Strategies to manage resistance to a particular insecticide have usually been devised after resistance has evolved. If it were possible to predict likely resistance mechanisms to novel insecticides before they evolved in the field, it might be feasible to have programmes that manage susceptibility. With this approach in mind, single-gene variants of the Australian sheep blowfly, Lucilia cuprina, resistant to dieldrin, diazinon and malathion, were selected in the laboratory after mutagenesis of susceptible strains. The genetic and molecular bases of resistance in these variants were identical to those that had previously evolved in natural populations. Given this predictive capacity for known resistances, the approach was extended to anticipate possible mechanisms of resistance to cyromazine, an insecticide to which L. cuprina populations remain susceptible after almost 20 years of exposure. Analysis of the laboratory-generated resistant variants provides an explanation for this observation. The variants show low levels of resistance and a selective advantage over susceptibles for only a limited concentration range. These results are discussed in the context of the choice of insecticides for control purposes and of delivery strategies to minimize the evolution of resistance. (+info)
(2/139) The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication.
The bystander effect (BSE) is an interesting and important property of the herpes thymidine kinase/ganciclovir (hTK/GCV) system of gene therapy for cancer. With the BSE, not only are the hTK expressing cells killed upon ganciclovir (GCV) exposure but also neighboring wild-type tumor cells. On testing a large number of tumor cell lines in vitro, a wide range of sensitivity to bystander killing was found. Since transfer of toxic GCV metabolites from hTK-modified to wild-type tumor cells via gap junctions (GJ) seemed to be a likely mechanism of the BSE, we tested GJ function in these various tumors with a dye transfer technique and pharmacological agents known to affect GJ communication. We confirmed that mixtures of tumor cell resistant to the BSE did not show dye transfer from cell to cell while bystander-sensitive tumor cells did. Dieldrin, a drug known to decrease GJ communication, diminished dye transfer and also inhibited the BSE. Forskolin, an upregulator of cAMP did increase GJ, but directly inhibited hTK and therefore its effect on BSE could not be determined. We conclude that these observations further support port the concept that functional GJ play an important role in the BSE and further suggest that pharmacological manipulation of GJ may influence the outcome of cancer therapy with hTK/GCV. (+info)
(3/139) Inhibition of transforming growth factor beta1-induced hepatoma cell apoptosis by liver tumor promoters: characterization of primary signaling events and effects on CPP32-like caspase activity.
The effects of the liver tumor promoters phenobarbital, clofibrate, dieldrin, and DDT on transforming growth factor-beta1 (TGFbeta)-induced apoptosis were studied in FTO-2B hepatoma cells. Inhibition of apoptosis by these compounds was strongly correlated with a decrease in CPP32-like caspase activity. Similar effects were obtained with insulin and dexamethasone. CPP32-like activity may thus provide a useful tool for quantiation of apoptosis under various treatment conditions. Diverse effects on apoptosis-associated cellular signaling proteins were observed: insulin led to an activation of the MAP kinases ERK1/2, of PKB/Akt and of NF-kappaB, phenobarbital and clofibrate enhanced NF-kappaB activity solely, while dexamethasone slightly enhanced NF-kappaB activity and increased the expression of Bcl-xL. Since inhibition of apoptosis was still detectable if the anti-apoptotic compounds were administered more than 10 h after TGFbeta, the diverse primary signals appear to converge at a presumably late stage of apoptosis, but upstream of activation of CPP32 or related caspases. (+info)
(4/139) Endrin inhibits adipocyte differentiation by selectively altering expression pattern of CCAAT/enhancer binding protein-alpha in 3T3-L1 cells.
The effects of selected chlorinated cyclodiene pesticides on the adipocyte differentiation process were examined using the 3T3-L1 adipocyte model in vitro. Endrin was found to cause a dose-dependent inhibition of adipocyte differentiation in 3T3-L1 cells. Aldrin and dieldrin were less potent than endrin in interfering with the adipogenic process. Endrin's inhibitory effect was effective only when the pesticide was present in the medium during the first 48 h after exposure of 3T3-L1 cells to adipogenic inducers. Immunoblots analysis revealed that endrin caused a dose-dependent, selective inhibition of the intracellular levels of CCAAT enhancer binding protein (C/EBP)alpha without altering the expression patterns of C/EBPbeta or C/EBPdelta along the differentiation. Supershift analysis showed that DNA-binding capacity of C/EBPalpha was affected most by endrin treatment. Endrin also caused a decrease in the elevation of the adipogenic factor peroxisome proliferator-activated receptor (PPAR)gamma elicited by the adipogenic inducers. However, the cotreatment with troglitazone, a thiazolidinedione known to activate PPARgamma, did not suppress the antiadipogenic action of endrin, indicating that its direct action site is not PPARgamma receptor. Endrin also altered the pattern of activation of nuclear factor-kappaB, a factor activated by 12-O-tetradecanoylphorbol-13-acetate and tumor necrosis factor-alpha, which are known to interfere with adipocyte differentiation. Thus, endrin inhibited the normal decrease in nuclear factor-kappaB-DNA binding observed as cells are acquiring the adipocyte phenotype at a late stage of differentiation. Our results suggest that endrin inhibits adipocyte differentiation through the specific suppression of C/EBPalpha. (+info)
(5/139) Cross-resistance with dieldrin of a novel tricyclic dinitrile GABA receptor antagonist.
