Formation of N-7-(2-carbamoyl-2-hydroxyethy1)guanine in DNA of the mouse and the rat following intraperitoneal administration of [14C]acrylamide

University of Washington Seattle, Seattle, Washington, United States
Carcinogenesis (Impact Factor: 5.33). 06/1995; 16(5):1161-5. DOI: 10.1093/carcin/16.5.1161
Source: PubMed


Acrylamide is an alkylating agent which reacts very slowly in direct reactions with DNA and is negative in the Ames test, but is carcinogenic in mice and rats. In order to explain the cancer-initiating properties of acrylamide we have studied DNA adduct formation in vitro with a metabolizing system and in vivo in mice and rats following i.p. administration of 14C-labeled acrylamide. A major adduct found in both species was N-7-(2-carbamoyl-2-hydroxy-ethyl)guanine, formed by reaction of the DNA with the epoxide metabolite glycidamide. The levels of this adduct were similar in the different organs of the two rodent species, which supports the notion that glycidamide is relatively evenly distributed among tissues and that the organ-specificity in acrylamide carcinogenesis cannot be explained by a selective accumulation of the DNA-reactive metabolite in target organs.

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    • "Glycidamide, the reactive metabolite of acrylamide, forms adducts on reaction with DNA and is thought to be involved in the genotoxicity of acrylamide, and may lead to the carcinogenicity of acrylamide (Dearfield et al., 1988, 1995; Doerge et al., 2005; Ghanayem et al., 2005; Segerbä ck et al., 1995; Von Tungeln et al., 2012; Zeiger et al., 2009). The extent of AAVal adduct formation is associated with the area under the curve for acrylamide in blood, which is dependent on the dose administered, and the extent of metabolism (Calleman et al., 1993; Fennell et al., 2005). "
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    ABSTRACT: Acrylamide is an industrial chemical used to manufacture polymers, and is produced in foods during cooking at high heat. Hemoglobin adducts provide a long-lived dosimeter for acrylamide and glycidamide. This study determined acrylamide and glycidamide hemoglobin adducts (AAVal and GAVal) during a lifetime carcinogenesis bioassay. Exposure to acrylamide in drinking water began in utero in pregnant rats on gestation day (GD) 6. Dams were administered acrylamide until weaning, and male and female F1 rats were exposed for a further 104 weeks. Acrylamide concentration in drinking water was adjusted to provide a constant dose of 0.5, 1.5, and 3 mg/kg/day. Blood was collected from animals euthanized at 2, 60, 90 and 120 days and 53, 79, and 104 weeks after weaning. Low levels of AAVal and GAVal at postnatal day (PND) 24 suggested that little exposure to acrylamide occurred by placental or lactational transfer, and extensive metabolism to glycidamide occurred with a GAVal:AAVal ratio of 4. Adduct levels varied somewhat from 60 days - 2 years, with a GAVal:AAVal ratio of approximately 1. Adduct formation/day estimated at each timepoint at 3 mg/kg/day for AAVal was 1293 ± 220 and 1096 ± 338 fmol/mg/day for male and female rats, respectively. Adduct formation per day estimated at each timepoint at 3 mg/kg/day for GAVal was 827 ± 78 fmol/mg/day for male rats, and 982 ± 222 fmol/mg/day for female rats. The study has provided estimates of linearity for dose response, and variability in internal dose throughout an entire 2-year bioassay, including the early phases of pregnancy and lactation. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.
    Toxicological Sciences 07/2015; 146(2). DOI:10.1093/toxsci/kfv104 · 3.85 Impact Factor
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    • "Recently, it was suggested that these tumors might be caused, at least in part, by the effects of acrylamide on hormones (Dourson et al., 2008; Haber et al., 2009). Although acrylamide can cause genotoxic damage in vitro and in vivo (Besaratinia and Pfeifer 2007; Shipp et al., 2006), there are indications that genotoxicity alone cannot explain the specific tumor patterns seen in rats (Dourson et al., 2008; Haber et al., 2009; Segerback et al., 1995). "
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    ABSTRACT: Acrylamide is present in mainstream cigarette smoke and in some foods prepared at high temperatures. Animal studies have shown that acrylamide exposure alters thyroid function; however, it is not known if this also occurs in humans. The study examined the association between the urinary levels of the acrylamide metabolite and serum thyroid measures in adolescents and young adults. We recruited 793 subjects (mean age, 21.3 years; range, 12-30 years) from a population-based sample of Taiwanese adolescents and young adults to determine if the urinary levels of the acrylamide metabolite N-acetyl-S-(propionamide)-cysteine (AAMA) and the 6 serum thyroid measures are associated. The mean (SD) AAMA were 76.54 (76.42) µg/L. Linear regression analyzes showed a 1-unit increase in natural log AAMA was significantly associated with a decrease in serum free thyroxine (T4) (ng/dL) (β=−0.041, SE=0.013, p=0.001) after controlling for covariates. Subpopulation analyzes showed AAMA and free T4 were significantly associated with females, age 20-30 years, non-current smokers, and non-alcohol consumers. In conclusion, higher urinary AAMA concentrations were associated with decreased levels of free T4 in this cohort. Further studies are warranted to determine if there is a causal relationship between acrylamide exposure and thyroid function.
    Environmental Research 01/2015; 136. DOI:10.1016/j.envres.2014.08.043 · 4.37 Impact Factor
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    • "AA is a neurotoxic agent to humans (Hagmar et al., 2001), and is classified as a probable carcinogen to human (Group 2A) by the International Agency for Research on Cancer (IARC, 1994). Both AA and its epoxy-metabolite, glycidamide (GA) are reactive towards biomacromolecules and are suspected to cause genotoxicity (Paulsson et al., 2003; Segerbäck et al., 1995). Several epidemiological studies have suggested its associations with various cancer risks, e.g., breast cancer (Olesen et al., 2008), renal cancer (Hogervorst et al., 2008), and lung cancer (Hogervorst et al., 2009), while a number of studies have shown no significant association with cancers of bowel, kidney, bladder, oral, esophageal, laryngeal, breast, ovary, or prostate (Mucci et al., 2003; Pelucchi et al., 2006). "
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    ABSTRACT: Acrylamide (AA), a probable human carcinogen, is present in high-temperature-processed foods, and has frequently been detected in humans worldwide. In the present study, the levels of a major AA metabolite, N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) were measured in urine samples collected in two separate events with 3d interval from Korean children (n=31, 10-13years old), and their diets were surveyed for 4d period prior to the second urine sampling. Daily AA intake was estimated from AAMA urinary levels and the influence of food consumption on urinary AAMA levels was investigated. The concentrations of metabolite AAMA in urine ranged between 15.4 and 196.3ng/mL, with a median level of 68.1ng/mL, and the levels varied by day considerably even in a given child. Children who were exposed to environmental smoke at home exhibited significantly higher levels of AAMA in urine, suggesting the importance of passive smoking as a source of AA exposure among children. Median (95th percentile) values of daily AA intake in Korean children were 1.04 (2.47)μg/kgbodyweight/day, which is higher than those reported elsewhere. After adjustment for gender, body mass index, and smoking status of family members, the consumptions of cracker and chocolate were identified to be significantly associated with the concentrations of AAMA in urine. The result of this study will provide information useful for developing public health and safety management for AA.
    Science of The Total Environment 04/2013; 456-457C:17-23. DOI:10.1016/j.scitotenv.2013.03.057 · 4.10 Impact Factor
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