The Experts below are selected from a list of 489 Experts worldwide ranked by ideXlab platform
Frederick A Beland - One of the best experts on this subject based on the ideXlab platform.
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carcinogenicity of Glycidamide in b6c3f1 mice and f344 n rats from a two year drinking water exposure
Food and Chemical Toxicology, 2013Co-Authors: Frederick A Beland, Matilde M Marques, Greg R Olson, Maria C B Mendoza, Daniel R DoergeAbstract:Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide Glycidamide. We have now examined the carcinogenic effects of Glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to Glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into Glycidamide.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
International Journal of Cancer, 2009Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Joseph G Shaddock, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Frederick A BelandAbstract:Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1-8 with 0.14 or 0.70 mmol acrylamide or Glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk(+/+) mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk(+/-) mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major Glycidamide-DNA adduct, decreased in the order 0.70 mmol Glycidamide > 0.70 mmol acrylamide > 0.14 mmol Glycidamide approximately 0.14 mmol acrylamide. Only Glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol Glycidamide. In mice dosed on PNDs 1-8, 0.70 mmol Glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to Glycidamide, whereas mutations resulting from dosing on PNDs 1-8 are due to another mechanism.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
Cancer Research, 2005Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Suzanne M Morris, Frederick A BelandAbstract:2110 Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or Glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from Glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg Glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg Glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg Glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg Glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg Glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon Glycidamide treatment, and the observations of micronuclei and mutant induction by Glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to Glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)
Daniel R Doerge - One of the best experts on this subject based on the ideXlab platform.
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carcinogenicity of Glycidamide in b6c3f1 mice and f344 n rats from a two year drinking water exposure
Food and Chemical Toxicology, 2013Co-Authors: Frederick A Beland, Matilde M Marques, Greg R Olson, Maria C B Mendoza, Daniel R DoergeAbstract:Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide Glycidamide. We have now examined the carcinogenic effects of Glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to Glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into Glycidamide.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
International Journal of Cancer, 2009Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Joseph G Shaddock, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Frederick A BelandAbstract:Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1-8 with 0.14 or 0.70 mmol acrylamide or Glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk(+/+) mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk(+/-) mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major Glycidamide-DNA adduct, decreased in the order 0.70 mmol Glycidamide > 0.70 mmol acrylamide > 0.14 mmol Glycidamide approximately 0.14 mmol acrylamide. Only Glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol Glycidamide. In mice dosed on PNDs 1-8, 0.70 mmol Glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to Glycidamide, whereas mutations resulting from dosing on PNDs 1-8 are due to another mechanism.
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niversity on Septem
2006Co-Authors: Célia Martins, Daniel R Doerge, Matilde M Marques, Nuno G. Oliveira, Marta Pingarilho, A Martins, Frederick A. Bel, José RueffAbstract:Cytogenetic damage induced by acrylamide and Glycidamide in mammalian cells: correlation with specific Glycidamide-DNA adducts
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
Cancer Research, 2005Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Suzanne M Morris, Frederick A BelandAbstract:2110 Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or Glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from Glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg Glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg Glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg Glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg Glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg Glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon Glycidamide treatment, and the observations of micronuclei and mutant induction by Glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to Glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)
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toxicokinetics of acrylamide and Glycidamide in b6c3f1 mice
Toxicology and Applied Pharmacology, 2005Co-Authors: Daniel R Doerge, John F Young, Patrice L Mcdaniel, Nathan C Twaddle, Mona I ChurchwellAbstract:Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite Glycidamide (GA) in serum and tissues of male and female B6C3F1 mice following acute dosing by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage dosing with an equimolar amount of GA. AA was rapidly absorbed from oral dosing, was widely distributed to tissues, was efficiently converted to GA, and increased levels of GA-DNA adducts were observed in liver after complete elimination from serum. GA dosing also resulted in rapid absorption, wide distribution to tissues, and produced liver DNA adduct levels that were approximately 40% higher than those from an equimolar dose of AA. While oral administration was found to attenuate AA bioavailability to 23% from the diet and to 32-52% from aqueous gavage, a first-pass effect or other kinetic change resulted in higher relative internal exposure to GA when compared to the intravenous route. A similar effect on relative GA exposure was also evident as the administered dose was reduced, which suggests that as dosing rate decreases, the conversion of AA to GA is more efficient. These findings are critical to the assessment of genotoxicity of AA at low doses in the food supply, which appears to depend on total exposure to GA.
