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Aldrin and its metabolite dieldrin are persistent organic pollutants that contaminate soil in many parts of the world. Given the potential hazards associated with these pollutants, an efficient degradation method is required. In this study, we investigated the ability of Pleurotus ostreatus to transform aldrin as well as dieldrin in pure liquid cultures. This fungus completely eliminated aldrin in potato dextrose broth (PDB) medium during a 14-day incubation period. Dieldrin was detected as the main metabolite, and 9-hydroxylaldrin and 9-hydroxyldieldrin were less abundant metabolites. The proposed route of aldrin biotransformation is initial metabolism by epoxidation, followed by hydroxylation. The fungus was also capable of degrading dieldrin, a recalcitrant metabolite of aldrin. Approximately 3, 9, and 18% of dieldrin were eliminated by P. ostreatus in low-nitrogen, high-nitrogen, and PDB media, respectively, during a 14-day incubation period. 9-Dihydroxydieldrin was detected as a metabolite in the PDB culture, suggesting that the hydroxylation reaction occurred in the epoxide ring. These results indicate that P. ostreatus has potential applications in the transformation of aldrin as well as dieldrin.

Pesticides are unique environmental contaminants that are specifically introduced into the environment to control pests, often by killing them. Although pesticide application serves many important purposes, including protection against crop loss and against vector-borne diseases, there are significant concerns over the potential toxic effects of pesticides to non-target organisms, including humans. In many cases, the molecular target of a pesticide is shared by non-target species, leading to the potential for untoward effects. Here, we review the history of pesticide usage and the neurotoxicity of selected classes of pesticides, including insecticides, herbicides, and fungicides, to humans and experimental animals. Specific emphasis is given to linkages between exposure to pesticides and risk of neurological disease and dysfunction in humans coupled with mechanistic findings in humans and animal models. Finally, we discuss emerging techniques and strategies to improve translation from animal models to humans.

Broflanilide is a new insecticide being developed for malaria vector control. As new insecticide chemistries become available, strategies to preserve the susceptibility of local malaria vectors and extend their useful life need to be considered before large scale deployment. This requires the development of appropriate testing procedures and identification of suitable discriminating concentrations for monitoring susceptibility in wild vector populations to facilitate decision making by control programmes. Dose-response WHO bottle bioassays were conducted using the insecticide-susceptible Anopheles gambiae s.s. Kisumu strain to determine a discriminating concentration of broflanilide. Bioassays were performed without the adjuvant Mero® and with two concentrations of Mero® (500 ppm and 800 ppm) to investigate its impact on the discriminating concentration of the insecticide. Probit analysis was used to determine the lethal doses at 50% (LC50) and 99% (LC99) at 24-, 48- and 72-hours post-exposure. Cross-resistance to broflanilide and pyrethroids, DDT, dieldrin and carbamates, was investigated using An. gambiae s.l. Covè and An. coluzzii Akron strains. The susceptibility of wild pyrethroid-resistant mosquitoes from communities in Southern Benin to broflanilide was assessed using the estimated discriminating concentrations. Broflanilide induced a dose-dependent and delayed mortality effect. Mortality rates in bottles treated without Mero® were <80% using the range of broflanilide doses tested (0-100 μg/bottle) leading to high and unreliable estimates of LC99 values. The discriminating concentrations defined as 2XLC99 at 72h post exposure were estimated to be 2.2 μg/bottle with 800 ppm of Mero® and 6.0 μg/bottle with 500 ppm of Mero®. Very low resistance ratios (0.6-1.2) were determined with the insecticide resistant An. gambiae s.l. Covè and An. coluzzii Akron strains suggesting the absence of cross-resistance via the mechanisms of resistance to pyrethroids, DDT, dieldrin and carbamates they possess. Bottle bioassays performed with broflanilide at both discriminating concentrations of 6 μg/bottle with 500 ppm of Mero® and 2.2 μg/bottle with 800 ppm of Mero®, showed susceptibility of wild highly pyrethroid-resistant An. gambiae s.l. from villages in Southern Benin. We determined discriminating concentrations for monitoring susceptibility to broflanilide in bottle bioassays, using susceptible An. gambiae vectors. Using the estimated discriminating concentrations, we showed that wild pyrethroid-resistant populations of An. gambiae s.l. from southern Benin were fully susceptible to the insecticide. Broflanilide also shows potential to be highly effective against An. gambiae s.l. vector populations that have developed resistance to other public health insecticides.

