In vitro genotoxic assessment of xenobiotic diacylglycerols in an in vitro micronucleus assay

Abstract

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.

Chromosome Missegregation and Aneuploidy Induction in Human Peripheral Blood Lymphocytes In vitro by Low Concentrations of Chlorpyrifos, Imidacloprid and α‐Cypermethrin

“…As it was detected in the present study, pesticide treatment may lead to significant increase in loss of heterozigosity. The effects of pesticide treatment on ploidy (threefold to 10‐fold increase in chromosome losses) have been reported by other authors (; Raimondi et al, ; Kayani et al, ). Study of Raimondi et al () reports 10‐fold increase in the loss of the chromosome 9 after exposure of human peripheral blood lymphocytes to benomyl, a benzimidazole derivative.…”

Organic micropollutants paracetamol and ibuprofen—toxicity, biodegradation, and genetic background of their utilization by bacteria

“…As Parolini et al ( 2011 ) suggested, living organisms are able to transform parent compound into more toxic intermediates. Such situation was observed by Kayani et al ( 2009 ) for ibuprofen conjugated with diacylglycerol (ibuprofen-DG), where conjugate was responsible for inhibition of cell division and nondisjunction in several pairs of chromosomes. Parolini et al ( 2011 ) demonstrated that chronic exposure to the environmentally relevant concentrations of ibuprofen (0.2, 2.0, and 8.0 μg/L) induced moderate genetic and cellular damage in zebra mussel, Dreissena polymorpha , a reference biological model sensitive to various pharmaceuticals, including antibiotics.…”

Ibuprofen as an emerging organic contaminant in environment, distribution and remediation

“…Furthermore, all additional consequences like changes in growth rate, behavior, reproduction and alterations at biochemical level are observed. Kayani et al (2009) observed that conjugation of Ibuprofen and diacylglycerol (ibuprofen-DG) was accountable for the inhibition of cell division and non-disjunction of chromosomes to several pairs. Han et al ( 2010) investigated the chronic toxicity of ibuprofen by hormonal balance under in vitro condition using the H295R cell line on Oryzias latips, Moina macrocopa and Daphenia magna.…”