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Abstract: We expressed the rat Nav1.3 and Nav1.6 sodium channel α subunit isoforms in Xenopus oocytes either alone or with the rat β1 and β2 auxiliary subunits in various combinations and assessed the sensitivity of the expressed channels to resting and use-dependent modification by the pyrethroid insecticide tefluthrin using the two-electrode voltage clamp technique. Coexpression with the β1 and β2 subunits, either individually or in combination, did not affecting the resting sensitivity of Nav1.6 channels to tefluthrin. Modification by tefluthrin of Nav1.6 channels in the absence of β subunits was not altered by the application of trains of high-frequency depolarizing prepulses. By contrast, coexpression of the Nav1.6 channel with the β1 subunit enhanced the extent of channel modification 2-fold following repeated depolarization. Coexpression of Nav1.6 with the β2 subunit also slightly enhanced modification following repeated depolarization, but coexpression of Nav1.6 with both β subunits caused enhanced modification following repeated depolarization that was indistinguishable from that found with Nav1.6+β1 channels. In contrast to Nav1.6, the resting modification by tefluthrin of Nav1.3 channels expressed in the absence of β subunits was reduced by repeated depolarization. However, tefluthrin modification of the Nav1.3 α subunit expressed with both β subunits was enhanced 1.7-fold by repeated depolarization, thereby confirming that β subunit modulation of use-dependent effects was not confined to the Nav1.6 isoform. These results show that the actions of pyrethroids on mammalian sodium channels in the Xenopus oocyte expression system are determined in part by the interactions of the sodium channel α subunit with the auxiliary β subunits that are part of the heteromultimeric sodium channel complexes found in neurons and other excitable cells. [Copyright &y& Elsevier]

Abstract: In rats expression of the Nav1.7 voltage-gated sodium channel isoform is restricted to the peripheral nervous system and is abundant in the sensory neurons of the dorsal root ganglion. We expressed the rat Nav1.7 sodium channel α subunit together with the rat auxiliary β1 and β2 subunits in Xenopus laevis oocytes and assessed the effects of the pyrethroid insecticide tefluthrin on the expressed currents using the two-electrode voltage clamp method. Tefluthrin at 100μM modified of Nav1.7 channels to prolong inactivation of the peak current during a depolarizing pulse, resulting in a marked “late current” at the end of a 40ms depolarization, and induced a sodium tail current following repolarization. Tefluthrin modification was enhanced up to twofold by the application of a train of up to 100 5ms depolarizing prepulses. These effects of tefluthrin on Nav1.7 channels were qualitatively similar to its effects on rat Nav1.2, Nav1.3 and Nav1.6 channels assayed previously under identical conditions. However, Nav1.7 sodium channels were distinguished by their low sensitivity to modification by tefluthrin, especially compared to Nav1.3 and Nav1.6 channels. It is likely that Nav1.7 channels contribute significantly to the tetrodotoxin-sensitive, pyrethroid-resistant current found in cultured dorsal root ganglion neurons. We aligned the complete amino acid sequences of four pyrethroid-sensitive isoforms (house fly Vssc1; rat Nav1.3, Nav1.6 and Nav1.8) and two pyrethroid-resistant isoforms (rat Nav1.2 and Nav1.7) and found only a single site, located in transmembrane segment 6 of homology domain I, at which the amino acid sequence was conserved among all four sensitive isoform sequences but differed in the two resistant isoform sequences. This position, corresponding to Val410 of the house fly Vssc1 sequence, also aligns with sites of multiple amino acid substitutions identified in the sodium channel sequences of pyrethroid-resistant insect populations. These results implicate this single amino acid polymorphism in transmembrane segment 6 of sodium channel homology domain I as a determinant of the differential pyrethroid sensitivity of rat sodium channel isoforms. [Copyright &y& Elsevier]

