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W D Gubler - One of the best experts on this subject based on the ideXlab platform.
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sensitivity of california isolates of uncinula necator to trifloxystrobin and spiroxamine and update on Triadimefon sensitivity
Plant Disease, 2004Co-Authors: Thomas C Miller, W D GublerAbstract:ABSTRACT Sensitivities of Uncinula necator to spiroxamine and trifloxystrobin were established by assay of 36 and 35 isolates, respectively, recovered from California grape vineyards in 2002 and increased as single-spore lines for laboratory testing. Twenty-nine single-spore isolates also were evaluated for levels of sensitivity to the fungicide Triadimefon to determine if there had been a reversion to sensitivity following the development of resistance in 1986. Although Triadimefon use was limited after 1992, other demethylation inhibitor (DMI) fungicides (fenarimol and myclobutanil) were used extensively in California vineyards. For spiroxamine, the sample mean value of the median effective concentration (EC50 value) was 365 μg/liter (95% confidence interval [CI] from 251 to 531 μg/liter) and values were distributed log-normally. The corresponding mean for trifloxystrobin was 12.8 μg/liter bounded by 8.9 to 18.5 μg/liter for the 95% CI. State-wide, the Triadimefon mean EC50 was 8.8 mg/liter, bounded by ...
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long term effect of temperature and Triadimefon on proliferation of uncinula necator implications for fungicide resistance and disease risk assessment
Plant Disease, 1997Co-Authors: H L Ypema, W D GublerAbstract:ABSTRACT Triadimefon has been used in California to control Uncinula necator, causal agent of grape powdery mildew, since 1982. Instances of unsatisfactory control have occurred mainly in the cooler coastal areas of California. The effect of temperature and application of Triadimefon was investigated over a 53-day-period on two U. necator isolates, sensitive and resistant to Triadimefon. At 15°C, 25°C, or temperatures fluctuating between 15 and 25°C, in absence of Triadimefon, the isolates continued to produce high numbers of conidia for the entire duration of the experiment. Sporulation declined at daily maximum temperatures of 32°C for 6 h, 36°C for 3 h, and 40°C for 1 h, but was detectable when the experiment was terminated. At these temperature regimes, sporulation of the Triadimefon-treated sensitive isolate ceased after 23 days. When treated with Triadimefon, sporulation of the resistant isolate was comparable to that of the water-treated control. At daily maximum temperatures of 32°C for 11 h, 36°C...
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sensitivity of uncinula necator to benomyl Triadimefon myclobutanil and fenarimol in california
Plant Disease, 1997Co-Authors: H L Ypema, M Ypema, W D GublerAbstract:ABSTRACT Sensitivity of Uncinula necator subcultures to benomyl and the demethylation-inhibiting (DMI) fungicides Triadimefon, myclobutanil, and fenarimol was assessed in 1993, 1994, and 1995 with leaf disk bioassays. In 1993, 1994, and 1995, 81.8, 96, and 96.7% of the subcultures, respectively, did not grow on leaf disks treated with 30 mg of benomyl per liter, whereas growth of the remaining subcultures was inhibited by more than 90%. Median EC50 values of Triadimefon, myclobutanil, and fenarimol decreased from 1993 to 1994, and those of Triadimefon decreased again from 1994 to 1995. In the same period, median EC50 values of all three DMI fungicides increased in a vineyard never exposed to DMI fungicides. The highest means and ranges of EC50 values found were those of Triadimefon. Means and ranges were lower for myclobutanil and lowest for fenarimol, reflecting differences in inherent activities of the fungicides and po-tential for development of resistance. Pairwise correlations between EC50 values of ...
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sensitivity of uncinula necator to benomyl Triadimefon myclobutanil and fenarimol in california
Plant Disease, 1997Co-Authors: H L Ypema, M Ypema, W D GublerAbstract:Sensitivity of Uncinula necator subcultures to benomyl and the demethylation-inhibiting (DMI) fungicides Triadimefon, myclobutanil, and fenarimol was assessed in 1993, 1994, and 1995 with leaf disk bioassays. In 1993, 1994, and 1995, 81.8, 96, and 96.7% of the subcultures, respectively, did not grow on leaf disks treated with 30 mg of benomyl per liter, whereas growth of the remaining subcultures was inhibited by more than 90%. Median EC50 values of Triadimefon, myclobutanil, and fenarimol decreased from 1993 to 1994, and those of Triadimefon decreased again from 1994 to 1995. In the same period, median EC50 values of all three DMI fungicides increased in a vineyard never exposed to DMI fungicides. The highest means and ranges of EC50 values found were those of Triadimefon. Means and ranges were lower for myclobutanil and lowest for fenarimol, reflecting differences in inherent activities of the fungicides and po-tential for development of resistance. Pairwise correlations between EC50 values of each DMI fungicide were positive and confirmed earlier indications of cross resistance.
