Sperm DNA Damage in Cancer Patients.

Fertility is a growing healthcare issue for a rising number of cancer survivors. In men, cancer itself and its treatment can negatively affect spermatogenesis by targeting the dividing spermatogonia and their cellular environment, ultimately leading to a reduction of testicular germ cells and sperm count. Experimental data and prospective longitudinal studies have shown that sperm production can recover after cancer treatment. But despite this, yet unpredictable, recovery in sperm production, cancer survivors are more at risk to produce sperm with aneuploidy, DNA damage, abnormal chromatin structure, and epigenetic defects even 2 years post-treatment. Sperm DNA alteration is of clinical concern, as these patients may father children or seek assisted reproduction technologies (ART) using gametes with damaged genome that could result in adverse progeny outcomes. Interestingly, large cohort studies revealed lower birth rate but no significant impact on the health of the children born from male cancer survivors (naturally or using ART). Nevertheless, a better understanding of how cocktail of chemotherapy and new anticancer agents affect spermatogenesis and sperm quality is needed to reduce side effects. Moreover, developing new fertility preservation strategies is essential as sperm cryopreservation before treatment is currently the only option but does not apply for prepubertal/young postpubertal patients.

In vitro study of doxorubicin-induced oxidative stress in spermatogonia and immature Sertoli cells.

Pediatric chemotherapy treatments can impair long-term male fertility. Unfortunately, no fertility preservation solution is available for pre-pubertal boys. Studies suggest that doxorubicin, used against pediatric cancers, induces oxidative stress in the testis. However, the targeted testicular cell types remain unknown. The goal of this study was to determine whether doxorubicin can induce oxidative stress in rat spermatogonia (GC-6Spg) and immature Sertoli (Ser-W3) cell lines, and to assess their protection by antioxidants. Using the MTT assay, we have shown that doxorubicin induces a time- and dose-dependent cytotoxicity in these two cell lines, Ser-W3 being more sensitive than GC-6Spg. After 3 h of treatment, reactive oxygen species and nuclear 8-oxo-deoxyguanosine increase in Ser-W3, but not in GC-6Spg. Moreover, after 6 h of treatment, intracellular reduced glutathione levels decrease significantly in Ser-W3 cells. These results show that doxorubicin induces oxidative stress in the Ser-W3 cell line. However, a depletion in glutathione does not affect their survival, and supplementation only offers a weak protection after exposure to doxorubicin, suggesting that the glutathione system is not essential for Ser-W3 cell line's defense against doxorubicin. On the other hand, among four antioxidants selected from the literature, none reduces the cytotoxicity of doxorubicin in Ser-W3 cells. Together, our data suggest that oxidative stress may not be a major pathway for doxorubicin's cytotoxicity in GC-6Spg and Ser-W3 lines. This study provides new insights in the mechanisms by which chemotherapies affect the pre-pubertal testis, with the long-term goal to help improve the quality of life of pediatric cancer survivors.