Acrylonitrile (AN) is used extensively in industry with potential exposure to hundreds of thousands of workers. Its potential danger to man has been recognized by OSHA. AN is a carcinogen in the rat and is unique in its ability to produce brain tumors in the adult rat. On the basis of metabolism studies, by others, and the structural similarity of AN to vinyl chloride it has been postulated that a metabolically activated form of AN, acrylonitrile epoxide (ANE) may be the ultimate carcinogenic form of AN. During the past grant period we have demonstrated that AN directly alkylates all bases in calf thymus DNA (in vitro) by Michael addition at physiological pH and temperature. Cyanoethyl-adducts were isolated with guanine and thymine and carboxyethyl-adducts resulted with adenine and cytosine. The carboxyethyl-adducts were identical to adducts resulting from the in vitro reaction of another rodent carcinogen, beta-propiolactone, with calf thymus DNA. Similar findings were observed when the industrially important and structurally related compounds acrylamide (AM) and acrylic acid (AA) were reacted with 2'-deoxy-nucleosides. The major objective of the proposed work is to determine the nature of the adducts formed with DNA in vivo, i.e., AN and/or ANE adducts. Thus, the structures of the adducts will be determined in female Sprague Dawley rat brain DNA (target tissue DNA), astrocyte cell DNA (target cell DNA) in tissue culture and mouse fibroblast C3H/10T1/2 clone 8 cell DNA in tissue culture following exposure to [2,3-C14]AN. In the case of the rats, exposure will be by water ingestion. Other objectives are the determination of the structure of adducts formed following in vitro reaction of AM, AA and acrylamide epoxide (AME) with calf thymus DNA for possible future studies on their in vivo reactions with DNA. ANE and AME will be used in complete carcinogenicity studies on the dorsal skins of female ICR/Ha mice. In addition, neoplastic transformation studies using AN, ANE, AM and AME will be conducted using astrocytes (from neonatal Sprague Dawley rat brains) and C3H/10T1/2 cells in tissue culture.
| Solomon, J J; Singh, U S; Segal, A (1993) In vitro reactions of 2-cyanoethylene oxide with calf thymus DNA. Chem Biol Interact 88:115-35 |
| Solomon, J J; Segal, A (1989) DNA adducts of propylene oxide and acrylonitrile epoxide: hydrolytic deamination of 3-alkyl-dCyd to 3-alkyl-dUrd. Environ Health Perspect 81:19-22 |
| Segal, A; Fedyk, J; Melchionne, S et al. (1987) The isolation and characterization of 2-carboxyethyl adducts following in vitro reaction of acrylic acid with calf thymus DNA and bioassay of acrylic acid in female Hsd:(ICR)Br mice. Chem Biol Interact 61:189-97 |
| Banerjee, S; Segal, A (1986) In vitro transformation of C3H/10T1/2 and NIH/3T3 cells by acrylonitrile and acrylamide. Cancer Lett 32:293-304 |
| Solomon, J J; Fedyk, J; Mukai, F et al. (1985) Direct alkylation of 2'-deoxynucleosides and DNA following in vitro reaction with acrylamide. Cancer Res 45:3465-70 |
