Tissue-specific genotoxic effects of acrylamide and acrylonitrile.
Acrylamide (AA) has been reported to induce dominant lethal mutations in male rat germ cells and tumors in a variety of organs, including the scrotum, thyroid and mammary glands, but not the liver of rats. The structurally similar vinyl monomer acrylonitrile (ACN) does not induce dominant lethal mutations but does induce tumors of the brain, Zymbal gland, forestomach and mammary gland, but not the liver of rats. Several in vitro and/or in vivo unscheduled DNA synthesis (UDS) assays were employed to examine the potential tissue-specific genotoxic activity of these compounds. Neither AA nor ACN induced DNA repair in either the in vitro or in vivo hepatocyte DNA repair assays. Glycidamide (GA), a mutagenic metabolite of AA, induced DNA repair in the in vitro hepatocyte DNA repair assay. Cyanoethylene oxide (CEO), a mutagenic metabolite of ACN, did not yield a DNA repair response in the in vitro hepatocyte DNA repair assay, but was highly toxic and could not be tested at doses equivalent to GA. AA, but not ACN, produced a DNA repair response in the in vivo spermatocyte DNA repair assay. AA produced a slight response in the in vitro human mammary epithelial cell (HMEC) DNA repair assay in normal cells derived from discarded surgical samples from five different women. GA produced a strong UDS response in all cases in the same assay. CEO, but not its parent compound ACN, produced a response in the HMEC DNA repair assay. These results show a highly tissue-specific pattern of genotoxic activity for AA and ACN that correlates, to the extent that it has been examined, with the tissue-specific pattern of carcinogenic and dominant lethal activity. The induction of DNA repair by GA and CEO confirms the genotoxic potential of these metabolites. While the observation of genotoxic activity of AA in the HMEC DNA repair assay suggests that mammary cells might be a target for carcinogenic activity of this compound in humans, other factors such as pharmacokinetics and epidemiology must be evaluated to establish that effect.
Butterworth
B E
BE
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina.
Eldridge
S R
SR
Sprankle
C S
CS
Working
P K
PK
Bentley
K S
KS
Hurtt
M E
ME
D020106:Acrylamide; D000178:Acrylamides / Q000494:pharmacology / Q000633:toxicity*; D000181:Acrylonitrile / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001940:Breast; D002478:Cells, Cultured; D004260:DNA Repair; D004848:Epithelium / Q000187:drug effects; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity*; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D013090:Spermatocytes / Q000187:drug effects* / Q000502:physiology
D000178:Acrylamides; D009153:Mutagens; D020106:Acrylamide; D000181:Acrylonitrile