Long-term imatinib treatment reduces spermatogenic cell proliferation in juvenile rat testes

Background: Long-term tyrosine kinase inhibitor (TKI) “targeted” treatment in pediatric patients with chronic myeloic leukemia reveals multiple off-target side effects. Specifically in testes, TKIs signaling cascades necessary for spermatogenesis are inhibited but the detailed action is not yet fully understood. Therefore, we investigated testicular tissue under TKI exposure in a juvenile rat model.

Methods: Growing Wistar rats (age: 4 weeks (w)) were exposed over 10 w to imatinib (IM) or dasatinib (DASA) at different concentrations (low dose [LD], high dose [HD], intermittent high dose [ID]). At prepubertal (age: 6 w), pubertal (8 w), and postpubertal stage (14 w) total testis weight and cellularity (spermatogonia, spermatocytes, spermatids, Ki-67 positive cells) in microscopic tubulus cross section were analyzed under IM exposure. Expression of genes involved in spermatogenesis was analyzed under DASA exposure.

Results: In total, 64 and 40 tissue specimen were analyzed for IM and DASA, respectively. Testis weight was not affected by TKI treatment. During IM treatment, compared to controls cell counts were significantly decreased in HD (p = 0.031) whereas LD and ID drug exposure minimized these adverse effects. However, proliferation as assessed by Ki-67 expression was significantly decreased at all IM doses applied. Long-term DASA HD exposure decreased gene expression of SCF, c-kit, PDGF-A/B, and PDGF-R α/β.

Conclusion: Long-term TKI exposure seems to influence spermatogenesis dose-dependently, therefore a negative effect on fertility can not be excluded.