Abstract
A concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Önfelt (Chem Biol Interact 126:97–123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof. Molecular structures of 26 chemicals, including steroids, were converted into single 3D models using Corina (version 3.20), and 11 descriptors of molecular properties were calculated. The data of 16 compounds assigned to a non-specific mode of action were imported into the QSAR module of the software package Cerius2 (version 4.10). Applying genetic function approximation (GFA), linear equations were set up relating molecular descriptors with experimental concentrations at which doubling of micronuclei occurred in V79 cells (exp −log C). The number of variables (molecular descriptors) was limited to a maximum of three, and linear and quadratic terms were allowed. Based on the descriptions provided by the GFA procedure, log P was the most suitable single property to describe non-specific genotoxicity [r 2 = 0.88], confirming the original concept of Schultz and Önfelt. Using more descriptors (up to three in combination) resulted in an optimization of correlations up to r 2 = 0.97. Such optimal correlation coefficients were obtained by combinations (a) of the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules on one hand, and by (b) the dipole moment, polar surface and total surface descriptors on the other hand. In essence, the relation of polar surface to the total molecular surface appears pivotal to determine the non-specific chromosomal genotoxicity of lipophilic compounds.
Similar content being viewed by others
References
Bolt HM, Degen GH (2004) Human carcinogenic risk evaluation, part II: contributions of the EUROTOX specialty section for carcinogenesis. Toxicol Sci 81:3–6
Bonacker D, Stoiber T, Böhm KJ, Unger E, Degen G, Thier R, Bolt HM (2004) Chromosomal genotoxicity of nitrobenzene and benzonitrile. Arch Toxicol 78:49–57
Bradley MO, Taylor VI, Armstrong MJ, Galloway SM (1987) Relationships among cytotoxicity, lysosomal breakdown, chromosome aberrations, and DNA double-strand breaks. Mutat Res 189:69–79
Cao LG, Wang YL (1996) Signals from the spindle midzone are required for the stimulation of cytokinesis in cultured epithelial cells. Mol Biol Cell 7:225–232
Di Virgilio AL, Iwami K, Wätjen W, Kahl R, Degen GH (2004) Genotoxicity of the isoflavones genistein, daidzein and equol in V79 cells. Toxicol Lett 151/152:151–162
Doncic A, Ben-Jacob E, Barkai N (2005) Evaluating putative mechanisms of the mitotic spindle checkpoint. Proc Natl Acad Sci USA 102:6332–6337
Dorn SB, Degen GH, Müller T, Bonacker D, Joosten HFP, van der Louw J, van Acker FAA, Bolt HM (2007a) Development of criteria for specific and non-specific chromosomal genotoxicity based on hydrophobic interactions. Mutat Res 628:67–75
Dorn SB, Bolt HM, Thevis M, Diel P, Degen GH (2007b) Induction of micronuclei in V79 cells by the anabolic doping steroids tetrahydrogestrinone and trenbolone. Arch Toxicol (published online Sep 1 2007), doi:10.1007/s00204-007-0241-2
European Agency for the Evaluation of Medicinal Products (1995) ICH topic S 2 A. Genotoxicity: Guidance on Specific Tests for Pharmaceuticals. ICH Harmonised Tripartite Guideline
Fishkind DJ, Wang YL (1993) Orientation and three-dimensional organization of actin filaments in dividing cultured cells. J Cell Biol 123:837–848
Galloway SM, Miller JE, Armstrong MJ, Bean CL, Skopek TR, Nichols WW (1998) DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. Mutat Res 400:169–186
Gardner MK, Odde DJ (2006) Modeling of chromosome motility during mitosis. Curr Opin Cell Biol 18:639–647
Joosten HFP, van Acker FAA, van den Dobbelsteen DJ, Horbach GJ, Krajnc EI (2004) Genotoxicity of hormonal steroids. Toxicol Lett 151:113–134
Önfelt A (1983) Spindle disturbances in mammalian cells. I. Changes on the quantity of free sulfhydryl groups in relation to survival and c-mitosis in V79 Chinese hamster cells after treatment with colcemid, diamide, carbaryl and methyl mercury. Chem Biol Interact 46:201–217
Önfelt A (1986) Mechanistic aspects on chemical induction of spindle disturbances and abnormal chromosome numbers. Mutat Res 168:249–300
Önfelt A (1987a) Spindle disturbances in mammalian cells. III. Toxicity, c-mitosis and aneuploidy with 22 different compounds. Specific and unspecific mechanisms. Mutat Res 182:135–154
Önfelt A (1987b) Spindle disturbances in mammalian cells. IV. The action of some glutathione-specific agents in V79 Chinese hamster cells, changes in levels of free sulfhydryls and ATP, c.mitosis and effects on DNA metabolism. Mutat Res 182:155–172
Önfelt A, Klasterska I (1983) Spindle disturbances in mammalian cells. II. Induction of viable aneuploid/polyploidy cells and multiple chromatid exchanges after treatment of V79 Chinese hamster cells with carbaryl. Modifying effects of glutathione and S9. Mutat Res 119:319–330
Önfelt A, Hellberg S, World S (1986) Relationships between induction of anaesthesia and mitotic spindle disturbances studied by means of principal component analysis. Mutat Res 174:109–113
Rappaport R (1986) Establishment of the mechanism of cytokinesis in animal cells. Int Rev Cytol 105:245–281
Rogers D, Hopfinger AJ (1994) Applications of genetic function approximation to quantitative structure-activity relationships and quantitative structure-property-relationships. J Chem Inf Comput Sci 34:854–862
Schultz N, Önfelt A (2000) Sensitivity of cytokinesis to hydrophobic interactions. Chemical induction of bi- and multinucleated cells. Chem Biol Interact 126:97–123
Scott D, Galloway SM, Marshall RR, Ishidate M, Brusick D, Ashby J, Myhr BC (1991) Genotoxicity under extreme culture conditions. A report from ICPEMC Task Group 9. Mutation Res. 257:147–204
VanBuren V, Odde DJ, Cassimeris L (2002) Estimates of lateral and longitudinal bond energies within the microtubule lattice. Proc Natl Acad Sci USA 99:6035–6040
Acknowledgments
The research work presented here has been financially supported by NV Organon, Oss, The Netherlands. The critical scientific input and valuable discussion of the results by Harrie F. P. Joosten (NV Organon) are highly appreciated. The data presented form part of the doctoral thesis of Susanne B. Dorn, which will be submitted to the Heinrich-Heine University of Düsseldorf, Germany.
Author information
Authors and Affiliations
Corresponding author
Additional information
An erratum to this article can be found at http://dx.doi.org/10.1007/s00204-008-0291-0
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Dorn, S.B., Degen, G.H., Bolt, H.M. et al. Some molecular descriptors for non-specific chromosomal genotoxicity based on hydrophobic interactions. Arch Toxicol 82, 333–338 (2008). https://doi.org/10.1007/s00204-007-0256-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-007-0256-8