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Theranostics 2020, Vol. 10, Issue 20 acute toxicity and biokinetics after repeated intravenous administration of AgNPs in mice. During the 14-day observation period, both the survival and behavior of the mice were normal. They found that AgNPs were widely distributed in tissues, especially in the spleen, followed by the liver. The biokinetics of AgNPs in the kidney and lung seem to show gender- related differences, i.e. the accumulation of silver in kidney and lung of female mice was higher than that of male mice, the longer elimination half-life and slower clearance of AgNPs in female mice than male mice. Besides, the KCs in the liver were mainly responsible for the retention and elimination of AgNPs. The silver content in the liver significantly decreased after one day. While in the spleen, the marginal zone and the red pulp macrophages contributed to the clearance of silver. Reproductive System Toxicity Biological barriers, such as the blood-testis barrier, placental barrier and epithelial barrier, can protect the reproductive system from infection and toxicity. AgNPs can cross the biological barriers to deposit in reproductive organs including testis, epididymis, ovary and uterus. Thus, AgNPs may damage germ cells and related cells, such as primary and secondary follicles, germline stem cells, Sertoli cells and Leydig cells [42, 347]. Besides, AgNPs can also cause changes in sexual behavior by affecting the secretion of hormones within the reproductive organs and glands. Further studies confirmed that the reproductive toxicities of AgNPs are achieved by increasing inflammation, disrupting DNA structure, down-regulating gene expression, decreasing mitochondrial function, inducing ROS production and apoptosis. These toxicities of AgNPs to the reproductive system are size-, time- and dose- dependent [347, 348]. Zhang et al. [347] investigated the effects of AgNPs with different sizes (10 nm and 20 nm) on male somatic Leydig cells and Sertoli cells, and found that cell viability was inhibited by AgNPs in size- and concentration-dependent manners. The 10 nm AgNPs showed more cytotoxicity than the 20 nm AgNPs. and cell proliferation was significantly decreased as the concentration of AgNPs increased from 0 to 100 μg/ml. AgNPs-treated Sertoli cells showed decreased mRNA levels of ZO-1 and Cx43, bothareinvolvedinencodingtightjunctionproteins which playing a crucial role in the formation of BTB. As well as AgNPs-treated somatic Leydig cells showed decreased mRNA levels of StAR, 3β-HSD and 17β-HSD, which are involved in the production of testosterone. It is widely acknowledged that spermatogonial stem cells (SSCs) can continuously proliferate, renew and produce sperms throughout 9023 male’s postnatal life. Cytokines secreted by Sertoli cells play an important role in the proliferation and renewal of SSCs. In this study, AgNPs-treated Leydig cells secreted decreased level of testosterone, which was responsible for inducing spermatogenesis and maintaining normal functions of Sertoli cells. These results suggest that AgNPs can impair the function of Leydig cells and Sertoli cells, then worsen the function of SSCs, ultimately suppress male fertility. Cynthia et al. [42] evaluated the fecundity and development of Drosophila fed with AgNPs at various concentrations from 0 to 5 μg/mL. AgNPs decreased the viability and delayed the development of Drosophila in a dose-dependent manner. Germline stem cells (GSCs) and early germ cells were concentrated at the apical tip of the testis. Among different treated groups, a significantly increased ROS level was observed at this tip area of Drosophila treated with 5 μg/mL AgNPs. They also proved that AgNPs might disrupt GSCs maintenance by triggering precocious differentiation of GSCs, thereby decreased the number of sperms. Besides, the first generation of Drosophila fed with a higher concentration of AgNPs showed delayed eclosion and decreased male offsprings as compared to control or lower concentration group. The mating success of Drosophila and the number of their second or third generations decreased in AgNPs-treated groups than the control group. This might suggest that AgNPs accumulated in GSCs could be passed onto offspring and affect the development and fecundity of the offspring. Lafuente et al. [37] studied parameters of epididymal sperm of rat fed with different doses of PVP-AgNPs (50, 100 and 200 mg/kg/day), including sperm morphology, motility and viability. PVP-AgNPs induced sperm morphology abnormalities in a dose-dependent manner. In their study, 100 mg/kg/day of PVP-AgNPs significantly increased abnormal morphologies in epididymal sperms, such as banana head, tail bending, head loss and neck abnormalities. Abnormal sperm morphology reduced sperm motility and vitality. Some studies focus on the effects of AgNPs on female reproduction. Chen et al. [349] evaluated the potential toxicity of AgNPs and Ag+ on zebrafish oocytes. Vacuolation or swollen mitochondria, and condensed nucleus were observed in AgNPs- and Ag+-treated follicular cells. Zebrafish oocytes treated with AgNPs or Ag+ showed a decreased concentration of cAMP, which plays a key roleinthemaintenanceofmeiosisarrest,andresults in meiosis resumption and subsequent oocyte maturation. Besides, AgNPs and Ag+ up-regulated caspase 3 and caspase 9, respectively, both of which play important roles in the initiation and execution of apoptosis, ultimately leading to apoptosis in ovarian http://www.thno.orgPDF Image | Silver nanoparticles Synthesis medical applications safety
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