Abstract
Leukemia and treatment of male patients with anticancer therapy (aggressive chemotherapy and/or radiotherapy) may lead to infertility or even permanent male sterility. Their mechanisms of spermatogenesis impairment and the decrease in male fertility are not yet clear. We showed that under acute myeloid leukemia (AML) conditions, alone and in combination with cytarabine (CYT), there was significant damage in the histology of seminiferous tubules, a significant increase in apoptotic cells of the seminiferous tubules, and a reduction in spermatogonial cells (SALL and PLZF) and in meiotic (CREM) and post-meiotic (ACROSIN) cells. In addition, we showed a significant impairment in sperm parameters and fertilization rates and offspring compared to control. Our results showed a significant decrease in the expression of glial cell line-derived neurotrophic factor (GDNF), macrophage colony-stimulating factor (MCSF) and stem cell factor (SCF) under AML conditions, but not under cytarabine treatment compared to control. In addition, our results showed a significant increase in the pro-inflammatory cytokine interleukin-1 (IL-1) alpha in whole testis homogenates in all treatment groups compared to the control. Increase in IL-1 beta level was shown under AML conditions. We identified for the first time the expression of GCSF receptor (GCSFR) in sperm cells. We showed that GCSF injection in combination with AML and cytarabine (AML + CYT + GCSF) extended the survival of mice for a week (from 6.5 weeks to 7.5 weeks) compared to (AML + CYT). Injection of GCSF to all treated groups (post hoc), showed a significant impact on mice testis weight, improved testis histology, decreased apoptosis and increased expression of pre-meiotic, meiotic and post- meiotic markers, improved sperm parameters, fertility capacity and number of offspring compared to the controls (without GCSF). GCSF significantly improved the spermatogonial niche expressed by increased the expression levels of testicular GDNF, SCF and MCSF growth factors in AML-treated mice and (AML + CYT)-treated mice compared to those groups without GCSF. Furthermore, GCSF decreased the expression levels of the pro-inflammatory cytokine IL-12, but increased the expression of IL-10 in the interstitial compartment compared to the relevant groups without GCSF. Our results show for the first time the capacity of post injection of GCSF into AML- and CYT-treated mice to improve the cellular and biomolecular mechanisms that lead to improve/restore spermatogenesis and male fertility. Thus, post injection of GCSF may assist in the development of future therapeutic strategies to preserve/restore male fertility in cancer patients, specifically in AML patients under chemotherapy treatments.
Highlights
Acute myeloid leukemia (AML) is a prevalent disease that appears at all ages, but is more frequent in adults
To evaluate the effect of post injection of Granulocyte colony-stimulating factor (GCSF) on the expression levels of testicular GCSF and its receptor (GCSFR), we used qPCR analysis using specific primers for each factor. qPCR results of each marker are presented as fold of increase compared to the control group (CT) (E)
Our results show that 3-week post-injection of GCSF did not significantly affect sperm parameters, fertility capacity and number of offspring into untreated group (GCSF) compared to control group (CT) (Figure 3A–G, respectively)
Summary
Acute myeloid leukemia (AML) is a prevalent disease that appears at all ages, but is more frequent in adults. Granulocyte colony-stimulating factor (GCSF) is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream [36] It is a member of the hematopoietic growth factor family, which regulates the proliferation, differentiation, and survival of hematopoietic progenitor cells [37]. Sertoli cells, peritubular cells and developed SSCs showed production of the IL-1 system (IL-1α, IL-1β, IL-1ra) under physiological conditions [25,26,27,28,29] These factors are involved in the proliferation/differentiation and apoptosis of SSCs and the functionality of Sertoli and Leydig cells [25,26,27,28,29].
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