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occurrence of resistance in uncinula necator to Triadimefon myclobutanil and fenarimol in california grapevines
Plant Disease, 1996Co-Authors: W D Gubler, H L Ypema, D G Ouimette, Larry J BettigaAbstract:Uncinula necator subcultures from 19 vineyards in four regions in California were analyzed for sensitivity to Triadimefon, myclobutanil, and fenarimol. The means of EC 50 values to Triadimefon, myclobutanil, and fenarimol of U. necator subcultures from a vineyard without previous exposure to demethylation inhibition (DMI) fungicides were 1.40, 0.15, and 0.13 mg/liter, respectively. The highest means of EC 50 values were found in the Central Coast region, and frequency distributions were skewed most toward higher resistance to all three fungicides. Subcultures with high resistance levels also were present in the other regions examined. A time course study performed in one vineyard, where resistant strains were reported, demonstrated a steady and significant increase in EC 50 values for all three fungicides during the growing season after multiple applications of Triadimefon. Increased resistance to Triadimefon, but not to myclobutanil and fenarimol, was maintained in early-formed ascospores released after the growing season.
R Panneerselvam - One of the best experts on this subject based on the ideXlab platform.
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Triadimefon and Hexaconazole Enhances the Photosynthetic Pigment Composition of Tapioca, an Important Tuber Crop
2015Co-Authors: M. Gomathinayagam, Cheruth Abdul Jaleel, M. M. Azooz, R PanneerselvamAbstract:Abstract: An investigation was carried out to study the effect of Triadimefon and Hexaconazole on the photosynthetic pigment characteristics of tapioca (Manihot esculenta Crantz) during the growth and maturation period. One litre of 20 mg L-1 Triadimefon and 15mg L-1 hexaconazole solution per plant was used for the treatment and control was treated with one litre of irrigation water. The treatment was given on 25,45,65 an
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Superoxide Dismutase and Ascorbate Perxidase Profile Changes with Triazole Applications in Manihot esculenta Crantz
2015Co-Authors: M. Gomathinayagam, Cheruth Abdul Jaleel, M. M. Azooz, R PanneerselvamAbstract:Abstract: In the present study, the effect of Triadimefon and Hexaconazole on the enzymatic antioxidans like Superoxide dismutase and ascorbate perxidase of Manihot esculenta Crantz during the growth and maturation period was analysed. One litre of 20 mg L Triadimefon and 15mg L hexaconazole solution per plant was used-1-1 for the treatment and control was treated with one litre of irrigation water. The treatment was given on 25,45,6
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Triazole Induced Alterations in the Peroxidation of Membrane Lipids and Antioxidant Status of Manihot esculenta Crantz
2014Co-Authors: M. Gomathinayagam, Cheruth Abdul Jaleel, M. M. Azooz, R PanneerselvamAbstract:Abstract: The main objectives of this study wre to asses the effect of Triadimefon and Hexaconazole on the non-enzymatic antioxidant potentials of Manihot esculenta Crantz during the growth and maturation period. One litre of 20 mg L Triadimefon and 15mg L hexaconazole solution per plant was used for the treatment-1-1 and control was treated with one litre of irrigation water. The treatment was given on 25,45,65 and 100 DA
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Changes in growth and pigment content in Sweet potato by Triadimefon and hexaconazole
Update Publishing House, 2009Co-Authors: R Panneerselvam, T. Sivakumar, A. SundaramanickamAbstract:           Triadimefon and hexaconazole are triazole group of fungicides have plant growth regulating properties. The present investigation aimed to study the growth regulating effect of these compounds on sweet potato (Ipomoea batatas L.). Each plant was treated with one litre of aqueous solutions containing 15mg L-1 Triadimefon and 10mg L-1 hexaconazole on 40 and 70 days after planting (DAP) by soil drenching. The growth parameters of the plants were estimated on 45, 60, 75, 90 and 105 DAP. Among the triazole, hexaconazole inhibited the number of leaves, total leaf area, stem length, internodal length, leaf and stem dry weight, relative shoot growth rate significantly when compared to Triadimefon. Triazole (chiefly available and plant control and yield production) treatments increase the root length, root and tuber dry weight, relative tuber growth rate, net assimilation rate root/shoot ratio, leaf dry weight per unit area, chlorophyll and carotenoid content
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growth and photosynthetic pigments responses of two varieties of catharanthus roseus to Triadimefon treatment
