Low-dose Toxin Research Articles

Acute toxicology report of the emerging marine biotoxin Brevetoxin 3 in mice: Food safety implications

Brevetoxins (PbTxs) are emerging marine toxins that can lead to Neurotoxic Shellfish Poisoning in humans by the ingestion of contaminated seafood. Recent reports on brevetoxin detection in shellfish in regions where it has not been described before, arise the need of updated guidelines to ensure seafood consumers safety. Our aim was to provide toxicological data for brevetoxin 3 (PbTx3) by assessing oral toxicity in mice and comparing it with intraperitoneal administration. We followed an Up-and-Down procedure administering PbTx3 to mice and registering clinical signs, neuromuscular function, histopathology, and blood changes. Neuromuscular dysfunction like seizures and ataxia, as well as loss of limb strength were observed at 6 h. Performance and clinical signs largely improved at 24 h, time at which no blood biochemical or histological alterations were detected independently of the administration route. However, PbTx3 oral administration results in lower toxicity than intraperitoneal administration. Mortality was only observed at 4000 μg/kg bw PbTx3 administered via oral, but we still found toxicity clinical signs at low toxin doses. We could stablish an oral Lowest-Observable-Adverse-Effect-Level for PbTx3 of 100 μg/kg bw and an oral No-Observable-Adverse-Effect-Level of 10 μg/kg bw in mice. The data here reported should be considered in the evaluation of risks of PbTxs for human health.

Low glyphosate doses change reproduction and produce tolerant offspring in dense populations of Hordeum vulgare.

Low toxin doses that do not affect mean responses in plant populations can still change the growth of subpopulations. Studies covering vegetative stages ascribed fast-growing plants higher thresholds for growth stimulation and inhibition, compared with the rest of the population. We hypothesized that such selective effects also play a role after reproduction; that is, the offspring of glyphosate-treated tolerant, fast-growing phenotypes is more tolerant than the offspring of untreated plants. An experimental, high-density barley population was exposed to a range of glyphosate concentrations in the greenhouse, and reproduction and final growth were analyzed for selective effects. Therefore, F0, F1 treated and F1 non-treated offspring were re-exposed to glyphosate. Low doses of glyphosate inhibited the growth and reproduction of slow-growing plants at concentrations that did not change the population mean. Concentrations that inhibited average-sized plants hormetically increased the biomass and seed yield of fast-growing plants. Compared with F0 and F1 non-treated offspring, F1-treated offspring from hormetically stimulated fast-growing plants were more glyphosate tolerant. Hence, a pesticide can shape the reproductive pattern of a plant population and alter offspring tolerance at concentrations that have no effect on average yield. Toxin levels that do not change the population mean still alter the reproductive output of individuals. Sensitive phenotypes suffer, whereas the reproduction of tolerant phenotypes is boosted compared with toxin-free conditions. Because glyphosate is one of the leading herbicides in the world, tolerant phenotypes may benefit from current agricultural practices. If these results apply to other toxicants, low toxin doses may increase the fitness of tolerant phenotypes in a way not previously anticipated. © 2021 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Ameliorative role of dietary activated carbon against ochratoxin-A induced oxidative damage, suppressed performance and toxicological effects

The present study reports that dietary addition of 2.5, 5.0, 10.0 g/kg activated charcoal (AC) in broiler feed contaminated with 0.15, 0.3 and 1.0 mg/kg ochratoxin A (OTA) showed a partial reduction in intensity of mycotoxins induced toxic effects; particularly against those induced at lower doses of toxin (0.15 and 0.3 mg/kg). The protection by AC was absent against 1.0 mg/kg OTA-mediated toxicities. Moreover, AC at 10 g/kg feed also imparted toxicological effects in broiler chicken. It can be concluded that AC possess limited adsorptive potential against OTA and increasing the dose of AC may be detrimental for animal health.

