Disorders of male reproductive health are becoming increasingly prevalent due to unknown reasons. Pharmaceutical agents and environmental chemicals can cause adverse effects on the reproductive system, but reproductive toxicity often remains unnoticed. Although the testing of chemicals and pharmaceuticals is increasing and regulated by EU legislation, data on reproductive toxicity is still very limited. Investigating the mechanisms underlying the increased rates of male reproductive health disorders is crucial when trying to stop this growing trend. Furthermore, the methods used in toxicology require continuous development, and a shift towards in vitro/ex vivo methods is highly desirable. My doctoral research focuses on analyzing the testicular toxicity of commonly used anticancer drugs (imatinib and dasatinib) and a ubiquitous environmental contaminant, perfluorooctanoic acid (PFOA), in rodent models, utilizing in vitro and ex vivo toxicological methods. Rodents, particularly mice and rats, are the most commonly used animal models in male reproductive toxicity research due to e.g. their similarities to human spermatogenesis and its regulation.
Male gonads are vulnerable to external harmful factors, especially during embryonic development, but they remain vulnerable also later in life. Consequently, we analyzed the effects of PFOA both on fetal and adult rat testes in the first part of my doctoral studies. The main results were that PFOA exposure ex vivo inhibits fetal rat steroidogenesis and induces germ cell apoptosis in adult rat testes. Therefore, exposure to PFOA poses a risk to male fertility, particularly through pregnant females carrying male embryos.
The growing population of cancer survivors at fertile age represents a significant challenge for clinicians and researchers. It is essential to recognize the risks associated with both cancer and its treatments on fertility, and to identify the least harmful yet most effective treatment options. In the second part of my doctoral studies, we analyzed the effects of imatinib and dasatinib on male rodent germ cells and germline stem cells. We showed that imatinib exposure, both in vitro and ex vivo, adversely affects the proliferation and survival of male rodent germ cells. The plausible mechanism of imatinib action in spermatogenic cells involves the inhibition of c-KIT/SCF signaling and reduced expression of c-KIT. However, dasatinib did not show to cause adverse effects at clinically relevant doses ex vivo, but inhibited male germline stem cell colony growth in vitro.