically affect pyrethroid binding.

SUBMITTER: Chen M

PROVIDER: S-EPMC5731473 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.

Chen Mengli M Du Yuzhe Y Nomura Yoshiko Y Zhu Guonian G Zhorov Boris S BS Dong Ke K

Neurotoxicology 20160618

Pyrethroid insecticides exert toxic effects by prolonging the opening of voltage-gated sodium channels. More than 20 sodium channel mutations from arthropod pests and disease vectors have been confirmed to confer pyrethroid resistance. These mutations have been valuable in elucidating the molecular interaction between pyrethroids and sodium channels, including identification of two pyrethroid receptor sites. Previously, two alanine to valine substitutions, one in the pore helix IIIP1 and the oth ...[more]

PMID: 27328896

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Project description:BackgroundUnderstanding the molecular basis of insecticide resistance is key to improve the surveillance and monitoring of malaria vector populations under control. In the major malaria vector Anopheles funestus, little is currently known about the role of the knockdown resistance (kdr) mechanism. Here, we investigated the presence and contribution of knockdown resistance (kdr) to pyrethroids/DDT resistance observed in Anopheles funestus across Africa.ResultsPyrosequencing genotyping and sequencing of the voltage gated sodium channel (VGSC) gene did not detect the common L1014F mutation in field collected An. funestus across Africa. Amplification and cloning of the full-length of the sodium channel gene in pyrethroid resistant mosquitoes revealed evidences of alternative splicing events with three transcripts of 2092, 2061 and 2117 amino acids (93% average similarity to An. gambiae). Several amino acid changes were detected close to the domain II of the protein such as L928R, F938 W, I939S, L802S and T1008 M. However, all these mutations are found at low frequency and their role in pyrethroid resistance could not be established. The presence of the exclusive alternative splicing at exon 19 was not associated with resistance phenotype. Analysis of patterns of genetic diversity of the VGSC gene revealed a high polymorphism level of this gene across Africa with no evidence of directional selection suggesting a limited role for knockdown resistance in pyrethroid resistance in An. funestus. Patterns of genetic differentiation correlate with previous observations of the existence of barriers to gene flow Africa-wide with southern population significantly differentiated from other regions.ConclusionDespite an apparent limited role of knockdown resistance in An. funestus, it is necessary to continue to monitor the contribution of the mutations detected here as increasing selection from insecticide-based interventions may change the dynamic in field populations as previously observed in other vectors.

Project description:UnlabelledBackgroundMany efforts have been recently devoted to design, investigate and synthesize biocompatible, biodegradable polymers for applications in medicine for either the fabrication of biodegradable devices or as drug delivery systems. Many of them consist of condensation of polymers having incorporated peptide linkages susceptible to enzymatic cleavage. Polyamides (PAs) containing α-amino acid residues such as L-leucine, L-alanine and L-phenylalanine have been reported as biodegradable materials. Furthermore, polyamides (PAs) derived from C10 and C14 dicarboxylic acids and amide-diamines derived from 1,6-hexanediamine or 1,12-dodecanediamine and L-phenylalanine, L-valyl-L-phenylalanine or L-phenylalanyl-L-valine residues have been reported as biocompatible polymers. We have previously described the synthesis and thermal properties of a new type of polyamides-containing amino acids based on eight new symmetric meta-oriented protected diamines derived from coupling of amino acids namely; Fomc-glycine, Fmoc-alanine, Fomc-valine and Fomc-leucine with m-phenylene diamine or 2,6-diaminopyridine. Results revealed that incorporation of pyridine onto the polymeric backbone of all series decreases the thermal stability.Here we describe another family of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid linked to benzidine and 4,4'-oxydianiline to study the effect of the dicarboxylic acid as well as the amino acids on the nature and thermal stability of the polymers.ResultsWe report here the preparation of a new type of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid linked to benzidine and 4,4'-oxydianiline to study the effect of the dicarboxylic acid as well as the amino acids on the nature and thermal stability of polymers. The thermal properties of the polymers were evaluated by different techniques. Results revealed that structure-thermal property correlation based on changing the dicarboxylic acid monomer or the diamine monomer demonstrated an interesting connection between a single change (changing the dicarboxylic acids in each series while the diamine is fixed) and thermal properties. The newly prepared polymers may possess biodegradability and thus may find some applications as novel biomaterials.ConclusionsThe thermal properties of the new type of polyamides based on benzene dicarboxylic acid, pyridine dicarboxylic acid, and α-amino acid (alanine and valine) linked to benzidine and 4,4'-oxydianiline were evaluated by thermal gravimetric (TG), differential thermal gravimetric (DTG) and differential thermal analysis (DTA) techniques. Results revealed that the structure-thermal property correlation based on changing the dicarboxylic acid monomer or the diamine monomer demonstrated an interesting connection between a single change (changing the dicarboxylic acids in each series while the diamine is fixed) and thermal properties. In addition, pyridine-containing polymers exhibited semicrystalline characteristic with melting temperature, Tm. where none of the valine-containing polymers showed a melting and crystallization peak indicating that the polymers were amorphous. This is expected since L-valine side chain can inhibit close packing and eliminate crystallization. The newly prepared polymers may possess biodegradability and thus may find some applications as novel biomaterials.

Project description:Although indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment.We aimed to estimate the effects of maternal insecticide exposure and neurodevelopment of toddlers living in a malaria-endemic region currently using IRS.The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort of 752 mother-child pairs in Limpopo, South Africa. We measured maternal exposure to DDT and its breakdown product, dichlorodiphenyldichloroethylene (DDE), in maternal serum, and measured pyrethroid metabolites in maternal urine. We assessed children's neurodevelopment at 1 and 2 y of age using the Bayley Scales of Infant Development, third edition (BSID-III), and examined associations with maternal exposure.DDT and DDE were not associated with significantly lower scores for any BSID-III scale. In contrast, each 10-fold increase in cis-DCCA, trans-DCCA, and 3-phenoxybenzoic acid were associated, respectively, with a -0.63 (95% CI: -1.14, -0.12), -0.48 (95% CI: -0.92, -0.05), and -0.58 (-1.11, -0.06) decrement in Social-Emotional scores at 1 y of age. In addition, each 10-fold increase in maternal cis-DBCA levels was associated with significant decrements at 2 y of age in Language Composite scores and Expressive Communication scores [?=-1.74 (95% CI: -3.34, -0.13) and ?=-0.40 (95% CI: -0.77, -0.04), respectively, for a 10-fold increase]. Significant differences by sex were estimated for pyrethroid metabolites and motor function scores at 2 y of age, with higher scores for boys and lower scores for girls.Prenatal exposure to pyrethroids may be associated at 1 y of age with poorer social-emotional development. At 2 y of age, poorer language development was observed with higher prenatal pyrethroid levels. Considering the widespread use of pyrethroids, these findings deserve further investigation. https://doi.org/10.1289/EHP2129.

Dataset Information

Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.

Publications

Alanine to valine substitutions in the pore helix IIIP1 and linker-helix IIIL45 confer cockroach sodium channel resistance to DDT and pyrethroids.

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