Novel insecticides are urgently needed to control insecticide-resistant populations of Anopheles malaria vectors. Broflanilide acts as a non-competitive antagonist of the gamma-aminobutyric acid receptor and has shown prolonged effectiveness as an indoor residual spraying product (VECTRON T500) in experimental hut trials against pyrethroid-resistant vector populations. This multi-centre study expanded upon initial discriminating concentration testing of broflanilide, using six Anopheles insectary colonies ( An. gambiae Kisumu KCMUCo, An. gambiae Kisumu NIMR, An. arabiensis KGB, An. arabiensis SENN, An. coluzzii N’Gousso and An. stephensi SK), representing major malaria vector species, to facilitate prospective susceptibility monitoring of this new insecticide; and investigated the potential for cross-resistance to broflanilide via the A296S mutation associated with dieldrin resistance ( rdl ). Across all vector species tested, the discriminating concentration for broflanilide ranged between LC 99  × 2 = 1.126–54.00 μg/ml or LC 95  × 3 = 0.7437–17.82 μg/ml. Lower concentrations of broflanilide were required to induce complete mortality of An. arabiensis SENN (dieldrin-resistant), compared to its susceptible counterpart, An. arabiensis KGB, and there was no association between the presence of the rdl mechanism of resistance and survival in broflanilide bioassays, demonstrating a lack of cross-resistance to broflanilide. Study findings provide a benchmark for broflanilide susceptibility monitoring as part of ongoing VECTRON T500 community trials in Tanzania and Benin.

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1 ) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABA A ) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABA A Rs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN ( 2 ) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABA A -RDL selectivity index. Minor changes to complex structures can exert major influences on synthesis strategy and functional properties but synthetic difficulties can obstruct the exploration of natural product function. Here the authors explore two parallel series of picrotoxinin analogs and identify leads with selectivity between mammalian and insect ion channels.

The annual global production of farmed salmon has increased by a factor of 40 during the past two decades. Salmon from farms in northern Europe, North America, and Chile are now available widely year-round at relatively low prices. Salmon farms have been criticized for their ecological effects, but the potential human health risks of farmed salmon consumption have not been examined rigorously. Having analyzed over 2 metric tons of farmed and wild salmon from around the world for organochlorine contaminants, we show that concentrations of these contaminants are significantly higher in farmed salmon than in wild. European-raised salmon have significantly greater contaminant loads than those raised in North and South America, indicating the need for further investigation into the sources of contamination. Risk analysis indicates that consumption of farmed Atlantic salmon may pose health risks that detract from the beneficial effects of fish consumption.

Meta-diamides (e.g. broflanilide) and isoxazolines (e.g. fluralaner) are novel insecticides that target the resistant to dieldrin (RDL) subunit of insect [gamma]-aminobutyric acid receptors (GABARs). In this study, we used in silico analysis to identify residues that are critical for the interaction between RDL and these insecticides. Substitution of glycine at the third position (G3') in the third transmembrane domain (TMD3) with methionine (G3'M .sub.TMD3 ), which is present in vertebrate GABARs, had the strongest effect on fluralaner binding. This was confirmed by expression of RDL from the rice stem borer, Chilo suppressalis (CsRDL) in oocytes of the African clawed frog, Xenopus laevis, where the G3'M.sub.TMD3 mutation almost abolished the antagonistic action of fluralaner. Subsequently, G3'M.sub.TMD3 was introduced into the Rdl gene of the fruit fly, Drosophila melanogaster, using the CRISPR/Cas9 system. Larvae of heterozygous lines bearing G3'M.sub.TMD3 did not show significant resistance to avermectin, fipronil, broflanilide, and fluralaner. However, larvae homozygous for G3'M.sub.TMD3 were highly resistant to broflanilide and fluralaner whilst still being sensitive to fipronil and avermectin. Also, homozygous lines showed severely impaired locomotivity and did not survive to the pupal stage, indicating a significant fitness cost associated with G3'M.sub.TMD3 . Moreover, the M3'G.sub.TMD3 mutation in the mouse Mus musculus [alpha]1[beta]2 GABAR increased sensitivity to fluralaner. Taken together, these results provide convincing in vitro and in vivo evidence for both broflanilide and fluralaner acting on the same amino acid site, as well as insights into potential mechanisms leading to target-site resistance to these insecticides. In addition, our findings could guide further modification of isoxazolines to achieve higher selectivity for the control of insect pests with minimal effects on mammals.

