Putative adverse outcome pathways for silver nanoparticle toxicity on mammalian male reproductive system: a literature review

Abstract

Background: Adverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms).

Methods: PubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization.

Results: We identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO).

Conclusion: This research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

Keywords: Adverse outcome; Adverse outcome pathways; Key events; Molecular initiating event; Reproductive toxicity; Silver nanoparticles.

Fig. 1

Scheme of evaluation of the literature between 2007 and 2022

Fig. 2

Size range of Ag NPs used for both in vivo and in vitro reproductive toxicity studies indicating the most prevalent size of Ag NPs (0–20 nm) employed for reproductive toxicity studies

Fig. 3

Proposed putative AOP: impairment of intracellular SH-containing biomolecules leading to impaired fertility

Fig. 4

Putative AOP (pAOP) on Ag NPs reproductive toxicity relations with already existing AOPs, AOP18 [138] PPARα activation in utero leading to impaired fertility in males, AOP64 [151] Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility, AOP207 [55] NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans