Genetic change may be caused by interference with protein-protein interactions

Area of Science:

• Toxicology
• Molecular Biology
• Genetics

Background:

• Aprotic polar solvents are increasingly used in various industries.
• Understanding their genotoxic potential is crucial for environmental and occupational safety.
• Mitotic aneuploidy can lead to genetic instability and disease.

Purpose of the Study:

• To investigate the potential of specific aprotic polar solvents to induce mitotic aneuploidy in yeast.
• To elucidate the underlying molecular mechanisms, particularly the interaction with tubulin.
• To compare the effects of different solvents on genetic endpoints and tubulin assembly.

Main Methods:

• Yeast strains were treated with various solvents to assess aneuploidy induction.
• In vitro assays using porcine brain tubulin were performed to evaluate effects on tubulin assembly and disassembly.
• Concentration-response relationships were analyzed for both yeast and in vitro experiments.

Main Results:

• Diethyl ketone, gamma-valerolactone, pyridine, and phenylacetonitrile induced aneuploidy in yeast and inhibited in vitro tubulin assembly.
• Pivalinic acid nitrile accelerated tubulin aggregation, while fumaric acid dinitrile induced aneuploidy in yeast but had no effect on tubulin assembly in vitro.
• Fumaric acid dinitrile also induced other genetic effects like mitotic crossing-over and gene conversion.

Conclusions:

• Some aprotic polar solvents can induce aneuploidy in yeast, likely by interfering with microtubule dynamics.
• Inhibition of tubulin assembly is a potential mechanism for aneuploidy induction by certain solvents.
• Fumaric acid dinitrile's unique profile suggests alternative mechanisms or species-specific differences in tubulin susceptibility.