Low toxin doses change plant size distribution in dense populations – Glyphosate exposed Hordeum vulgare as a greenhouse case study

Numerous intentionally released toxins persist in agricultural or natural environments at low concentrations. Such low toxin doses are regularly associated with hormesis, i.e., growth stimulation, and they are suspected to affect mortality and within-population plant size distribution in dense plant stands. However, it is not known whether all these low-dose effects exist when plants grow in soil. We exposed barley to a range of low glyphosate doses and let the plants grow in dense stands for several weeks in soil. Six experiments were done that contained altogether 10,260 seedlings in 572 pots. We evaluated if the changes in average biomass and shoot length occur at the same concentrations as do the effects on slow- and fast-growing individuals, if seed size or early vigor explains variation in the response to glyphosate, and if low toxin doses change within-population mortality.Plant biomass, length and survival of subpopulations changed at doses that did not affect mean biomass. Effects of early vigor faded early, but differences in seed size and particularly vegetative growth had impacts: fast-growing plants hardly showed hormesis, whereas hormesis was particularly strong among slow-growing individuals. Compared to the population mean, glyphosate effects started at lower doses among slow-growing individuals and at higher doses among fast-growing individuals. Several times higher doses were needed before the fast-growing individuals showed the same toxicity as most of the population. Low toxin doses regularly enhanced the growth of the smallest individuals, which reduced size variation within populations and was associated with a higher number of surviving plants. Indeed, in one experiment self-thinning was not observed at low doses that stimulated the growth of slow-growing plants.As glyphosate levels in this study match those observed in agricultural fields and natural environments, we conclude that even low-levels of agro-environmental contamination are likely to shape phenotypic response, which might lead to adaptation and cascading ecological impacts.

Toxin-induced hormesis may restrain aging.

Mild environmental stress might have beneficial effects in aging by activating maintenance and repair processes in cells and organs. These beneficial stress effects fit to the concept of hormesis. Prominent stressors acting in a hormetic way are physical exercises, fasting, cold and heat. This review will introduce some toxins, which have been found to induce hormetic responses in animal models of aging research. To highlight the molecular signature of these hormetic effects we will depict signaling pathways affected by low doses of toxins on cellular and organismic level. As prominent examples for signaling pathways involved in both aging processes as well as toxin responses, PI3K/Akt/mTOR- and AMPK-signal transduction will be described in more detail. Due to the striking overlap of signaling pathways mediating toxin induced responses and aging processes we propose considering the ability of low doses of toxins to slow down the rate of aging.

Fumonisins in pig feed

Fumonisins are mycotoxins belonging to a group of potential carcinogens for humans. It is well known that they also have potentially harmful effects on various species of animals. After consumption, in the horse they may cause leukoencefalomalation, and in pig pulmonary edema. The legal regulations in Serbia do not prescribe the maximum allowed levels (ML) of fumonisins in feed. As products of Fusarium, fumonisins are often detected in corn, and their presence in wheat is also proven. However, there is not enough data on the occurrence and levels of these mycotoxins in feed. Considering the harmful effect of fumonisin on pig health and data on corn contamination, the aim of this paper is to examine the concentration of fumonisins in feed for pigs. A sum of fumonisins (B1, B2 and B3) in a total of 30 samples of feed for different categories of pigs was tested. Fumonisins were found in 83% of the examined samples. Although no sample contained more than 5 mg/kg (the maximum recommended level according to EU regulation), studies on the effect of low-dose toxin on pig health and the frequent grain contamination with multiple mycotoxins pointed out the necessity of monitoring of fumonisins levels in pig feed.

Suppression of colorectal tumorigenesis by recombinant Bacteroides fragilis enterotoxin-2 in vivo.

AIMTo evaluate the impact of recombinant Bacteroides fragilis enterotoxin-2 (BFT-2, or Fragilysin) on colorectal tumorigenesis in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS).METHODSRecombinant proBFT-2 was expressed in Escherichia coli strain Rosetta (DE3) and BFT-2 was obtained and tested for its biological activity via colorectal adenocarcinoma cell strains SW-480. Seventy C57BL/6J mice were randomly divided into a blank (BC; n = 10), model (AD; n = 20), model + low-dose toxin (ADLT; n = 20, 10 μg), and a model + high-dose toxin (ADHT; n = 20, 20 μg) group. Mice weight, tumor formation and pathology were analyzed. Immunohistochemistry determined Ki-67 and Caspase-3 expression in normal and tumor tissues of colorectal mucosa.RESULTSRecombinant BFT-2 was successfully obtained, along with its biological activity. The most obvious weight loss occurred in the AD group compared with the ADLT group (21.82 ± 0.68 vs 23.23 ± 0.91, P < 0.05) and the ADHT group (21.82 ± 0.68 vs 23.57 ± 1.06, P < 0.05). More tumors were found in the AD group than in the ADLT and ADHT groups (19.75 ± 3.30 vs 6.50 ± 1.73, P < 0.05; 19.75 ± 3.30 vs 6.00 ± 2.16, P < 0.05). Pathology showed that 12 mice had adenocarcinoma and 6 cases had adenoma in the AD group. Five mice had adenocarcinoma and 15 had adenoma in the ADLT group. Four mice had adenocarcinoma and 16 had adenoma in the ADHT group. The incidence of colorectal adenocarcinoma in both the ADHT group and the ADHT group was reduced compared to that in the AD group (P < 0.05, P < 0.05). The positive rate of Ki-67 in the ADLT group and the ADHT group was 50% and 40%, respectively, both of which were lower than that found in the AD group (94.44%, P < 0.05, P < 0.05). Caspase-3 expression in the ADLT group and the ADHT group was 45% and 55%, both of which were higher than that found in the BC group (16.67%, P < 0.05, P < 0.05).CONCLUSIONOral administration with lower-dose biologically active recombinant BFT-2 inhibited colorectal tumorigenesis in mice.

