Tetravinyl-tetramethylcyclo-tetrasiloxane (tetravinyl D4) is a mutagen in Rat2lambda lacI fibroblasts.
Small fragments of silicone gels injected intraperitoneally have been used to induce plasmacytomas in genetically susceptible mice. Silicone oils, in contrast to silicone gels, are apparently not tumorigenic in the mouse plasmacytoma system. The reason for this difference as well as the mechanism of silicone gel-induced plasmacytoma development is poorly understood. We chose to examine the possibility that low molecular wt silicone compounds such as siloxanes, leaking from the complex silicone gel matrix into the surrounding tissue, may be mutagenic. We postulate that this mutagenicity may be a critical determinant of the plasmacytoma inducing potency of silicone gels. Six siloxane compounds, either linear or cyclic di-, tri-, or tetrasiloxanes substituted with methyl or vinyl moieties, were selected as model compounds to study mutagenicity in Rat2lambda lacI fibroblasts in vitro. Using phage lambda-derived lacI/lacZ genes as target/reporter genes to quantitate mutagenesis, and gamma-cyclodextrin as vehicle to effectively deliver siloxanes, we found that exposure to 50 microM of tetravinyl-tetramethylcyclo-tetrasiloxane (tetravinyl D4) resulted in a modest 1.7-fold increase of mutant frequencies over controls in Rat2lambda lacI cells. In related toxicity experiments, tetravinyl D4 was shown to perturb lipid membranes leading to a loss of cytosolic glutathione (GSH), which by itself resulted in a 1.5-fold increased mutant rate in Rat2lambda lacI cells. We conclude that certain siloxanes may act as direct mutagens in mammalian cells. In addition, siloxane-induced mutagenicity may be enhanced by the depletion of intracellular GSH caused by the interaction of lipophilic siloxanes with cell membranes.
Felix
K
K
Laboratory of Genetics, DBS, NCI, NIH, Bethesda, MD 20892, USA. felixk@dc37a.nci.nih.gov
Lin
S
S
Bornkamm
G W
GW
Janz
S
S
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D005982:Glutathione Transferase / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007763:Lac Operon; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D012833:Siloxanes / Q000494:pharmacology*
D006571:Heterocyclic Compounds; D009153:Mutagens; D012833:Siloxanes; C110979:tetravinyl-tetramethylcyclo-tetrasiloxane; D005982:Glutathione Transferase