Study On The Characteristics And Mechanisms Of The Spermatogenic Cell Apoptosis Induced By Antineoplastic Hydroxyurea

The reproductive toxicity of xenobiotics has been attracting more attention over the years. With the prolonged survival of tumor patients, the long-term adverse effects of antineoplastic drugs have become a focus of the relevant studies. Hydroxyurea (HU) is the only antineoplastic used clinically as an RNR (Riboneocleotide Reductase) inhibitor for such diseases as melanoma, resistant chronic myelocytic leukemia, and inoperable carcinoma of the ovary and so on. It is currently used for an increasing number of symptoms, and with a good clinical effect. However, there have been insufficient studies on male reproductive toxicity of HU. The relevant studies are most been conducted on mice, and the systematic reproductive toxicity approaches are still unavailable. In this study, both the in vitro and in vivo toxicological experiments on HU were conducted to thoroughly investigate the characteristics and mechanism of the reproductive toxicity of this chemical. Furthermore, after verifying that HU could cause spermatogenic cells apoptosis in rats, the mechanisms of this kind of apoptosis induced by HU were studied in depth using a FasL transgenic mice model and the relevant technologies of molecular toxicology. In vitro and in vivo reproductive toxicity of HUAt first, it is shown that HU exhibited an obvious toxicity to the germ cells of male rats in Sertoli cell germ cell co-culture model, at the concentrations of 0.001-0.1 M. The main manifestations of HU in this model are the increases in both the detached germ cells and the leakage of LDH from these detached cells, and the decreases of the viability of detached cells, all in a dose and time dependent manner. Secondly, the micromass culture of midbrain cells from rats indicated that HU could dose-dependently inhibit both the proliferation and differentiation of midbrain cells, the half inhibition concentrations to cell viability (IV₅₀) and differentiation (ID₅₀) for HU were 0.078 and 0.018mM, respectively. The ratio of IV₅₀ to IC₅₀ was 4.33, indicating that HU is a strong embryotoxicant.Lastly, in the in vivo dosing study, HU were administrated to male Wistar rats at doses of 100, 200 and 400mg/kg, once a day for 10 consecutive days. From the 7th day after first dosing, the body weight of animals in 200 and 400mg/kg HU groups were...