Comptes Rendus Biologies, 2008Co-Authors: Cheruth Abdul Jaleel, Ragupathi Gopi, R PanneerselvamAbstract:Abstract Triadimefon, potential fungicide cum plant-growth retardant was used in this study to investigate its effect on the growth and the photosynthetic pigment contents of two varieties of Catharanthus roseus (L.) G. Don. The plants of both varieties were subjected to 15 mg l −1 Triadimefon treatment by soil drenching 30, 45, 60, and 75 days after planting (DAP). Plants were uprooted on 90 DAP, and morphological parameters, like plant height, number of leaves, leaf area, root length and fresh and dry weights were determined. The photosynthetic pigments, like chlorophylls a and b , total chlorophyll, carotenoids, floral pigment, anthocyanin, were extracted and estimated. It was observed that plant height, number of leaves and leaf area were decreased and that root length, fresh and dry weights were increased under Triadimefon treatment. The photosynthetic and floral pigments were increased under Triadimefon treatment in both varieties. The results suggest that the application of this plant-growth retardant (Triadimefon) has favourable effects on the reduction of plant height; it can thus be used for replacing manual hand pruning and for improving floral and vegetation colour in bedding plants like C. roseus . To cite this article: C.A. Jaleel et al., C. R. Biologies 331 (2008).
Douglas C Wolf - One of the best experts on this subject based on the ideXlab platform.
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disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat
Toxicological Sciences, 2007Co-Authors: Amber K Goetz, Hongzu Ren, Judith E Schmid, Chad R Blystone, Inthirany Thillainadarajah, Deborah S Best, Harriette P Nichols, Lillian F Strader, Douglas C WolfAbstract:Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or Triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and Triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and Triadimefon, and at PND50 by propiconazole and Triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and Triadimefon treatment. Serum testosterone was increased at PND50 by Triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and Triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose Triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.
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toxicity profiles in mice treated with hepatotumorigenic and non hepatotumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: James W Allen, Tanya Moore, Guobin Sun, Sheaufung Thai, Douglas C Wolf, Michael H George, Susan D Hester, Don A Delker, Carlton P Jones, Gail M NelsonAbstract:Conazoles comprise a class of fungicides used in agriculture and as pharmaceutical products. The fungicidal properties of conazoles are due to their inhibition of ergosterol biosynthesis. Certain conazoles are tumorigenic in rodents; both propiconazole and Triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. As a component of a large-scale study aimed at determining the mode(s) of action for tumorigenic conazoles, we report the results from comparative evaluations of liver and body weights, liver histopathology, cell proliferation, cytochrome P450 (CYP) activity, and serum cholesterol, high-density lipoprotein and triglyceride levels after exposure to propiconazole, Triadimefon, and myclobutanil. Male CD-1 mice were treated in the feed for 4, 30, or 90 days with Triadimefon (0, 100, 500, or 1800 ppm), propiconazole (0, 100, 500, or 2500 ppm) or myclobutanil (0, 100, 500, or 2000 ppm). Alkoxyresorufin O-dealkylation (AROD) assays indicated that all 3 chemicals induced similar patterns of dose-related increases in metabolizing enzyme activity. PROD activities exceeded those of MROD, and EROD with propiconazole inducing the highest activities of PROD. Mice had similar patterns of dose-dependent increases in hepatocyte hypertrophy after exposure to the 3 conazoles. High-dose exposures to propiconazole and myclobutanil, but not Triadimefon, were associated with early (4 days) increases in cell proliferation. All the chemicals at high doses reduced serum cholesterol and high-density lipoprotein (HDL) levels at 30 days of treatment, while only Triadimefon had this effect at 4 days of treatment and only myclobutanil and propiconazole at 90 days of treatment. Overall, the tumorigenic and nontumorigenic conazoles induced similar effects on mouse liver CYP enzyme activities and pathology. There was no specific pattern of tissue responses that could consistently be used to differentiate the tumorigenic conazoles, propiconazole, and Triadimefon, from the nontumorigenic myclobutanil. These findings serve to anchor other transcriptional profiling studies aimed at probing differences in key events and modes of action for tumorigenic and nontumorigenic conazoles.
