Probing Structural Features and Binding Mode of 3-Arylpyrimidin-2,4-diones within Housefly γ-Aminobutyric Acid (GABA) Receptor

In order to obtain structural features of 3-arylpyrimidin-2,4-diones emerged as promising inhibitors of insect γ-aminobutyric acid (GABA) receptor, a set of ligand-/receptor-based 3D-QSAR models for 60 derivatives are generated using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA). The statistically optimal CoMSIA model is produced with highest q2 of 0.62, r2ncv of 0.97, and r2pred of 0.95. A minor/bulky electronegative hydrophilic polar substituent at the 1-/6-postion of the uracil ring, and bulky substituents at the 3′-, 4′- and 5′-positions of the benzene ring are beneficial for the enhanced potency of the inhibitors as revealed by the obtained 3D-contour maps. Furthermore, homology modeling, molecular dynamics (MD) simulation and molecular docking are also carried out to gain a better understanding of the probable binding modes of these inhibitors, and the results show that residues Ala-183(C), Thr-187(B), Thr-187(D) and Thr-187(E) in the second transmembrane domains of GABA receptor are responsible for the H-bonding interactions with the inhibitor. The good correlation between docking observations and 3D-QSAR analyses further proves the model reasonability in probing the structural features and the binding mode of 3-arylpyrimidin-2,4-dione derivatives within the housefly GABA receptor

Impact of fipronil, a new generation pesticide, on avian development and health

Fipronil is a new-generation pesticide aerially applied in semi-arid and agricultural areas of Australia to control locust outbreaks. Seasonal conditions that give rise to locust plagues are also ideal for breeding birds, with over 100 different avian species observed in areas of locust control operations. Despite the potential for exposure, there is very little research regarding the toxicological effects of fipronil in birds. Available avian toxicity information shows a high species-specific variability in fipronil sensitivity across the few species tested, making it extremely difficult to predict the toxicity of fipronil on unstudied species at high risk of exposure in the wild. The aim of this thesis was to increase our understanding of the impact of fipronil on native birds at risk of exposure as a result of locust-control spraying. This was done firstly by examining the toxicity, effects, and duration of symptoms following exposure to fipronil and it’s major metabolite, fipronil-sulfone, in sensitive and non-sensitive avian species; secondly by evaluating the metabolism of fipronil in a selected bird species to gain insight into the mechanisms underlying variation in species sensitivity; and thirdly by examining whether exposure to fipronil at sub-lethal levels adversely affects exposed birds and their offspring

Diacetone alcohol, a dispersant solvent, contributes to acute toxicity of a fipronil-based insecticide in a passerine bird

Fipronil, a phenyl pyrazole pesticide, is aerially applied in eastern Australia to control locust outbreaks, usually as &ldquo;Adonis 3UL Insecticide&reg;&rdquo; (BASF), an ultra low (UL) volume formulation containing 0.3% active pesticide. We tested the toxicities of technical-grade fipronil, the Adonis 3UL formulation and its components in zebra finch, a native bird at risk of exposure in locust control regions. We estimated oral-dose LD50 by the Up-and-Down method. Under laboratory conditions, we identified unexpectedly high toxicities due exclusively to diacetone alcohol (DAA), a solvent making up 12.5% of the Adonis 3UL formulation. In contrast, finches were asymptomatic when exposed to 0.3% technical grade fipronil dissolved in a minimum amount of acetone. Depending upon the behaviour and persistence of DAA under field conditions, this formulation of Adonis 3UL may pose a far greater threat to the health of small birds and possibly other vertebrates than expected for fipronil alone.<br /

Physiological assessment of avian exposure to fipronil, a new-generation pesticide

Fipronil, a phenyl pyrazole pesticide, is aerially applied in semi-arid and agricultural areas of Australia to control locust outbreaks. Locust populations build to plague proportions when rainfall occurs in late winter and spring, promoting early vegetation growth. These conditions also attract breeding birds. Over 100 species have been observed coincident with locust control operations. Avian exposure to fipronil occurs via direct contact and by ingesting contaminated insects or seeds. Avian toxicity information demonstrates there is high species-specific variability in fipronil sensitivity in the few avian species studied. There is no research, however, explaining this variability, nor is there research regarding physiological or behavioural sub-lethal effects on avian species. This makes it extremely difficult to predict the toxicity of fipronil on unstudied species at high risk of exposure. Our research aims to resolve this lack of essential information in two ways: firstly we examine whether fipronil has identifiable sublethal effects in exposed birds and their offspring that compromise population health, and secondly evaluate avian metabolism of fipronil in selected species to gain insight into the mechanisms underlying variation in species sensitivity. Our results provide critically needed information for evaluating field effects of locust-control spraying in Australia.<br /

Adverse effects of fipronil on avian reproduction and development : maternal transfer of fipronil to eggs in zebra finch Taeniopygia guttata and in ovo exposure in chickens Gallus domesticus

Two studies were carried out to examine the impact of maternal fipronil exposure on embryonic and offspring development. In the first study, breeding female zebra finches were orally dosed with single sublethal levels of fipronil (1, 5, and 10 mg/kg body weight) to determine behavioural and developmental consequences on chicks following maternal pesticide exposure. Significant levels of fipronil and fipronil-sulfone residues were detected in eggs laid by females in all dosed groups, however, these were undetectable in eggs laid 13 days after treatment. The level of sulfone detected in eggs was consistently higher than that of the parent fipronil compound. Of the seven eggs laid in the treatment groups, only one (14%) chick hatched and this was from the lowest dose group. This chick was severely underdeveloped at 10 days of age in comparison to control chicks and fiproles were detected in brain, liver, and adipose tissues collected following euthanasia of this individual. In contrast, there was 100% hatchability of control group eggs and all chicks fledged nests on schedule. In the second study, domestic chicken eggs were injected with 5.5, 17.5, and 37.5 mg/kg egg weight of fipronil directly into the yolk sac on day 12 of incubation. Treatment did not affect hatching success, however, behavioural and developmental abnormalities were observed in hatchlings from the highest dose group. These chicks also demonstrated reduced feeding rates, as indicated by reduced body mass at 48 h period post hatch. Both fipronil and fipronil-sulfone residues were detected in brain and liver tissue of hatchlings at all pesticide dose levels tested. 2011 Springer Science+Business Media, LLC