Metal Oxide Nanoparticles: Evidence of Adverse Effects on the Male Reproductive System

Abstract

Metal oxide nanoparticles (MONPs) are inorganic materials that have become a valuable tool for many industrial sectors, especially in healthcare, due to their versatility, unique intrinsic properties, and relatively inexpensive production cost. As a consequence of their wide applications, human exposure to MONPs has increased dramatically. More recently, their use has become somehow controversial. On one hand, MONPs can interact with cellular macromolecules, which makes them useful platforms for diagnostic and therapeutic interventions. On the other hand, research suggests that these MONPs can cross the blood-testis barrier and accumulate in the testis. Although it has been demonstrated that some MONPs have protective effects on male germ cells, contradictory reports suggest that these nanoparticles compromise male fertility by interfering with spermatogenesis. In fact, in vitro and in vivo studies indicate that exposure to MONPs could induce the overproduction of reactive oxygen species, resulting in oxidative stress, which is the main suggested molecular mechanism that leads to germ cells' toxicity. The latter results in subsequent damage to proteins, cell membranes, and DNA, which ultimately may lead to the impairment of the male reproductive system. The present manuscript overviews the therapeutic potential of MONPs and their biomedical applications, followed by a critical view of their potential risks in mammalian male fertility, as suggested by recent scientific literature.

Keywords: biomedicine; male infertility; metal-oxide nanoparticles; nanotoxicity; oxidative stress; reproductive system; spermatogenesis.

Figure 1

Classification of nanoparticles according to their origin, composition, morphology, and dimension with some examples. Metal oxide nanoparticles are engineered, inorganic nanoparticles, that can be synthesized by physical, chemical, or biological techniques, created with Biorender.com (accessed on 27 June 2021).

Figure 2

Summary of the biomedical applications of MONPs. The latter were divided into six categories, namely antimicrobial activity, anticancer activity, antidiabetic activity, drug delivery, imaging, and reproductive medicine, created with Biorender.com (accessed on 27 June 2021).

Figure 3

Schematic representation of spermatogenesis in the cross-section of a seminiferous tubule. Spermatogenesis is initiated at puberty by the hypothalamus, which produces GnRH, which, in turn, stimulates the release of FSH and LH at the reproductive tract. LH stimulates Leydig cells to produce testosterone and FSH stimulates Sertoli cells that provide support and nutrition for sperm survival, proliferation, and differentiation [102]. Sertoli cells then initiate the functional responses required for spermatogenesis. Spermatogenesis starts when type A spermatogonia (2n) commit to differentiating into type B spermatogonia. Then, through mitosis, B-spermatogonia (2n) give rise to primary spermatocytes (2n). The latter undergo a long meiotic phase that originates the secondary spermatocytes (n), which ends with spermatids (n) generation [103]. The round spermatids then go through substantial morphological changes during spermiogenesis originating highly specialized spermatozoa through the reorganization of the entire cell, where the nuclear envelope seems to be crucially involved [104,105]. The next event is spermiation, in which mature spermatids are released from the supporting Sertoli cells into the lumen of the seminiferous tubule, and the remainder of the spermatid cytoplasm, known as the residual body, is phagocytosed by the Sertoli cells [106]. However, at this stage, spermatozoa still lack motility. Immotile spermatozoa are then transported into the epididymis where the final steps of maturation occur [107]. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; BTB, blood–testis-barrier; 2n, diploid cell; n, haploid cell, created with Biorender.com (accessed on 2 July 2021).

Figure 4

The main reproductive toxic events induced by MONPs at the cellular level. MONPs, Metal Oxide Nanoparticles; ROS, Reactive Oxygen Species; MMP, Mitochondria Membrane Potential; ATP, Adenosine Triphosphate; BTB, Blood-Testis-Barrier; ↑, increase; ↓, decrease; x, impaired, created with Biorender.com (accessed on 30 May 2021).