Selective toxin effects on faster and slower growing individuals in the formation of hormesis at the population level — A case study with Lactuca sativa and PCIB

Natural plant populations have large phenotypic plasticity that enhances acclimation to local stress factors such as toxin exposures. While consequences of high toxin exposures are well addressed, effects of low-dose toxin exposures on plant populations are seldom investigated. In particular, the importance of ‘selective low-dose toxicity’ and hormesis, i.e. stimulatory effects, has not been studied simultaneously. Since selective toxicity can change the size distribution of populations, we assumed that hormesis alters the size distribution at the population level, and investigated whether and how these two low-dose phenomena coexist.The study was conducted with Lactuca sativa L. exposed to the auxin-inhibitor 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB) in vitro. In two separate experiments, L. sativa was exposed to 12 PCIB doses in 24 replicates (50 plants/replicate). Shoot/root growth responses at the population level were compared to the fast-growing (≥90% percentile) and the slow-growing subpopulations (≤10% percentile) by Mann-Whitney U testing and dose-response modelling.In the formation of pronounced PCIB hormesis at the population level, low-dose effects proved selective, but widely stimulatory which seems to counteract low-dose selective toxicity. The selectivity of hormesis was dose- and growth rate-dependent. Stimulation occurred at lower concentrations and stimulation percentage was higher among slow-growing individuals, but partly or entirely masked at the population level by moderate or negligible stimulation among the faster growing individuals. We conclude that the hormetic effect up to the maximum stimulation may be primarily facilitated by an increase in size of the most slow-growing individuals, while thereafter it seems that mainly the fast-growing individuals contributed to the observed hormesis at the population level. As size distribution within a population is related to survival, our study hints that selective effects on slow- and fast-growing individuals may change population dynamics, providing that similar effects can be repeated under field conditions.

An intrinsically disordered entropic switch determines allostery in Phd-Doc regulation.

Conditional cooperativity is a common mechanism involved in transcriptional regulation of prokaryotic type II toxin-antitoxin operons and is intricately related to bacterial persistence. It allows the toxin component of a toxin-antitoxin module to act as a co-repressor at low doses of toxin as compared to antitoxin. When toxin level exceeds a certain threshold, however, the toxin becomes a de-repressor. Most antitoxins contain an intrinsically disordered region (IDR) that typically is involved in toxin neutralization and repressor complex formation. To address how the antitoxin IDR is involved in transcription regulation, we studied the phd-doc operon from bacteriophage P1. We provide evidence that the IDR of Phd provides an entropic barrier precluding full operon repression in the absence of Doc. Binding of Doc results in a cooperativity switch and consequent strong operon repression, enabling context-specific modulation of the regulatory process. Variations of this theme are likely to be a common mechanism in the autoregulation of bacterial operons that involve intrinsically disordered regions.

Subclinical mastitis disrupts oocyte cytoplasmic maturation in association with reduced developmental competence and impaired gene expression in preimplantation bovine embryos.