Mona I Churchwell - One of the best experts on this subject based on the ideXlab platform.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
International Journal of Cancer, 2009Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Joseph G Shaddock, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Frederick A BelandAbstract:Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1-8 with 0.14 or 0.70 mmol acrylamide or Glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk(+/+) mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk(+/-) mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major Glycidamide-DNA adduct, decreased in the order 0.70 mmol Glycidamide > 0.70 mmol acrylamide > 0.14 mmol Glycidamide approximately 0.14 mmol acrylamide. Only Glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol Glycidamide. In mice dosed on PNDs 1-8, 0.70 mmol Glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to Glycidamide, whereas mutations resulting from dosing on PNDs 1-8 are due to another mechanism.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
Cancer Research, 2005Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Suzanne M Morris, Frederick A BelandAbstract:2110 Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or Glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from Glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg Glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg Glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg Glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg Glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg Glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon Glycidamide treatment, and the observations of micronuclei and mutant induction by Glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to Glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)
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toxicokinetics of acrylamide and Glycidamide in b6c3f1 mice
Toxicology and Applied Pharmacology, 2005Co-Authors: Daniel R Doerge, John F Young, Patrice L Mcdaniel, Nathan C Twaddle, Mona I ChurchwellAbstract:Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite Glycidamide (GA) in serum and tissues of male and female B6C3F1 mice following acute dosing by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage dosing with an equimolar amount of GA. AA was rapidly absorbed from oral dosing, was widely distributed to tissues, was efficiently converted to GA, and increased levels of GA-DNA adducts were observed in liver after complete elimination from serum. GA dosing also resulted in rapid absorption, wide distribution to tissues, and produced liver DNA adduct levels that were approximately 40% higher than those from an equimolar dose of AA. While oral administration was found to attenuate AA bioavailability to 23% from the diet and to 32-52% from aqueous gavage, a first-pass effect or other kinetic change resulted in higher relative internal exposure to GA when compared to the intravenous route. A similar effect on relative GA exposure was also evident as the administered dose was reduced, which suggests that as dosing rate decreases, the conversion of AA to GA is more efficient. These findings are critical to the assessment of genotoxicity of AA at low doses in the food supply, which appears to depend on total exposure to GA.
Matilde M Marques - One of the best experts on this subject based on the ideXlab platform.
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carcinogenicity of Glycidamide in b6c3f1 mice and f344 n rats from a two year drinking water exposure
Food and Chemical Toxicology, 2013Co-Authors: Frederick A Beland, Matilde M Marques, Greg R Olson, Maria C B Mendoza, Daniel R DoergeAbstract:Acrylamide is a contaminant in baked and fried starchy foods, roasted coffee, and cigarette smoke. Previously we reported that acrylamide is a multi-organ carcinogen in B6C3F1 mice and F344/N rats, and hypothesized that acrylamide is activated to an ultimate carcinogen through metabolism to the epoxide Glycidamide. We have now examined the carcinogenic effects of Glycidamide administered at 0, 0.0875, 0.175, 0.35 and 0.70 mM in drinking water to the same strains of rodents for two years. In male and female mice, there were significant increases in tumors of the Harderian gland, lung, forestomach, and skin. Female mice also had an increased incidence of tumors of the mammary gland and ovary. In male and female rats, there were significant increases in thyroid gland and oral cavity neoplasms and mononuclear cell leukemia. Male rats also had increases in tumors of the epididymis/testes and heart, while female rats demonstrated increases in tumors of the mammary gland, clitoral gland, and forestomach. A similar spectrum of tumors was obtained in mice and rats administered acrylamide. These data indicate that, under the conditions of these bioassays, acrylamide is efficiently metabolized to Glycidamide and that the carcinogenic activity of acrylamide is due to its conversion into Glycidamide.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
International Journal of Cancer, 2009Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Joseph G Shaddock, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Frederick A BelandAbstract:Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1-8 with 0.14 or 0.70 mmol acrylamide or Glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk(+/+) mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk(+/-) mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major Glycidamide-DNA adduct, decreased in the order 0.70 mmol Glycidamide > 0.70 mmol acrylamide > 0.14 mmol Glycidamide approximately 0.14 mmol acrylamide. Only Glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol Glycidamide. In mice dosed on PNDs 1-8, 0.70 mmol Glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to Glycidamide, whereas mutations resulting from dosing on PNDs 1-8 are due to another mechanism.
