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Comparison of Germ Cell Mutagenicity in Male CYP2E1-Null and Wild-Type Mice Treated with Acrylamide: Evidence Supporting a Glycidamide-Mediated Effect

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Biology of Reproduction (Impact Factor: 3.45). 02/2005; 72(1):157-63. DOI: 10.1095/biolreprod.104.033308
Source: PubMed

ABSTRACT Acrylamide is an animal carcinogen and probable human carcinogen present in appreciable amounts in heated carbohydrate-rich foodstuffs. It is also a germ cell mutagen, inducing dominant lethal mutations and heritable chromosomal translocations in postmeiotic sperm of treated mice. Acrylamide's affinity for male germ cells has sometimes been overlooked in assessing its toxicity and defining human health risks. Previous investigations of acrylamide's germ cell activity in mice showed stronger effects after repeated administration of low doses compared with a single high dose, suggesting the possible involvement of a stable metabolite. A key oxidative metabolite of acrylamide is the epoxide glycidamide, generated by cytochrome P4502E1 (CYP2E1). To explore the role of CYP2E1 metabolism in the germ cell mutagenicity of acrylamide, CYP2E1-null and wild-type male mice were treated by intraperitoneal injection with 0, 12.5, 25, or 50 mg acrylamide (5 ml saline)(-1) kg(-1) day(-1) for 5 consecutive days. At defined times after exposure, males were mated to untreated B6C3F1 females. Females were killed in late gestation and uterine contents were examined. Dose-related increases in resorption moles (chromosomally aberrant embryos) and decreases in the numbers of pregnant females and the proportion of living fetuses were seen in females mated to acrylamide-treated wild-type mice. No changes in any fertility parameters were seen in females mated to acrylamide-treated CYP2E1-null mice. Our results constitute the first unequivocal demonstration that acrylamide-induced germ cell mutations in male mice require CYP2E1-mediated epoxidation of acrylamide. Thus, CYP2E1 polymorphisms in human populations, resulting in variable enzyme metabolic activities, may produce differential susceptibilities to acrylamide toxicities.

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    • "Ghanayem et al., (2005b) have investigated the role of cytochrome P450 in the metabolism of AA using mice differing in CYP2EI expression (wild type CYP2EI +/-and CYP2EI-/-m knockout mice). Additionally Ghanayem et al. (2005a) also confirmed that the AA to GA transformation leads to the formation of GA-DNA adducts in liver, lung and testes. In a recent in vivo study, pre-treatment with 1-aminobenzotriazole, a non specific P450 inhibitor abrogated or reduced the dominant lethal effect of AA in mice suggesting that GA is the cause of germ cell mutation in mouse spermatids (Alder et al., 2000; Sumner et al., 1999). "
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    • "Ghanayem et al., (2005b) have investigated the role of cytochrome P450 in the metabolism of AA using mice differing in CYP2EI expression (wild type CYP2EI +/-and CYP2EI-/-m knockout mice). Additionally Ghanayem et al. (2005a) also confirmed that the AA to GA transformation leads to the formation of GA-DNA adducts in liver, lung and testes. In a recent in vivo study, pre-treatment with 1-aminobenzotriazole, a non specific P450 inhibitor abrogated or reduced the dominant lethal effect of AA in mice suggesting that GA is the cause of germ cell mutation in mouse spermatids (Alder et al., 2000; Sumner et al., 1999). "
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    ABSTRACT: ABSTRACT The micronucleus test is an effective method for determination of the evolution of genotoxic or clastogenic agents of physical and chemical functions. The micronuclei are formed due to the condensation lagging off of acentric chromosomes, chromatid fragments or entire chromosomes and also due to non introduction of them in main daughter nuclei during metaphase or anaphase of cell division. Formation of micronuclei reflects chromosome damage and thus provide a marker for carcinogenesis analysis. Acrylamide is an important industrial chemical used in waste water treatment, adhesives and grout, cosmetics and also in laboratories. It is genotoxic, in in vitro and in vivo, in both somatic and germ cells. Acrylamide induces chromosomal aberrations, micronuclei formation, sister chromatid exchanges, SS-DNA breaks, polyploidy, aneuploidy and other mitotic disturbances, dominant lethal and specific locus mutations. Therefore a study was made on micronuclei assay to evaluate the degree of genotoxicity of acrylamide and its toxicologic effects on rat’s reproductive system after intraperitoneal injection of different doses of acrylamide. The Acrylamide treatment to rats caused damage not only to peripheral blood cells and reticulocytes but also to spermatids. The formation of micronuclei was evidence in our present study though acrylamide may not be used directly. The indirect consumption of acrylamide definitely causes damage to almost all type of cells in the rats.
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    • "Ghanayem et al., (2005b) have investigated the role of cytochrome P450 in the metabolism of AA using mice differing in CYP2EI expression (wild type CYP2EI +/-and CYP2EI-/-m knockout mice). Additionally Ghanayem et al. (2005a) also confirmed that the AA to GA transformation leads to the formation of GA-DNA adducts in liver, lung and testes. In a recent in vivo study, pre-treatment with 1-aminobenzotriazole, a non specific P450 inhibitor abrogated or reduced the dominant lethal effect of AA in mice suggesting that GA is the cause of germ cell mutation in mouse spermatids (Alder et al., 2000; Sumner et al., 1999). "
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