Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer

Chemotherapeutic drugs can affect DNA in male germ cells, thereby impacting on the integrity of the genome transmitted to offspring. Drug metabolizing enzymes can protect cells from xenobiotic insult. We analyzed the expression pattern of such enzymes in isolated round spermatids from rats exposed to drugs used to treat testicular cancer: bleomycin, etoposide, and cisplatin (BEP). The number of isozymes expressed and the overall relative expression values were highest for the glutathione S-transferases (GSTs). Moreover, BEP treatment significantly increased the expression of 8 GSTs and 3 aldehyde dehydrogenases. Increased expression of GST isozymes was confirmed by qRT-PCR and Western blot analysis. Although Gst genes can be targets for epigenetic modifications, promoter DNA methylation was not affected by BEP treatment. As GSTs are involved in drug resistance mechanisms, we hypothesize that BEP induction of GST expression may lead to the survival of damaged germ cells and the production of abnormal sperm.

► In round spermatids, glutathione S-transferases are expressed at a higher level than any other drug metabolizing enzyme family.
► Treatment with drugs used for testis cancer increases the expression of glutathione S-transferases and aldehyde dehydrogenases.
► Changes in the expression of glutathione S-transferases in response to our drug treatments are not regulated by alterations in DNA methylation.
► We hypothesize that induction of the expression of glutathione S-transferases may lead to the survival of damaged germ cells and the production of abnormal sperm.