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niversity on Septem
2006Co-Authors: Célia Martins, Daniel R Doerge, Matilde M Marques, Nuno G. Oliveira, Marta Pingarilho, A Martins, Frederick A. Bel, José RueffAbstract:Cytogenetic damage induced by acrylamide and Glycidamide in mammalian cells: correlation with specific Glycidamide-DNA adducts
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
Cancer Research, 2005Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Suzanne M Morris, Frederick A BelandAbstract:2110 Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or Glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from Glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg Glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg Glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg Glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg Glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg Glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon Glycidamide treatment, and the observations of micronuclei and mutant induction by Glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to Glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)
Goncalo Gamboa Da Costa - One of the best experts on this subject based on the ideXlab platform.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
International Journal of Cancer, 2009Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Joseph G Shaddock, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Frederick A BelandAbstract:Acrylamide, a food contaminant, is carcinogenic in experimental animals, with both genotoxic and nongenotoxic pathways being proposed. To obtain information regarding mechanisms of acrylamide tumorigenesis, we compared the extent of DNA adduct formation and induction of micronuclei and mutations in mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8 and 15 or PNDs 1-8 with 0.14 or 0.70 mmol acrylamide or Glycidamide per kg body weight per day. One day after the final dose, B6C3F1/Tk(+/+) mice were killed to measure DNA adduct levels and peripheral blood micronuclei. Three weeks after the last treatment, B6C3F1/Tk(+/-) mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. The levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine, the major Glycidamide-DNA adduct, decreased in the order 0.70 mmol Glycidamide > 0.70 mmol acrylamide > 0.14 mmol Glycidamide approximately 0.14 mmol acrylamide. Only Glycidamide increased the frequency of micronucleated reticulocytes and normochromatic erythrocytes. In mice treated on PNDs 1, 8 and 15, the Hprt mutant frequency was increased by 0.70 mmol Glycidamide. In mice dosed on PNDs 1-8, 0.70 mmol Glycidamide caused extensive mortality; each of the other treatments increased the Tk mutant frequency, whereas acrylamide increased the Hprt mutant frequency. These data suggest that the mutagenic response in neonatal mice treated on PNDs 1, 8 and 15 is due to Glycidamide, whereas mutations resulting from dosing on PNDs 1-8 are due to another mechanism.
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dna adduct formation and induction of micronuclei and mutations in b6c3f1 tk mice treated neonatally with acrylamide or Glycidamide
Cancer Research, 2005Co-Authors: Linda S Von Tungeln, Mona I Churchwell, Daniel R Doerge, Lynda J Mcgarrity, Robert H Heflich, Goncalo Gamboa Da Costa, Matilde M Marques, Suzanne M Morris, Frederick A BelandAbstract:2110 Acrylamide, a water-soluble α,β-unsaturated amide, is a high-volume industrial chemical, a component of cigarette smoke, and more recently, has been detected as a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread. Acrylamide is a carcinogen in experimental animals; however, the mechanism of tumor induction is controversial, with both genotoxic and nongenotoxic pathways being proposed. Since neonatal mice are very sensitive to the effects of genotoxic carcinogens, we have compared the extent of DNA adduct formation and the induction of micronuclei and mutations in B6C3F1/Tk mice treated neonatally with acrylamide and its electrophilic metabolite Glycidamide to obtain information concerning the mechanism of acrylamide carcinogenicity. Male and female B6C3F1/Tk mice were treated intraperitoneally on postnatal days (PNDs) 1, 8, and 15 with 0.14 and 0.70 mmol/kg acrylamide or Glycidamide. On PND 16, the B6C3F1/Tk+/+ mice were killed and hepatic DNA adduct levels and the extent of peripheral blood micronuclei were measured. Three weeks after the last treatment, the B6C3F1/Tk+/− mice were killed to assess the Hprt and Tk mutant frequencies in spleen lymphocytes. Hepatic levels of N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua), the major adduct formed from Glycidamide, were determined by HPLC coupled with electrospray ionization tandem mass spectrometry and found to be 3.5 ± 0.1 adducts/106 nucleotides for 0.14 mmol/kg acrylamide, 7.2 ± 0.5 adducts/106 nucleotides for 0.70 mmol/kg acrylamide, 4.5 ± 0.2 adducts/106 nucleotides for 0.14 mmol/kg Glycidamide, and 25.7 ± 1.0 adducts/106 nucleotides for 0.70 mmol/kg Glycidamide, as compared to 0.01 ± 0.01 adducts/106 nucleotides in control mice. N3-(2-Carbamoyl-2-hydroxyethyl)adenine was also detected, at approximately 1% of the level of N7-GA-Gua. The induction of micronuclei was assessed in reticulocytes and normochromatic erythrocytes; only 0.70 mmol/kg Glycidamide caused a significant induction (0.33 ± 0.02% and 0.27 ± 0.02%, respectively, versus 0.18 ± 0.01 and 0.16 ± 0.01% in the control mice). Both 0.14 and 0.70 mmol/kg Glycidamide induced a significant increase in the Tk mutant frequency (59 ± 5 and 51 ± 7 mutants/106 lymphocytes, respectively, versus 25 ± 5 mutants/106 lymphocytes in the control mice); only 0.70 mmol/kg Glycidamide caused a significant increase in the Hprt mutant frequency (6.8 ± 2.1 mutants/106 lymphocytes versus 0.8 ± 0.3 mutants/106 lymphocytes in the controls). The higher adduct levels obtained upon Glycidamide treatment, and the observations of micronuclei and mutant induction by Glycidamide only, suggest that the genotoxicity of acrylamide is mediated through its metabolism to Glycidamide. (Supported by an Interagency Agreement between the FDA/NCTR and NIEHS/NTP.)