Abstract
Hydroxyurea (HU) is an FDA-approved drug used to treat a variety of diseases, especially malignancies, but is harmful to fertility. We used porcine oocytes as an experimental model to study the effect of HU during oocyte maturation. Exposure of cumulus–oocyte complexes (COCs) to 20 µM (P<0.01) and 50 µM (P<0.001) HU reduced oocyte maturation. Exposure to 20 µM HU induced approximately 1.5- and 2-fold increases in Caspase-3 (P<0.001) and P53 (P<0.01) gene expression levels in cumulus cells, respectively, increased Caspase-3 (P<0.01) and P53 (P<0.001) protein expression levels in metaphase II (MII) oocytes and increased the percentage of apoptotic cumulus cells (P<0.001). In addition, HU decreased the mitochondrial membrane potential (Δφm) (P<0.01 and P<0.001) and glutathione (GSH) levels (P<0.01 and P<0.001) of both cumulus cells and MII oocytes, while increasing their reactive oxygen species (ROS) levels (P<0.001). Following parthenogenetic activation of embryos derived from MII oocytes, exposure to 20 µM HU significantly reduced total blastocyst cell numbers (P<0.001) and increased apoptosis of blastocyst cells (P<0.001). Moreover, HU exposure reduced the rate of development of two-celled, four- to eight-celled, blastocyst, and hatching stages after parthenogenetic activation (P<0.05). Our findings indicate that exposure to 20 µM HU caused significant oxidative stress and apoptosis of MII oocytes during maturation, which affected their developmental ability. These results provide valuable information for safety assessments of HU.
Highlights
Hydroxyurea (HU), a United States Food and Drug Administration-approved drug [1], is an inhibitor of ribonucleotide reductase commonly used to treat myeloproliferative disorders and sickle cell anemia [2]
Porcine cumulus–oocyte complexes (COCs) were cultured in in vitro maturation (IVM) media supplemented with 1, 10, 20, or 50 μM HU to determine the effect of HU on metaphase II (MII) oocyte development
MII oocytes cultured in IVM media with (20 μM) or without HU were subsequently cultured in in vitro culture (IVC) media to examine post-meiotic development to the blastocyst stage
Summary
Hydroxyurea (HU), a United States Food and Drug Administration-approved drug [1], is an inhibitor of ribonucleotide reductase commonly used to treat myeloproliferative disorders and sickle cell anemia [2]. HU has several adverse effects and should be used with caution in pregnant women and children. Studies have shown that use of HU in pregnant women or babies can cause harmful effects [10,11]. HU can be extremely toxic to preimplantation embryos because it impacts blastocyst formation and development, compromises folliculogenesis, and reduces ovulation [12]. HU inactivates ribonucleotide reductase and inhibits DNA synthesis in proliferating cells, and can increase apoptosis and induce cell cycle changes [11,13,14]. HU exposure induced apoptosis of fetal tissue cells, which resulted in abnormal tissue development in offspring [15].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
