Abstract
Hydroxyurea (HU), a DNA synthesis inhibitor, is one of the most common chemotherapeutic drugs that have been widely applied to treat a variety of cancers. HU treatment exhibits severe side effects including renal toxicity, skin toxicity and embryo-toxicity. However, the influence of HU on the female gamete development has not yet fully clarified. Here, we found that HU exposure induced the degeneration of activated follicles after primordial follicle stage, resulting in the depletion of the ovarian reserve. HU exposure also led to the oocyte meiotic maturation arrest via disrupting normal spindle assembly, chromosome alignment and kinetochore-microtubule attachment. Furthermore, exposure to HU impaired the dynamics of ovastacin and Juno, two critical fertilization regulators. Notably, we illustrated that Shoutai pills (STP), a traditional Chinese medicine drug that has been commonly used for the treatment of miscarriage in China, partially restored all of the defects of oocyte development resulting from HU exposure through inhibiting the occurrence of oxidative stress-induced apoptosis. Taken together, our data not only reveal the adverse impact of HU exposure on the female gamete development, but also provide an effective strategy to prevent it, potentially contributing to the improvement of the quality of oocytes from patients treated with HU.
Highlights
Hydroxyurea (HU) is a ribonucleotide reductase inhibitor clinically used as an oral antineoplastic for treating several types of cancers including chronic myelogenous leukemia, acute myelogenous leukemia, head and neck cancer, malignant melanoma, ovarian cancer, and polycythemia vera [1]
Pretreatment of rabbits with antioxidants or a free radical scavenger www.aging-us.com (D-mannitol) delays the onset of embryonic cell death and lowers the incidence of malformations caused by HU [12,13,14], suggesting that the oxidative stress induced by reactive oxygen species (H2O2, ·OH) contributes to the developmental toxicity of HU
Hydroxyurea, a DNA synthesis inhibitor, is one of the most common chemotherapeutic drugs that have been widely used in the treatment of inoperable carcinoma of the ovary [25, 26]
Summary
Hydroxyurea (HU) is a ribonucleotide reductase inhibitor clinically used as an oral antineoplastic for treating several types of cancers including chronic myelogenous leukemia, acute myelogenous leukemia, head and neck cancer, malignant melanoma, ovarian cancer, and polycythemia vera [1]. HU treatment causes growth retardation, mortality, and malformations in many experimental species [6,7,8,9]. HU inhibits ribonucleotide diphosphatase reductase, the enzyme that catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides that are required for de novo DNA synthesis, and leading to the cell death in the embryos [10]. Pretreatment of rabbits with antioxidants (propyl gallate, ethoxyquin, nordihydroguaiaretic acid) or a free radical scavenger www.aging-us.com (D-mannitol) delays the onset of embryonic cell death and lowers the incidence of malformations caused by HU [12,13,14], suggesting that the oxidative stress induced by reactive oxygen species (H2O2, ·OH) contributes to the developmental toxicity of HU. Various side effects induced by HU treatment have been observed, the adverse impact of HU on the development of female germ cell has not yet been clearly determined
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