Subclinical chronic mastitis was induced to examine the effects on oocyte developmental competence. Uninfected Holstein cows were intramammary administrated with serial (every 48h for 20 days) low doses of toxin of Staphylococcus aureus origin (Gram-positive; G+), endotoxin of Escherichia coli origin (Gram-negative; G-) or sterile saline (control). Follicular fluid of toxin- and saline-treated cows was aspirated from preovulatory follicles and used as maturation medium. Oocytes harvested from ovaries collected at the abattoir were matured and then fertilised and cultured for 8 days. The percentage of oocytes undergoing nuclear maturation, determined by meiotic nuclear stages, did not differ between groups. Cytoplasmic maturation, determined by cortical granule distribution, was affected by both toxins (PPPPTGS2) mRNA increased, whereas that of growth differentiation factor 9 (GDF9) decreased in matured oocytes. In addition, PTGS2 expression increased and POU class 5 homeobox 1 (POU5F1) expression decreased in 4-cell embryos developed from both G+ and G- oocytes. Thus, regardless of toxin type, subclinical mastitis disrupts oocyte cytoplasmic maturation and alters gene expression in association with reduced developmental competence.

Modulation of Behavior and Glutamate Receptor mRNA Expression in Rats after Sub-chronic Administration of Benzo(a)pyrene

Objective The present study aimed to test whether exposure to benzo(a)pyrene [B(a)P] affects spatial learning and short-term memory by modulating the expression of the Gria1 and Grin2a glutamate receptor subunit genes in the hippocampus. Methods Thirty-six 21–24-day-old, male rats were randomly assigned into high-, medium-, and low-dose toxin exposure groups (6.25, 2.5, and 1 mg/kg, respectively) and a control group, each containing nine rats. The behavioral performance of adult rats exposed to sub-chronic administration of B(a)P was monitored by learning and memory tests (Morris water maze). Real-time PCR assays were used to quantify Gria1 and Grin2a gene expression in the hippocampus. Results At medium and high doses, B(a)P impaired spatial learning performance. The crossing-platform-location frequency and the time spent swimming in the platform area, which both relate to short-term memory, were significantly decreased in B(a)P-treated rats compared with controls. The level of Gria1 mRNA increased 2.6–5.9-fold, and the level of Grin2a mRNA increased 10–14.5-fold, with a greater fold increase associated with higher doses of B(a)P. Conclusion We demonstrated that sub-chronic administration of B(a)P inhibits spatial learning and short-term memory, and increases Gria1 and Grin2a expression in the hippocampus. This suggests a relationship of B(a)P exposure levels with Gria1 and Grin2a expression and impairment of short-term and spatial memory.

Hormesis, cell death and aging

Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress response that raise the resistance of the organism against high doses of the same agent. This phenomenon, which is known as "hormesis", is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction.

Effect of the selective A1 adenosine antagonist 8-cyclopentyl-1,3-dipropylxanthine on acute renal dysfunction induced by Escherichia coli endotoxin in rats.

The effect of the selective A1 adenosine antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), on Escherichia coli endotoxin-induced acute renal dysfunction was determined in anaesthetized rats. Bolus administration of endotoxin at doses of either 1 or 20 mg kg-1 evoked decreases in inulin clearance, renal blood flow, urine flow and excretion of sodium, potassium and chloride. The changes in renal function produced by 20 mg kg-1 endotoxin were more severe than those noted with 1 mg kg-1 toxin and, by contrast to this lower dose, renal function showed no signs of recovery. Intravenous administration of CPX (0.1 mg kg-1) elicited a statistically significant, although modest, attenuation of the decline in inulin clearance, renal blood flow, urine output and electrolyte excretion induced by 20 mg kg-1 endotoxin. By contrast, treatment with 0.1 mg kg-1 CPX resulted in statistically significant protection against the falls in excretory function evoked by 1 mg kg-1 endotoxin but not against the reductions in renal blood flow and inulin clearance produced by the lower dose of toxin. These results suggest that adenosine may play a role, albeit not a major one, in the pathophysiology of endotoxaemic acute renal failure.

Heterodimeric integrin complexes containing β1-integrin promote internalization and lethality of anthrax toxin

