Mechanisms of acrylamide induced rodent carcinogenesis.
Acrylamide is a monomer of polyacrylamide, used in biochemistry, in paper manufacture, in water treatment, and as a soil stabilizer. The monomer can cause several toxic effects and has the potential for human exposure either through the environment or from occupational exposure. Recently, additional concern for the potential toxicity of acrylamide in humans has arisen with the finding of acrylamide formation in some processed foods. It has been established that following chronic exposure, rats exhibited an increase in the incidence of adrenal pheochromocytomas, testicular mesotheliomas, thyroid adenomas and mammary neoplasms in F344 rats. This has raised increased concerns regarding the carcinogenic risk to humans from acrylamide exposure. Studies examining the DNA reactivity of acrylamide have been performed and have had differing results. The tissue and organ pattern of neoplastic development seen in the rat following acrylamide exposure is not consistent with that seen with other strictly DNA reactive carcinogens. Based on the pattern of neoplastic development, it appears that acrylamide is targeting endocrine sensitive tissues. In the current monograph, studies on the effect of acrylamide on DNA reactivity and on altered cell growth in the target tissues in the rat are reported. DNA synthesis was examined in F344 rats treated with acrylamide (0, 2, or 15 mg/kg/day) for 7, 14, or 28 days. Acrylamide increased DNA synthesis in the target tissues (thyroid, testicular mesothelium, adrenal medulla) at all doses and time points examined. In contrast, in a non-target tissue (liver), no increase in DNA synthesis was seen. Examination of DNA damage using single cell gel electrophoresis (the Comet assay) showed an increase in DNA damage in the target tissues, but not in non-target tissue (liver). In addition, a cellular transformation model, (the Syrian Hamster Embryo (SHE) cell morphological transformation model), was used to examine potential mechanisms for the observed carcinogenicity of acrylamide. SHE cell studies showed that glutathione (GSH) modulation by acrylamide was important in the cell transformation process. Treatment with a sulfhydryl donor compound (NAC) reduced acrylamide transformation while depletion of GSH (BSO) resulted in an enhancement of transformation. In summary, acrylamide caused both an increase in DNA synthesis and DNA damage in mammalian tissues and cells suggesting that DNA reactivity and cell proliferation, in concert, may contribute to the observed acrylamide-induced carcinogenicity in the rat and has implication on the possible risk for human neoplasm development.
Klaunig
James E
JE
Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., MS 551, Indianapolis, Indiana 46202, USA. jklauni@iupui.edu
Kamendulis
Lisa M
LM
D020106:Acrylamide / Q000633:toxicity*; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D020552:Comet Assay; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes / Q000494:pharmacology; D005511:Food Handling; D005978:Glutathione / Q000378:metabolism; D008647:Mesocricetus; D009369:Neoplasms / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D002273:Carcinogens; D018736:DNA Adducts; D005456:Fluorescent Dyes; D020106:Acrylamide; D004247:DNA; D001973:Bromodeoxyuridine; D005978:Glutathione