Assessment of the potential toxic effect of magnetite nanoparticles on the male reproductive system based on immunological and molecular studies

Abstract

Magnetite nanoparticles (MNPs) are the most conventional type of iron oxide nanoparticles used in the food industrial processes, removal of heavy metals, and biomedical applications in vivo or in vitro. Until now, there is no sufficient information that can confirm its effect on the body's immune system and reproductive health in males. The purpose of this research is to estimate the immunotoxic and reproductive toxic effects of MNPs in male rats. This study included 36 adult male albino rats divided into three groups. The experimental groups were intraperitoneally injected with MNPs at doses of 5 and 10 mg/kg body weight 3 times/week for 60 days, while the control group was injected with saline solution. MNPs caused a significant decrease in the body weight change of the high‐treated group. MNPs produced changes in the lymphocyte proliferation rate which referred to a significant immunotoxic effect measured by the 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide reduction method. The testicular tissue of male‐treated rats showed some moderate and severe degenerative changes. The sperm parameters of count, motility, and viability were significantly decreased. Sperm morphological abnormalities were detected in all treated animals. MNPs produced a significant decrease in testosterone levels, increased the level of malondialdehyde, impaired the activity of the antioxidant enzymes and induced testicular DNA damage. In conclusion, MNPs affected the normal immune state in male rats and facilitated the generation of reactive oxygen species subsequently triggering testicular oxidative stress damages. All these consequences had a negative impact on male reproductive health.

Toxicity Factors of Magnetite Nanoparticles and Methods of Their Research

“…Parameters of the count, motility, and viability of spermatozoa were reduced. Along with the morphological abnormalities of the sperm, a decrease in the testosterone level, an increase in the content of malondialdehyde, a decrease in the activity of antioxidant enzymes and damage of testicular DNA were found [52].…”

“…Fruit flyes (Drosophila melanogaster) [82] Mussels (Mytilus galloprovincialis) [44] Snails (Cornu aspersum) [73] Ray-finned fish (Capoeta fusca) [45] Zebrafish (Danio rerio) [58,68,73] Prussian carp (Carassius gibelio) [73] Spur frogs (Xenopus laevis) [47] Wistar rats (Ratus norvegicus) [48][49][50]52] Sprague-Dawley rats (Ratus norvegicus) [75] Laboratory mice (Mus musculus) [51,59,81] Human stem cells represent an innovative cell-based model for primary screening and testing for the magnetite NP toxicity. For this purpose, it has been proposed to use mesenchymal stem cells obtained from the membrane lining of the umbilical cord [42].…”

“…The gonadotoxicity of magnetite NPs was studied in male albino rats [52]. The experimental groups were intraperitoneally injected with NPs at doses of 5 and 10 mg/kg of body weight three times a week for 60 days, and a significant decrease in the body weight was noted in the group receiving a high dose of NPs.…”

生物医学检测中常用氧化铁磁性纳米颗粒的生物适应性与毒性研究进展

“…IONPs 静脉注射后，可穿过血睾屏障在睾丸中聚集。研究表明，高剂量或长期的 IONPs 给药会对雄性睾丸组织和精子质量造成负面影响。如，Varzeghani 等人的研究表明，腹腔注 射 300mg/kg IONPs 后，小鼠的精子活力、睾丸总体积、曲细精管长度、间质组织体积，以 及白细胞、绒毛细胞、精母细胞、精子细胞和精原细胞的总数均明显减少 [73] 。另有研究给 成年雄性白化大鼠腹腔注射 IONPs，剂量分别为 5mg 和 10mg/kg，每周 3 次，连续 60 天， 结果表明，雄性大鼠的睾丸组织出现了一些中度和严重的退行性变化，精子的数量、活力和 存活率都明显下降， 所有经处理的动物均发现精子形态异常 [74] 。 但也有研究表明， 注射 IONPs 后虽然精子数量减少，活性降低，但小鼠的生殖能力不变，而且停止注射一段时间后，精液 参数可以恢复，说明 IONPs 可对雄性小鼠的生殖系统造成的损伤是可逆的 [75] 。IONPs 对雌 性动物子宫的毒性也与剂量密切相关。 Rahi 等人给 604 只成熟雌性大鼠分别口服蒸馏水和 1、 5、10mg/kg/天的 IONPs 溶液，发现低剂量的 IONPS 对雌性大鼠生殖甚至有改善作用，而 中高剂量则对生殖器官存在负面影响 [76] 。Bakhtari 等人用葡聚糖包裹的 SPIONs 处理小鼠卵 母细胞和颗粒细胞，研究结果表明，卵母细胞和颗粒细胞的破坏与 SPIONs 的剂量依赖性增 加直接相关，高剂量(250μg/ml)SPIONs 组的大多数颗粒细胞的细胞核破碎，细胞膜紊乱， 颗粒细胞之间有明显的纳米颗粒聚集，同时降低了卵原细胞向卵母细胞发育潜能 [77] 。IONPs 期观察到的后代子宫组织学变化也很轻微 [78] 。因此，IONPs 在体的使用应尽量避免大剂量 和长期持续用药，以免对生殖系统造成不可逆的损伤。 2.7 IONPs 对骨髓的毒性研究 IONPs 进入体内后容易被巨噬细胞吞噬清除，因此，随着巨噬细胞活动有可能会扩散到 红骨髓。关于 IONPs 对骨髓的影响的研究较少，Faraj 等的研究表明，聚乙二醇和羧基修饰 的 IONPs 对骨髓衍生巨噬细胞的生物相容性较好，骨髓细胞中活性氧的释放量低，细胞活 力和线粒体膜电位都没有变化 [79] 。另外有研究表明，IONPs 对骨髓细胞没有细胞毒性，也 不影响细胞表面标志物的表达和脂多糖诱导的小鼠骨髓树突状细胞分泌细胞因子 [80] 。当然 剂量也是影响 IONPs 对骨髓中细胞的毒性的主要因素之一， 在 Shi 等人的一项研究中验证了 IONPs 对成骨细胞的毒性，他们使检测了不同浓度 IONPs 处理下成骨细胞的凋亡率，同时， 使用激光扫描共聚焦显微镜也显示了成骨细胞细胞骨架的破坏， 也发现使用低浓度的 IONPs 对避免成骨细胞受损非常重要 [24] 。 全血中的炎症反应，包括激活补体系统和增加细胞因子的分泌 [89] 。Gerogianni 等人研究了 10-30nmIONPs 在人类全血中与内皮细胞相互作用产生的血栓炎症反应，结果表明，IONPs 主要在 C3 水平上诱导补体活化；此外，小颗粒 IONPs 还介导了强烈的血栓炎症反应，27 种分析细胞因子中有 21 种的释放量显著增加，并显示出细胞毒性作用，但研究还表明通过 补体抑制有望改善 IONPs 的血液相容性 [90] 。最后，也有研究表明，白蛋白包裹的 IONPs 可 作为一种血管安全载体进一步研究 [91]…”

Functional roles of magnetic nanoparticles for the identification of metastatic lymph nodes in cancer patients

“…Similarly, Gamal et al found that MNPs could alter the activity of antioxidant enzymes and stimulate ROS production, ultimately leading to damage due to oxidative stress in the rat testes [ 118 ]. However, coating MNPs with chemical modification might alleviate their toxic impacts.…”