Abstract: The Nav1.6 voltage-gated sodium channel α subunit isoform is the most abundant isoform in the brain and is implicated in the transmission of high frequency action potentials. Purification and immunocytochemical studies imply that Nav1.6 exist predominantly as Nav1.6+β1+β2 heterotrimeric complexes. We assessed the independent and joint effects of the rat β1 and β2 subunits on the gating and kinetic properties of rat Nav1.6 channels by recording whole-cell currents in the two-electrode voltage clamp configuration following transient expression in Xenopus oocytes. The β1 subunit accelerated fast inactivation of sodium currents but had no effect on the voltage dependence of their activation and steady-state inactivation and also prevented the decline of currents following trains of high-frequency depolarizing prepulses. The β2 subunit selectively retarded the fast phase of fast inactivation and shifted the voltage dependence of activation towards depolarization without affecting other gating properties and had no effect on the decline of currents following repeated depolarization. The β1 and β2 subunits expressed together accelerated both kinetic phases of fast inactivation, shifted the voltage dependence of activation towards hyperpolarization, and gave currents with a persistent component typical of those recorded from neurons expressing Nav1.6 sodium channels. These results identify unique effects of the β1 and β2 subunits and demonstrate that joint modulation by both auxiliary subunits gives channel properties that are not predicted by the effects of individual subunits. [Copyright &y& Elsevier]

Abstract: We expressed rat Nav1.6 sodium channels in combination with the rat β1 and β2 auxiliary subunits in Xenopus laevis oocytes and evaluated the effects of the pyrethroid insecticides S-bioallethrin, deltamethrin, and tefluthrin on expressed sodium currents using the two-electrode voltage clamp technique. S-Bioallethrin, a type I structure, produced transient modification evident in the induction of rapidly decaying sodium tail currents, weak resting modification (5.7% modification at 100μM), and no further enhancement of modification upon repetitive activation by high-frequency trains of depolarizing pulses. By contrast deltamethrin, a type II structure, produced sodium tail currents that were ~9-fold more persistent than those caused by S-bioallethrin, barely detectable resting modification (2.5% modification at 100μM), and 3.7-fold enhancement of modification upon repetitive activation. Tefluthrin, a type I structure with high mammalian toxicity, exhibited properties intermediate between S-bioallethrin and deltamethrin: intermediate tail current decay kinetics, much greater resting modification (14.1% at 100μM), and 2.8-fold enhancement of resting modification upon repetitive activation. Comparison of concentration–effect data showed that repetitive depolarization increased the potency of tefluthrin ~15-fold and that tefluthrin was ~10-fold more potent than deltamethrin as a use-dependent modifier of Nav1.6 sodium channels. Concentration–effect data from parallel experiments with the rat Nav1.2 sodium channel coexpressed with the rat β1 and β2 subunits in oocytes showed that the Nav1.6 isoform was at least 15-fold more sensitive to tefluthrin and deltamethrin than the Nav1.2 isoform. These results implicate sodium channels containing the Nav1.6 isoform as potential targets for the central neurotoxic effects of pyrethroids. [Copyright &y& Elsevier]

MON 87411 maize, which expresses DvSnf7 RNA, was developed to provide an additional mode of action to confer protection against corn rootworm ( Diabrotica spp.). A critical step in the registration of a genetically engineered crop with an insecticidal trait is performing an ecological risk assessment to evaluate the potential for adverse ecological effects. For MON 87411, an assessment plan was developed that met specific protection goals by characterizing the routes and levels of exposure, and testing representative functional taxa that would be directly or indirectly exposed in the environment. The potential for toxicity of DvSnf7 RNA was evaluated with a harmonized battery of non-target organisms (NTOs) that included invertebrate predators, parasitoids, pollinators, soil biota as well as aquatic and terrestrial vertebrate species. Laboratory tests evaluated ecologically relevant endpoints such as survival, growth, development, and reproduction and were of sufficient duration to assess the potential for adverse effects. No adverse effects were observed with any species tested at, or above, the maximum expected environmental concentration (MEEC). All margins of exposure for NTOs were >10-fold the MEEC. Therefore, it is reasonable to conclude that exposure to DvSnf7 RNA, both directly and indirectly, is safe for NTOs at the expected field exposure levels. [ABSTRACT FROM AUTHOR]

