Dysfunction of the ubiquitin proteasome system causes abnorm

Dysfunction of the ubiquitin-proteasome system causes abnormal organelle morphology and impairs sperm formation and maturation steps resulting in male infertility [[7], [8], [9]]; this indicates that ubiquitination is essential for spermatogenesis and sperm function during fertilization. β-catenin is a well-known target protein for ubiquitination, and its cellular level is tightly controlled by ubiquitination-mediated degradation [10]. In fertilization, β-catenin degradation is triggered by membrane adhesion between sperm and egg, and treatment of wild-type eggs, but not β-catenin-deficient eggs, with PYR-41 affects sperm-egg fusion [11]. To further investigate the effect of PYR-41 on egg function, we here examined wild-type and β-catenin-deficient eggs pretreated or treated continuously with PYR-41.
Materials and methods
Results
Discussion PYR-41 inhibits UBE1 activity that catalyses an initial step in the ubiquitination reaction. In the present study, we examined the role of this enzyme in sperm-egg fusion by inhibiting UBE1 enzymatic activity in eggs. Our results suggest that PYR-41 pretreatment disturbs the intrinsic fusion competence in eggs as follows: first, PYR-41 treatment reduced fertilization efficiency; second, this pretreatment specifically reduced the efficiency of sperm fusion with eggs; third, this pretreatment suppressed sperm enlargement leading to impaired meiotic chromosomal separation after fusion with the egg. PYR-41 is a derivative of pyrazone, the abbreviated term for the herbicidal substance 5-amino-4-chloro-2-phenyl-3 (2H) pyridazinone, which acts in vivo as an inhibitor of photosynthesis in plants [13]. Since pyrazone is also able to remove excess uric acid, which causes gout or gouty arthritis, its treatment reduces the risk of complications in patients with conditions such as kidney stones. In mammalian reproduction, loss of p53 in female mice significantly decreases fertility because of reduced embryo implantation ability [14]. PYR-41 suppresses the degradation of p53 proteins and also activates its transcriptional activity by inhibiting UBE1 activity, resulting in differential killing of transformed Carprofen sale [[5], [6]]. Hence, PYR-41 is a potential anti-cancer drug. Pyrazone is useful for therapeutic treatment of some types of human diseases [15]; however, our results imply that it might have adverse effects for mammalian female reproduction. Our study contributes to the understanding of the molecular mechanisms of mammalian fertilization, and the cause of female infertility.
Declaration of interest
Author contributions
Acknowledgement This study was supported by a Grant-in-aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 26670733 and No. 26293363 to K. Miyado).
Introduction Lead (Pb) is an important environmental pollutant can be obtained from Pb paint as well as soil, drinking water, and food [10]. Numerous studies have shown that Pb can damage to the nervous, renal, hematopoietic, reproductive, gastrointestinal, and cardiovascular system [38,39]. In addition, the skeleton is an important target organ of Pb; once absorbed, more than 90% of Pb accumulates and remains in the bones [1]. This accumulation can cause osteomalacia, osteoporosis and increased incidence of fracture [11]. Previous studies have shown how Pb exposure can alter the bone mineral composition and affect bone maturation [28]. Furthermore, other studies have also demonstrated that increased Pb exposure is associated with decreased bone mineral density, as well as diminished bone strength and structural properties [2,22]. The mechanism of the toxic effects of Pb on bone mineralization most likely involves multiple metabolic processes, which may exert both direct and indirect effects on the processes regulating bone turnover mechanisms. For direct effects, Pb2+ can replace calcium ions, Ca2+, in the apatite lattice and consequently lead to the loss of calcium and phosphorus from bone tissue, resulting in a decrease in bone mineral density and the occurrence of osteoporosis. For indirect effects, Pb exposure may alter hormonal regulation in organisms and damage bone cell functions [7]. Further mechanism studies showed that Pb can directly reduce the activity of osteoblasts through inhibiting osteonectin secretion, decreasing alkaline phosphatase (ALP) activity, and suppressing type I collagen (COL1) synthesis [21]. With osteoblast proliferation and growth factor responses are reduced, bone nodule formation and calcification are also inhibited by Pb [5]. However, the underlying molecular mechanism has not fully known.