Evaluation of toxicity and mutagenicity of oxaliplatin on germ cells in an alternative in vivo model Caenorhabditis elegans.

Abstract

The platinum compound oxaliplatin is a widely used chemotherapeutic drug that shows a broad spectrum of activity in various human tumors. While the treatment-related side effects of oxaliplatin on directly treated individuals have been well-documented, little is known about the influence of oxaliplatin on germ cells and non-exposed progenies. Here we investigated the reproductive toxicity of oxaliplatin in a 3R-compliant in vivo model Caenorhabditis elegans, and evaluated the germ cell mutagenicity of oxaliplatin by using whole genome sequencing. Our results indicated that oxaliplatin treatment significantly disrupts development of spermatids and oocytes. By treating parental worms with oxaliplatin for three successive generations, sequencing data unveiled the mutagenic effects of oxaliplatin on germ cells. Analysis of genome-wide mutation spectra showed the preferentially induction of indels by oxaliplatin. In addition, we uncovered the involvement of translesion synthesis polymerase ζ in modulating mutagenic effects of oxaliplatin. These findings suggest that germ cell mutagenicity is worthy of consideration for the health risk assessment of chemotherapeutic drugs, while the combined use of alternative in vivo models and next generation sequencing technology appears to be a promising way for the preliminary safety assessment of various drugs.