Short-term temperature variability (TV) is associated with the exacerbation of asthma, but little is known about the relative effects of intra- and inter-day TV. We aimed to assess the relative impacts of intra- and inter-day TV on childhood asthma and to explore the modification effects by season. A quasi-Poisson generalized linear regression model combined with a distributed lag nonlinear model was adopted to evaluate the nonlinear and lagged effects of TV on childhood asthma in Shanghai from 2009 to 2017. Intra- and inter-day TV was measured with diurnal temperature range (DTR) and temperature changes between neighboring days (TCN), respectively. Increased DTR was associated with the elevated relative risk (RR) of daily outpatient visits for childhood asthma (DOVCA) in both the whole year (RR lag0-14 for the 99th percentile: 1.264, 95% confidence interval (CI): 1.052, 1.518) and cold season (RR lag0-12 for the 99th percentile: 1.411, 95% CI: 1.053, 1.889). Higher TCN in the warm season was associated with the increased RR of DOVCA (RR lag0-14 for the 99th percentile: 2.964, 95% CI: 1.636, 5.373). The number and fraction of DOVCA attributed to an interquartile range (IQR) increase of TCN were higher than those attributed to DTR in both the whole year period and warm season. However, the number and fraction of DOVCA attributed to an IQR increase of DTR were greater than those attributed to TCN in the cold season. Our results provide novel evidence that both intra- and inter-day TV might be a trigger of childhood asthma. Higher DTR appeared to have greater impacts on childhood asthma in the cold season while an increase in TCN seemed to have bigger effects in the warm season. [ABSTRACT FROM AUTHOR]

There has been increasing interest in identifying the adverse effects of ambient environmental factors on asthma exacerbations (AE), but season-stratified effects of meteorological factors on childhood asthma remain unclear. We explored the season-stratified effects of meteorological factors on childhood AE in Shanghai, China. Poisson generalized linear regression model combined with a distributed lag nonlinear model was used to examine the lagged and nonlinear effects of meteorological factors on childhood AE after adjustment for putative confounders. We also performed a season-stratified analysis to determine whether the season modified the relationship between meteorological factors and childhood AE. There were 23,103 emergency department visits (EDVs) for childhood AE, including 15,466 boys and 7637 girls during 2008–2017. Most meteorological factors (e.g., temperature, diurnal temperature range (DTR), relative humidity (RH) and wind speed (WS)) were significantly associated with EDVs for childhood AE, even after adjustment for the confounding effects of air pollutants. In the whole year, extreme cold, moderate heat, higher DTR, lower RH and WS increased the relative risk (RR) for childhood AE. In the cold season, lower RH and wind speed increased the risks of childhood AE (RR lag0-28 for the 5th percentile (p5) of RH: 9.744, 95% CI: 3.567, 26.616; RR lag0-28 for the p5 of wind speed: 10.671, 95% CI: 1.096, 103.879). In the warm season, higher temperature and DTR, lower RH and WS increased the RR for childhood AE (RR lag0-5 for the p95 of temperature: 1.871, 95% CI: 1.246, 2.810; RR lag0-2 for the p95 of DTR: 1.146, 95% CI: 1.010, 1.300; RR lag0-5 for the p5 of RH: 1.931, 95% CI: 1.191, 3.128; RR lag0-2 for the p5 of WS: 1.311, 95% CI: 1.005, 1.709). Extreme meteorological factors appeared to be triggers of EDVs for childhood AE in Shanghai and the effects modified by season. These findings provide evidence for developing season-specific and tailored strategies to prevent and control childhood AE. • Extreme meteorological conditions increased emergency department visits for childhood asthma. • The effects of meteorological factors on childhood asthma were markedly seasonal and lagged. • There was a "U" type of association between maximum and mean temperatures and risk for childhood asthma. • Non-optimal temperature, humidity, diurnal temperature range and wind speed were potential triggers of childhood asthma. [ABSTRACT FROM AUTHOR]