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transcriptional profiles in liver from rats treated with tumorigenic and non tumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: Susan D Hester, Stephen Nesnow, Douglas C Wolf, Sheaufung ThaiAbstract:Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, Triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230_2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by Triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for Triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and Triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish Triadimefon from propiconazole and myclobutanil.
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toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: Douglas C Wolf, Tanya Moore, Guobin Sun, Sheaufung Thai, James W Allen, Michael H George, Susan D Hester, Don A Delker, Ernest Winkfield, Sharon LeavittAbstract:Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that Triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for Triadimefon. Male Wistar/Han rats were treated with Triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only Triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only Triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of Triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and Triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose Triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for Triadimefon-induced thyroid gland tumors was not supported by the data.
H L Ypema - One of the best experts on this subject based on the ideXlab platform.
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long term effect of temperature and Triadimefon on proliferation of uncinula necator implications for fungicide resistance and disease risk assessment
Plant Disease, 1997Co-Authors: H L Ypema, W D GublerAbstract:ABSTRACT Triadimefon has been used in California to control Uncinula necator, causal agent of grape powdery mildew, since 1982. Instances of unsatisfactory control have occurred mainly in the cooler coastal areas of California. The effect of temperature and application of Triadimefon was investigated over a 53-day-period on two U. necator isolates, sensitive and resistant to Triadimefon. At 15°C, 25°C, or temperatures fluctuating between 15 and 25°C, in absence of Triadimefon, the isolates continued to produce high numbers of conidia for the entire duration of the experiment. Sporulation declined at daily maximum temperatures of 32°C for 6 h, 36°C for 3 h, and 40°C for 1 h, but was detectable when the experiment was terminated. At these temperature regimes, sporulation of the Triadimefon-treated sensitive isolate ceased after 23 days. When treated with Triadimefon, sporulation of the resistant isolate was comparable to that of the water-treated control. At daily maximum temperatures of 32°C for 11 h, 36°C...
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sensitivity of uncinula necator to benomyl Triadimefon myclobutanil and fenarimol in california
Plant Disease, 1997Co-Authors: H L Ypema, M Ypema, W D GublerAbstract:ABSTRACT Sensitivity of Uncinula necator subcultures to benomyl and the demethylation-inhibiting (DMI) fungicides Triadimefon, myclobutanil, and fenarimol was assessed in 1993, 1994, and 1995 with leaf disk bioassays. In 1993, 1994, and 1995, 81.8, 96, and 96.7% of the subcultures, respectively, did not grow on leaf disks treated with 30 mg of benomyl per liter, whereas growth of the remaining subcultures was inhibited by more than 90%. Median EC50 values of Triadimefon, myclobutanil, and fenarimol decreased from 1993 to 1994, and those of Triadimefon decreased again from 1994 to 1995. In the same period, median EC50 values of all three DMI fungicides increased in a vineyard never exposed to DMI fungicides. The highest means and ranges of EC50 values found were those of Triadimefon. Means and ranges were lower for myclobutanil and lowest for fenarimol, reflecting differences in inherent activities of the fungicides and po-tential for development of resistance. Pairwise correlations between EC50 values of ...
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sensitivity of uncinula necator to benomyl Triadimefon myclobutanil and fenarimol in california
Plant Disease, 1997Co-Authors: H L Ypema, M Ypema, W D GublerAbstract:Sensitivity of Uncinula necator subcultures to benomyl and the demethylation-inhibiting (DMI) fungicides Triadimefon, myclobutanil, and fenarimol was assessed in 1993, 1994, and 1995 with leaf disk bioassays. In 1993, 1994, and 1995, 81.8, 96, and 96.7% of the subcultures, respectively, did not grow on leaf disks treated with 30 mg of benomyl per liter, whereas growth of the remaining subcultures was inhibited by more than 90%. Median EC50 values of Triadimefon, myclobutanil, and fenarimol decreased from 1993 to 1994, and those of Triadimefon decreased again from 1994 to 1995. In the same period, median EC50 values of all three DMI fungicides increased in a vineyard never exposed to DMI fungicides. The highest means and ranges of EC50 values found were those of Triadimefon. Means and ranges were lower for myclobutanil and lowest for fenarimol, reflecting differences in inherent activities of the fungicides and po-tential for development of resistance. Pairwise correlations between EC50 values of each DMI fungicide were positive and confirmed earlier indications of cross resistance.
