Is polyploidy an important genotoxic lesion?
The importance of polyploidy as a genotoxic lesion is uncertain and there have been few publications and no reviews which have included data on spontaneous or induced polyploidy in routine genotoxicity screening. We have attempted to clarify some of the issues by reviewing the published literature and by reference to our historical data base for metaphase analysis of cultured human lymphocytes. In our studies on pharmaceutical compounds polyploidy was the lesion most often found, being induced by approximately 40% of the compounds tested. The mean spontaneous frequency was between 0.1 and 0.3%, and values for polyploidy induction were 5-fold to > 100-fold the spontaneous value. Spontaneous polyploids tended to be near-exact multiples of the haploid chromosome number whereas induced 'polyploids' were, in fact, very heteroploid with a wide range of chromosome numbers. Polyploidy induction often occurred at non-toxic concentrations, usually there were well defined no-effect (threshold) levels and it was unrelated to other genetic effects. Such observations would be expected for inducers of polyploidy because the target molecules are not DNA and for these non-DNA targets there is usually a degree of redundancy. Therefore, inducers of polyploidy are only likely to be a hazard for humans if they are positive at or below therapeutic concentrations. We conclude that polyploidy/near-polyploidy (shown as 'polyploidy' throughout) should be scored as accessory data which becomes important only when induction occurs at therapeutic levels.
Mitchell
I D
ID
Toxicology Department, SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
Lambert
T R
TR
Burden
M
M
Sunderland
J
J
Porter
R L
RL
Carlton
J B
JB
D002869:Chromosome Aberrations / Q000235:genetics; D005796:Genes / Q000187:drug effects*; D006801:Humans; D007621:Karyotyping; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D009152:Mutagenicity Tests; D011123:Polyploidy; D015995:Prevalence