Dieldrin and endrin are persistent organic pollutants that cause serious environmental problems. Although these compounds have been prohibited over the past decades in most countries around the world, they are still routinely found in the environment, especially in the soil in agricultural fields. Bioremediation, including phytoremediation and rhizoremediation, is expected to be a useful cleanup method for this soil contamination. This review provides an overview of the environmental contamination by dieldrin and endrin, along with a summary of our current understanding and recent advances in bioremediation and phytoremediation of these pollutants. In particular, this review focuses on the types and abilities of plants and microorganisms available for accumulating and degrading dieldrin and endrin.

Understanding the dynamics of insecticide resistance genes in mosquito populations is pivotal for a sustainable use of insecticides. Dieldrin resistance in Aedes albopictus is conferred by the alanine to serine substitution (A302S or RdlR allele) in the γ-aminobutyric acid (GABA) receptor encoded by the Rdl gene. On Reunion Island, dieldrin resistance was initially reported in natural Ae. albopictus populations sampled in 2008 despite the ban of dieldrin since 1994. To monitor insecticide resistance in Ae. albopictus on the island and to identify its drivers, we measured (i) the frequency of resistance alleles in 19 distinct natural populations collected between 2016 and 2017, (ii) fitness costs associated with dieldrin resistance in laboratory-controlled experiments, and (iii) the resistance conferred by RdlR to fipronil, an insecticide widely used on the island and reported to cross-react with RdlR. The results show a persistence of RdlR in Ae. albopictus natural populations at low frequencies. Among the measured life history traits, mortality in pre-imaginal stages, adults’ survival as well as the proportion of egg-laying females were significantly affected in resistant mosquitoes. Finally, bioassays revealed resistance of RdlR mosquitoes to fipronil, suggesting that the use of fipronil in natura could select for the RdlR allele. This study shows that dieldrin resistance is persistent in natural mosquito populations likely as a result of combined effects between fitness costs associated with RdlR and selection exerted by cross-reacting environmental insecticides such as fipronil.

Meta-diamides (e.g. broflanilide) and isoxazolines (e.g. fluralaner) are novel insecticides that target the resistant to dieldrin (RDL) subunit of insect γ-aminobutyric acid receptors (GABARs). In this study, we used in silico analysis to identify residues that are critical for the interaction between RDL and these insecticides. Substitution of glycine at the third position (G3’) in the third transmembrane domain (TMD3) with methionine (G3’M TMD3 ), which is present in vertebrate GABARs, had the strongest effect on fluralaner binding. This was confirmed by expression of RDL from the rice stem borer, Chilo suppressalis ( Cs RDL) in oocytes of the African clawed frog, Xenopus laevis , where the G3’M TMD3 mutation almost abolished the antagonistic action of fluralaner. Subsequently, G3’M TMD3 was introduced into the Rdl gene of the fruit fly, Drosophila melanogaster , using the CRISPR/Cas9 system. Larvae of heterozygous lines bearing G3’M TMD3 did not show significant resistance to avermectin, fipronil, broflanilide, and fluralaner. However, larvae homozygous for G3’M TMD3 were highly resistant to broflanilide and fluralaner whilst still being sensitive to fipronil and avermectin. Also, homozygous lines showed severely impaired locomotivity and did not survive to the pupal stage, indicating a significant fitness cost associated with G3’M TMD3 . Moreover, the M3’G TMD3 mutation in the mouse Mus musculus α1β2 GABAR increased sensitivity to fluralaner. Taken together, these results provide convincing in vitro and in vivo evidence for both broflanilide and fluralaner acting on the same amino acid site, as well as insights into potential mechanisms leading to target-site resistance to these insecticides. In addition, our findings could guide further modification of isoxazolines to achieve higher selectivity for the control of insect pests with minimal effects on mammals.