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occurrence of resistance in uncinula necator to Triadimefon myclobutanil and fenarimol in california grapevines
Plant Disease, 1996Co-Authors: W D Gubler, H L Ypema, D G Ouimette, Larry J BettigaAbstract:Uncinula necator subcultures from 19 vineyards in four regions in California were analyzed for sensitivity to Triadimefon, myclobutanil, and fenarimol. The means of EC 50 values to Triadimefon, myclobutanil, and fenarimol of U. necator subcultures from a vineyard without previous exposure to demethylation inhibition (DMI) fungicides were 1.40, 0.15, and 0.13 mg/liter, respectively. The highest means of EC 50 values were found in the Central Coast region, and frequency distributions were skewed most toward higher resistance to all three fungicides. Subcultures with high resistance levels also were present in the other regions examined. A time course study performed in one vineyard, where resistant strains were reported, demonstrated a steady and significant increase in EC 50 values for all three fungicides during the growing season after multiple applications of Triadimefon. Increased resistance to Triadimefon, but not to myclobutanil and fenarimol, was maintained in early-formed ascospores released after the growing season.
Sheaufung Thai - One of the best experts on this subject based on the ideXlab platform.
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toxicity profiles in mice treated with hepatotumorigenic and non hepatotumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: James W Allen, Tanya Moore, Guobin Sun, Sheaufung Thai, Douglas C Wolf, Michael H George, Susan D Hester, Don A Delker, Carlton P Jones, Gail M NelsonAbstract:Conazoles comprise a class of fungicides used in agriculture and as pharmaceutical products. The fungicidal properties of conazoles are due to their inhibition of ergosterol biosynthesis. Certain conazoles are tumorigenic in rodents; both propiconazole and Triadimefon are hepatotoxic and hepatotumorigenic in mice, while myclobutanil is not a mouse liver tumorigen. As a component of a large-scale study aimed at determining the mode(s) of action for tumorigenic conazoles, we report the results from comparative evaluations of liver and body weights, liver histopathology, cell proliferation, cytochrome P450 (CYP) activity, and serum cholesterol, high-density lipoprotein and triglyceride levels after exposure to propiconazole, Triadimefon, and myclobutanil. Male CD-1 mice were treated in the feed for 4, 30, or 90 days with Triadimefon (0, 100, 500, or 1800 ppm), propiconazole (0, 100, 500, or 2500 ppm) or myclobutanil (0, 100, 500, or 2000 ppm). Alkoxyresorufin O-dealkylation (AROD) assays indicated that all 3 chemicals induced similar patterns of dose-related increases in metabolizing enzyme activity. PROD activities exceeded those of MROD, and EROD with propiconazole inducing the highest activities of PROD. Mice had similar patterns of dose-dependent increases in hepatocyte hypertrophy after exposure to the 3 conazoles. High-dose exposures to propiconazole and myclobutanil, but not Triadimefon, were associated with early (4 days) increases in cell proliferation. All the chemicals at high doses reduced serum cholesterol and high-density lipoprotein (HDL) levels at 30 days of treatment, while only Triadimefon had this effect at 4 days of treatment and only myclobutanil and propiconazole at 90 days of treatment. Overall, the tumorigenic and nontumorigenic conazoles induced similar effects on mouse liver CYP enzyme activities and pathology. There was no specific pattern of tissue responses that could consistently be used to differentiate the tumorigenic conazoles, propiconazole, and Triadimefon, from the nontumorigenic myclobutanil. These findings serve to anchor other transcriptional profiling studies aimed at probing differences in key events and modes of action for tumorigenic and nontumorigenic conazoles.
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transcriptional profiles in liver from rats treated with tumorigenic and non tumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: Susan D Hester, Stephen Nesnow, Douglas C Wolf, Sheaufung ThaiAbstract:Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, Triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230_2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by Triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for Triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and Triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish Triadimefon from propiconazole and myclobutanil.
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toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides propiconazole Triadimefon and myclobutanil
Toxicologic Pathology, 2006Co-Authors: Douglas C Wolf, Tanya Moore, Guobin Sun, Sheaufung Thai, James W Allen, Michael H George, Susan D Hester, Don A Delker, Ernest Winkfield, Sharon LeavittAbstract:Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that Triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for Triadimefon. Male Wistar/Han rats were treated with Triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only Triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only Triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of Triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and Triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose Triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for Triadimefon-induced thyroid gland tumors was not supported by the data.