A novel tricyclic dinitrile, KN244, blocked the wild-type (dieldrin-sensitive) homo-oligomeric gamma-aminobutyric acid (GABA)-gated chloride channel of Drosophila melanogaster expressed in Xenopus oocytes. Sensitivity to the block by KN244 of the response to 30 microM GABA (IC50=41.6 nM, wild-type RDLac) was reduced abut 100 fold (IC50=4.5 microM) in the dieldrin-resistant (RDLacA302S) form of RDL. (+info)
(6/139) Activation of neutrophil calcium-dependent and -independent phospholipases A2 by organochlorine compounds.
The production of reactive oxygen species by organochlorine pesticides has been implicated in the toxicity and carcinogenicity of these compounds; however, the mechanism by which these agents stimulate the production of oxygen radicals is unknown. Phospholipase A2 (PLA2)-mediated release of arachidonic acid has been shown to play an essential role in superoxide anion (O2-) production in neutrophils exposed to various physiologic and pharmacologic agents. Therefore, studies were performed to determine if the organochlorine pesticides, lindane and dieldrin, activate neutrophils to produce O2- by a mechanism that requires PLA2. Production of O2- and 3H-AA release increased with similar kinetics and concentration-response relations in neutrophils activated with either dieldrin or lindane. Significant release of 3H-AA was seen in neutrophils stimulated with dieldrin or lindane in calcium-free medium and in the presence of the intracellular calcium chelator BAPTA-AM, suggesting that these agents stimulate a PLA2 that does not require calcium for activation. In addition, both O2- production and 3H-AA release were inhibited in a concentration-dependent manner by BEL, a mechanism-based inhibitor of calcium-independent PLA2. These data suggest that dieldrin and lindane stimulate O2- production by a mechanism that involves PLA2. However, release of 3H-AA was not abrogated completely by BEL nor, in the case of dieldrin, preserved entirely in the absence of calcium. This suggests that more than one isoform of PLA2 is activated by dieldrin and by lindane, and that one isoform is calcium-dependent. (+info)
(7/139) Susceptibility to infections and immune status in Inuit infants exposed to organochlorines.
We investigated whether organochlorine exposure is associated with the incidence of infectious diseases in Inuit infants from Nunavik (Arctic Quebec, Canada). We compiled the number of infectious disease episodes during the first year of life for 98 breast-fed and 73 bottle-fed infants. Concentrations of organochlorines were measured in early breast milk samples and used as surrogates to prenatal exposure levels. Immune system parameters were determined in venous blood samples collected from infants at 3, 7, and 12 months of age. Otitis media was the most frequent disease, with 80. 0% of breast-fed and 81.3% of bottle-fed infants experiencing at least one episode during the first year of life. During the second follow-up period, the risk of otitis media increased with prenatal exposure to p,p'-DDE, hexachlorobenzene, and dieldrin. The relative risk (RR) for 4- to 7-month-old infants in the highest tertile of p, p'-DDE exposure as compared to infants in the lowest tertile was 1. 87 [95% confidence interval (CI), 1.07-3.26]. The RR of otitis media over the entire first year of life also increased with prenatal exposure to p,p'-DDE (RR, 1.52; CI, 1.05-2.22) and hexachlorobenzene (RR, 1.49; CI, 1.10-2.03). Furthermore, the RR of recurrent otitis media ( [Greater/equal to] 3 episodes) increased with prenatal exposure to these compounds. No clinically relevant differences were noted between breast-fed and bottle-fed infants with regard to immunologic parameters, and prenatal organochlorine exposure was not associated with immunologic parameters. We conclude that prenatal organochlorine exposure could be a risk factor for acute otitis media in Inuit infants. (+info)
(8/139) Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification.
Alpha-thujone is the toxic agent in absinthe, a liqueur popular in the 19th and early 20th centuries that has adverse health effects. It is also the active ingredient of wormwood oil and some other herbal medicines and is reported to have antinociceptive, insecticidal, and anthelmintic activity. This study elucidates the mechanism of alpha-thujone neurotoxicity and identifies its major metabolites and their role in the poisoning process. Four observations establish that alpha-thujone is a modulator of the gamma-aminobutyric acid (GABA) type A receptor. First, the poisoning signs (and their alleviation by diazepam and phenobarbital) in mice are similar to those of the classical antagonist picrotoxinin. Second, a strain of Drosophila specifically resistant to chloride channel blockers is also tolerant to alpha-thujone. Third, alpha-thujone is a competitive inhibitor of [(3)H]ethynylbicycloorthobenzoate binding to mouse brain membranes. Most definitively, GABA-induced peak currents in rat dorsal root ganglion neurons are suppressed by alpha-thujone with complete reversal after washout. alpha-Thujone is quickly metabolized in vitro by mouse liver microsomes with NADPH (cytochrome P450) forming 7-hydroxy-alpha-thujone as the major product plus five minor ones (4-hydroxy-alpha-thujone, 4-hydroxy-beta-thujone, two other hydroxythujones, and 7,8-dehydro-alpha-thujone), several of which also are detected in the brain of mice treated i.p. with alpha-thujone. The major 7-hydroxy metabolite attains much higher brain levels than alpha-thujone but is less toxic to mice and Drosophila and less potent in the binding assay. The other metabolites assayed are also detoxification products. Thus, alpha-thujone in absinthe and herbal medicines is a rapid-acting and readily detoxified modulator of the GABA-gated chloride channel. (+info)