To kill macrophages, the lethal factor component of Bacillus anthracis toxin binds to a carrier protein (PA), which then interacts with the CMG2 receptor protein on the cell surface and is endocytosed into the cytoplasm. CMG2, as well as TEM8, a second PA receptor not present on macrophages, contain a von Willebrand A domain that is crucial for toxin binding. Here we report that integrin beta1, another cell surface von Willebrand A domain protein, can mediate and potentiate anthrax toxin endocytosis. By using microarray-based analysis to globally correlate gene expression profiles with toxin sensitivity, we associated toxin effects with the integrin-activating proteins osteopontin and CD44. Further study showed that PA binds to alpha4beta1- and alpha5beta1-integrin complexes, leading to their conjoint endocytosis, and also interacts-weakly relative to CMG2 but comparably to TEM8--with purified alpha5beta1 complex in vitro. Monoclonal antibody directed against beta1-integrin or its alpha integrin partners reduced PA/integrin endocytosis and anthrax toxin lethality, and hyaluronic acid--which interferes with CD44-mediated integrin activation--had similar effects. Remarkably, whereas deficiency of CMG2 protected macrophages from rapid killing by large toxin doses (>50 ng/mL), by 24 h the toxin-treated cells were dead. Such late killing of CMG2-deficient cells by high dose toxin as well as the late death observed during exposure of CMG2-producing macrophages to low-dose toxin (<1 ng/mL), was dependent on integrin function. Effects of inactivating both CMG2 and integrin were synergistic. Collectively, our findings argue strongly that beta1-integrin can both potentiate CMG2-mediated endocytosis and serve independently as a low-affinity PA receptor.

Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration

The endothelial damage induced by Stx represents the main pathogenic event in the HUS associated with STEC infections in humans. Stx, released in the gut by bacteria, enter the bloodstream and are targeted to renal endothelia. The role of PMN as a toxin carrier has been the object of controversy. In this paper, we confirm the binding of Stx1 to PMN, also showing its degranulating effects on full-loaded leukocytes, and support the carrier role of PMN by using a two-chamber transmigration device, in which PMN, loaded in vitro with different amounts of Stx1, transmigrated through confluent monolayers of endothelial cells, mimicking the toxin-induced renal endothelial injury. Stx1 was transferred during PMN transmigration, impairing protein synthesis and triggering production of proinflammatory cytokines in endothelial cells. PMN, carrying low toxin amounts, induced the release of high levels of cytokines in viable endothelial cells, whereas cytokine production was blocked in cells challenged with PMN fully loaded with Stx as a result of an almost total impairment of translation and of the activation of the apoptotic program. In agreement with previous unexplained observations in animal models, the results obtained with our experimental setting suggest that a self-amplifying circle triggered by low doses of toxin may lead to the production of proinflammatory mediators of renal damage in HUS.

2Am-DNT Induces Cell Death and Apoptosis in Human Cells

During microbial or mammalian cell metabolism, TNT (2,4,6-tinitrotoluene) is reduced to 2Am-DNT (2-amino-4,6-dinitrotoluene), 4Am-DNT, or 2,4-diamino-NT (2,4-diaminonitrotoluelne) depending on the specific organism. The metabolite 2Am-DNT is the most common of the TBT biotransformation pathways in bacterial and fungal species studied to date. in the mammalian liver cells, TNT is metabolized to 2Am-DNT by the P450 enzyme system. Apoptosis is rapidly emerging as a relevant endpoint for detecting low-dose toxin exposure. We report in this study that 2Am-DNT treatment of mammalian cells causes cell death by apoptosis. Cell death was assayed by the Trypan Blue method. Apoptotic changes, such as DNA break down, were detected in treated cells by the production of a dark-brown DAB (diaminobenzidine) signal using the Fragel Klenow DNA fragment detection system, by immunohistochemical techniques with fluorescence microscopy, and by using a microplate reader for a single-stranded DNA binding assay. All of these results showed that 2am-DNT is toxic to mammalian cells and induces apoptosis.

The first study on the effects of microcystin-RR on gene expression profiles of antioxidant enzymes and heat shock protein-70 in Synechocystis sp. PCC6803

Microcystins are heptapeptide toxins produced by cyanobacteria. Microcystin-RR (MC-RR) is a common variant among the 80 variants identified so far. There have been many investigations documenting the toxic effects of microcystins on animals and higher plants, but little is known on the toxic effects of microcystins on algae, especially at molecular level. We studied the effects of MC-RR on gene expression profile of a few antioxidant enzymes and heat shock protein-70 (Hsp70) in Synechocystis sp. PCC6803. After two days post-exposure, a high dose toxin (5 mg/l, about 4.8 × 10 −3 mM) significantly increased expression levels of the genes gpx1, sodB, katG, acnB, γ-TMT and dnaK2, while a relatively low dose toxin (1 mg/l, about 9.63 × 10 −4 mM) induced a moderate and slow increase of gene expression. Our results indicate that MC-RR could induce the oxidative stress in Synechocystis sp. PCC6803 and the increase in gene expression of antioxidant enzymes and Hsp70 might protect the organism from the oxidative damage. In addition, cell aggregation was observed during the early period of exposure, which might be a specific oxidative stress reaction to MC-RR.

