Effects of medicinal compounds on the differentiation of the eukaryotic microorganism dictyostelium discoideum: can this model be used as a screening test for reproductive toxicity in humans?
Dictyostelium discoideum is a single-cell, eukaryotic microorganism that can undergo multicellular development in order to produce dormant spores. We investigated the capacity of D. discoideum to be used as a rapid screening system for potential developmental toxicity of compounds under development as pharmaceuticals. We used a set of four transgenic D. discoideum strains that expressed a reporter gene under the control of promoters that are active at certain time periods and in distinct cell types during D. discoideum development. We found that teratogens such as valproic acid, tretinoin, or thalidomide interfered to various extents with D. discoideum development, and had different effects on prestalk and prespore cell-specific reporter gene expression. Phenytoin was inactive in this assay, which may point to limitations in metabolization of the compound in Dictyostelium required to exert developmental toxicity. D. discoideum cell culture is cheap and easy to handle compared to mammalian cell cultures or animal teratogenicity models. Although the Dictyostelium-based assay described in this report may not securely predict the teratogenic potential of these drugs in humans, this organism may be qualified for rapid large-scale screenings of synthetic compounds under development as new pharmaceuticals for their potential to interfere with developmental processes and thus help to reduce the amount of teratogenicity tests in animal models.
Dannat
K
K
Institut für Pharmazeutische Biologie, Universität Frankfurt/M. (Biozentrum), Universität Leipzig, Germany.
Tillner
J
J
Winckler
T
T
Weiss
M
M
Eger
K
K
Dingermann
T
T
D000818:Animals; D003470:Culture Media; D004023:Dictyostelium / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D004054:Diethylstilbestrol / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D008954:Models, Biological; D010672:Phenytoin / Q000633:toxicity; D012098:Reproduction / Q000187:drug effects*; D013723:Teratogens / Q000633:toxicity*; D013792:Thalidomide / Q000633:toxicity; D014212:Tretinoin / Q000633:toxicity
D003470:Culture Media; D013723:Teratogens; D013792:Thalidomide; D014212:Tretinoin; D010672:Phenytoin; D004054:Diethylstilbestrol