<p>ZnO Nanoparticles Induced Male Reproductive Toxicity Based on the Effects on the Endoplasmic Reticulum Stress Signaling Pathway</p>

Abstract

PurposeThe aim of this study was to evaluate the adverse effects of ZnO NPs on male reproductive system and explore the possible mechanism.MethodsIn this study, the effect of oral administration of 50, 150 and 450 mg/kg zinc oxide nanoparticles (ZnO NPs) in adult male mice was studied over a 14-day period.ResultsThe results showed that the number of sperms in the epididymis and the concentration of testosterone in serum were decreased with an increased dose of ZnO NPs. Testicular histopathological lesions like detachment, atrophy and vacuolization of germ cells were observed. The results showed that increased dosage of ZnO NPs correspondingly up-regulated the IRE1α, XBP1s, BIP, and CHOP (P<0.05) which are genes related to ER stress. These observations indicated that ZnO NPs had adverse effects on the male reproductive system in a dose-dependent manner possibly through ER stress. The expression of caspase-3 was significantly increased in all the treated groups (P<0.001), which reflected the possible activation of apoptosis. Additionally, there was significant down-regulation of the gene StAR (P<0.05), a key player in testosterone synthesis. When an ER-stress inhibitor salubrinal was administered to the 450 mg/kg ZnO NPs treatment group, the damages to the seminiferous tube and vacuolization of Sertoli and Leydig cells were not observed. Furthermore, the testosterone levels in the serum were similar to the control group after the subsequent salubrinal treatment.ConclusionIt may be inferred that the ZnO NP's reproductive toxicity in male mice occurred via apoptosis and ER-stress signaling pathway.

The Impact of Zinc Oxide Nanoparticles on Male (In)Fertility

“…Interestingly, Hussein et al, 2016 revealed that these changes in sperm quality could be alleviated by co-exposure with quercetin, a potent antioxidant. The number of Leydig cells also decreases after exposure to a low concentration of ZnO NPs, and as a consequence, serum testosterone levels decrease, as reported in Wistar Han rats [78] and Kunming mice [75,86]. Additionally, the same authors explored the influence of ZnO NPs on steroidogenesis enzymes by assessing the mRNA levels of steroidogenic proteins in testis samples, namely 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenases (17β-HSD), and steroidogenic factor 1 (Nr5A1) [78].…”

“…Most of the in vivo studies reported in Table 2 evaluate changes in testicular and epididymal tissues after exposure of rats or mice to different ZnO NPs concentrations. The histological pattern was similar in both rats or mice, with the formation of multinucleated giant cells [76,77], disorganization of germ cells layers, detachment and sloughing of immature germ cells, and vacuolization of the epithelium of ST after exposure to a high concentrations of ZnO NPs [75][76][77][78]80,86]. These histological alterations are indicative of functional damage in Sertoli cells, which are responsible for the support and protection of germ cells during spermatogenesis [76].…”

“…The appearance of immature germinal cells in the epididymis [77], as well as degenerated and desquamated spermatocytes [77,78] and sperm cells [77] in the STs lumen and epididymis, respectively, is evident. In addition, the number of germinative cells is reduced [75][76][77][78]86] and the STs of Wistar Han rats were almost empty of spermatids and spermatozoa after exposure to 400 mg/kg of ZnO NPs. The number of Leydig cells, an important cell responsible for testosterone production, also decreased in exposed animals [87,88].…”

“…These results are consistent with data obtained from in vitro study using a Leydig cell line, which reports a decrease in Leydig cells' viability and an increase of apoptosis after in vitro exposure to ZnO NPs [71] (Figure 2). Furthermore, according to a recent study, the testis toxicity after exposure to ZnO NPs occurs via apoptosis and the ER-stress signaling pathway, activated by ROS [86].…”

“…Nr5A1 is a transcription factor that regulates the expression of several steroidogenic enzymatic genes on Leydig cells (such as 3β-HSD and aromatase) and is involved in the steroidogenesis pathway and synthesis of testosterone [88]. Moreover, a recent study reported a significant down-regulation of steroidogenic acute regulatory protein (StAR) in testis, very important in testosterone synthesis, responsible for the transport of hydrophobic low-density cholesterol from the cytosol to the mitochondrial inner membrane [86,89]. The expression of mRNA steroidogenic proteins showed a significant decrease in ZnO NPs-exposed groups, which justifies the lowering in serological testosterone levels [78,86].…”