In vitro genotoxic assessment of xenobiotic diacylglycerols in an in vitro micronucleus assay.
Xenobiotic diacylglycerols (DG) may induce pathological disorders by causing abnormal chromosomal segregation, which could be aneuploid. In this study, seven xenobiotic-diacylglycerols (four of drug origin and three of pesticide origin) were evaluated for their ability to induce aneuploidy in mammalian cultures using in vitro cytokinesis blocked micronucleus (CBMN) assay coupled with kinetochore labeling and interphase fluorescent in situ hybridization. Out of seven xeno-DGs, two (ibuprofen-DG and fenbufen-DG) induced statistically significant (P < 0.001) and dose-dependent increase in micronucleus induction, but this apparent micronucleus induction was very weak in case of fenbufen-DG. These MN were produced predominantly by aneugenic and clastogenic mechanisms, respectively, confirmed by immunofluorescent labeling of kinetochores. Fluorescent in situ hybridization analysis revealed that ibuprofen-DG induced significantly higher nondisjunction for chromosomes 10, 17, and 18. Other xenobiotic diacylglycerols (indomethacin-DG, salicylic acid-DG, 4-(2-methyl-4-chlorophenoxy) butanoic acid-DG (MCPB-DG), 2-(2-methyl-4-chlorophenoxy) propanoic acid-DG (MCPP-DG) and 2-(4-dichlorophenoxy)-butanoic acid-DG (2,4 DB-DG) did not induce micronuclei, but the concentrations tested did not reach levels that caused the marked growth suppression typically required for testing for regulatory testing purposes. However, the levels of growth suppression achieved were similar to that seen with ibuprofen-DG, which was positive. This study shows that xeno-DGs, which have been neglected in the past for their possible link to any pathological disorders, need serious assessment of their mutagenic potential.
Kayani
Mahmood A
MA
Centre of Molecular Genetics and Toxicology, School of Biological Sciences, University of Wales, Swansea, SA2 8PP, United Kingdom. mkayani@comsats.edu.pk
Parry
James M
JM
Vickery
Susan
S
Dodds
Peter F
PF
D000782:Aneuploidy; D045744:Cell Line, Tumor / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects*; D002995:Clofibric Acid / Q000737:chemistry / Q000633:toxicity; D004075:Diglycerides / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000633:toxicity; D015162:Micronucleus Tests / Q000379:methods*; D008958:Models, Molecular; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D010654:Phenylbutyrates / Q000737:chemistry / Q000633:toxicity; D020156:Salicylic Acid / Q000737:chemistry / Q000633:toxicity; D015262:Xenobiotics / Q000737:chemistry / Q000633:toxicity*
D004075:Diglycerides; D009153:Mutagens; D010654:Phenylbutyrates; D015262:Xenobiotics; D002995:Clofibric Acid; C010725:fenbufen; D020156:Salicylic Acid; D007052:Ibuprofen