Molecular biology of botulinum neurotoxin serotype A: a cosmetic perspective

Cosmetic use of botulinum neurotoxin serotype A (BoNT/A) involves low doses of toxin administered for facial wrinkles and hyperhidrosis. The structural and functional properties of BoNT/A can affect the degree and duration of effect. Actively using the injected muscle is favorable as it exposes more receptors to BoNT/A. Divided doses of BoNT/A at an interval of more than 3 days may be longer lasting than single dose by blocking nascent neuronal sprouts. Antibodies are unlikely to be effective in BoNT/A neutralization because of the large area of receptor interaction. Several commonly used drugs including zinc and chloroquine can interact with BoNT/A, necessitating dosage adjustment for optimum effect. Serotype E (BoNT/E) can emerge as an antidote for BoNT/A for cosmetic use.

Blepharospasmus und Spasmus hemifacialis - Einteilung, Ätiopathogenese, Diagnostik und Therapie

Die differenzialdiagnostische Abklärung von Spasmen der Gesichtsmuskulatur wird in der neurologischen Praxis relativ häufig angefordert. Neben dem gutartigen „Lidflattern” ohne Krankheitswert sind der Blepharospasmus und der Spasmus hemifacialis die häufigsten Krankheitsbilder. Die Diagnose ist überwiegend klinisch zu stellen. Mögliche Differenzialdiagnosen lassen sich meist relativ einfach durch die neurologische Untersuchung oder durch Einsatz elektrophysiologischer und bildgebender Verfahren abgrenzen. Während es sich beim Blepharospasmus um eine Dystonie mit wahrscheinlicher Pathologie im Bereich der Basalganglien handelt, liegt beim Spasmus hemifacialis eine periphere Pathologie vor. Für beide Erkrankungen hat sich trotz der unterschiedlichen Ätiologien die Behandlung mit Botulinumtoxininjektionen als Therapie der Wahl etabliert. Sie ist in den meisten Fällen effektiv, die Nebenwirkungen sind tolerabel und reversibel. Aufgrund der niedrigen Toxindosen ist das Risiko der Bildung neutralisierender Antikörper gering. Probleme treten häufig bei der Behandlung des Blepharospasmus vom palpebralen Typ auf, bei dem die Botulinumtoxinbehandlung häufig nur zu einer mäßigen Symptomverbesserung führt. Beim Spasmus hemifacialis ist die Behandlung des unwillkürlichen Lidschlusses gut möglich; die Injektion der perioralen mimischen Muskulatur infolge der kosmetisch störenden Paresen ist allerdings nur mit Zurückhaltung zu empfehlen. Insgesamt lässt sich bei den meisten Patienten durch die Botulinumtoxinbehandlung eine spürbare Verbesserung der Lebensqualität erreichen.

The compatibility of a nucleopolyhedrosis virus control with resistance management for Bacillus thuringiensis: Co-infection and cross-resistance studies with the diamondback moth, Plutella xylostella

The use of genetically modified crops expressing Bacillus thuringiensis ( Bt) toxins can lead to the reduction in application of broad-spectrum pesticides and an increased opportunity for supplementary biological control. Bt microbial sprays are also used by organic growers or as part of integrated pest management programs that rely on the use of natural enemies. In both applications the evolution of resistance to Bt toxins is a potential problem. Natural enemies (pathogens or insects) acting in combination with toxins can accelerate or decelerate the evolution of resistance to Bt. In the present study we investigated whether the use of a nucleopolyhedrovirus (AcMNPV) could potentially affect the evolution of resistance to the Bt toxin Cry1Ac in Plutella xylostella. At low toxin doses there was evidence for antagonistic interactions between AcMNPV and Cry1Ac resistant and susceptible insects. However, this antagonism was much stronger and more widespread for susceptible larvae; interactions were generally not distinguishable from additive for resistant larvae. Selection for resistance to Cry1Ac in two populations of P. xylostella with differing resistance mechanisms did not produce any correlated changes in resistance to AcMNPV. Stronger antagonistic interactions between Bt and AcMNPV on susceptible rather than resistant larvae can decrease the relative fitness between Bt-resistant and susceptible larvae. These interactions and the lack of cross-resistance between virus and toxin suggest that the use of NPV is compatible with resistance management to Bt products.