A fruit fly in the nanoworld: once again Drosophila contributes to environment and human health

Abstract

Drosophila was the most important model organism used in the fields of medicine and biology over the last century. Recently, Drosophila was successfully used in several studies in the field of nanotoxicology. However, only a part of its potential has been exploited in this field until now. In fact, apart from macroscopic observations of the effect due to the interaction between nanomaterials and living organism (i.e. lifespan, fertility, phenotypic aberrations, etc.), Drosophila has the potential to be a very useful tool to deeply analyze the molecular pathways involved in response to the interactions at nano-bio level. The aim of this editorial is to encourage the use of Drosophila by the different research groups working in the fields of nanotoxicology and nanomedicine, in order to define the effects induced by nanomaterials at molecular level for their subsequent exploitation in the field of nanomedicine.

• Nanomedicine
• nanotoxicology
• particle toxicology
• risk assessment

Drosophila melanogaster is certainly the most famous non-mammalian model organism used in the field of biomedical research. The fruit fly owes its fame to T.H. Morgan, who chose it as a model for his studies on the genetic inheritance in the early 1900s. Since then, the reputation of Drosophila grew rapidly, making this insect the model organism preferred by geneticists from around the world. In the following years, the innovation and development of tools for gene discovery and genetic analysis in Drosophila has permitted a deep knowledge of the relationships between the causes and effects of gene mutations at biomolecular level (Adams & Sekelsky, 2002). Today, Drosophila is considered one of the most effective tools for analyzing the function of human disease genes. It should be, in fact, mentioned that about the 75% of human disease-related genes are believed to have a functional homolog in the fly (Lloyd & Taylor, 2010), including those responsible for developmental and neurological disorders, cancer, cardiovascular disease, metabolic and storage diseases, as well as genes required for the function of the visual, auditory and immune systems (Bier, 2005). Furthermore, many fundamental biological mechanisms and molecular pathways, such as physiological and neurological properties, are conserved between Drosophila and mammals (Pandey & Nichols, 2011; Wang et al., 2012). The great similarities between human and flies were recognized and appreciated by scientists working in biology and medicine, making Drosophila the non-mammal model organism par excellence, even in those disciplines where mammal model organisms are considered irreplaceable (i.e. pharmacology (Pandey & Nichols, 2011) and genotoxicology (Mukhopadhyay et al., 2004)). A large part of the success of this model organism is due to the advantages that Drosophila offers with respect to the vertebrate animal models. As an example, the care and culture of this fruit fly is simple, inexpensive, it has a short generation time (about 10 days at 25 °C), together with a high fecundity (a single pair of flies can produce hundreds of offspring within a couple of weeks, and the offspring become sexually mature within one week). All these characteristics enable to study several generations in few weeks. In addition, the genome of Drosophila is small in terms of base pairs and it is organized in a low number of chromosomes (one X/Y pair and three autosomes), and its organs and tissues are easy to recognize, collect and study (Adams et al., 2000; Sullivan et al., 2000). Finally, Drosophila lets scientists to bypass some of the ethical issues concerning the biomedical research on vertebrate organisms (Jennings, 2011), in accordance with the “Replacement, Refinement and Reduction of Animals in Research (NC3Rs) principles” (Flecknell, 2002).

Probably, when Morgan chose a fruit fly for his genetic studies, he never envisaged that this little organism would have made an important contribution to humanity, both over the last century and up to the nowadays “age of nanotechnology”, in which the rapid growth of nanoscale-controlled processes has led to a widespread use of engineered nanomaterials (ENMs). These are a new class of materials with unique physico-chemical characteristics. In fact, ENMs, initially confined to research laboratories, are now included in the formulation of a wide variety of products used daily around the world. Unfortunately, the rapid worldwide spread of ENMs was not complemented by simultaneous thorough hazard identification. The worldwide use of ENMs continues, while their effects on the environment and human health are mostly still unknown. This is a crucial point to be considered: the lack of standardized risk assessment and toxicological classification of ENMs poses serious limitations to (i) understand their potential harmful effects and (ii) regulate their use. The continued spread of new ENMs, together with the lack of a clear and unambiguous toxicological classification, constitute thus a serious concern, especially regarding the ENMs manufacturing, their use and their final disposal. However, this toxicological classification results rather difficult and slow since the ENMs characteristics are very different from the “classical” drugs, biological molecules (i.e. toxins), and chemicals tested till now. Hence, while we witnessed the birth of a new discipline aimed to analyze the potential toxic effects of nanomaterials, unanimously named as nanotoxicology (Maynard et al., 2011), the nanomaterials are entering our homes in form of cosmetics, clothes, electronic equipment, etc. and are consequently spread in our environment polluting air, soil and water.

In this hardly reassuring scenario, once again, this little fly has been chosen as a model organism to study the toxic effects of nanomaterials: Drosophila has been recruited one more time to help humans!

First exploited to assess the effects of different carbon-based nanomaterials on larval dietary and motor skills of adult flies, by Liu et al. (2009), Drosophila has quickly attracted the attention of many research groups, establishing as the standard model organisms in the field of nanotoxicology research. Quickly, the toxic effects of some nanomaterials were tested using fruit flies and, turning the tide of some preconceptions, results have confirmed the predictions about the risk to human health and the environment due to the indiscriminate use of nanomaterials. In this context, a particular example is represented by gold nanoparticles (AuNPs), which displayed significant toxicity, despite the well-known biocompatibility of gold in bulk form (Sabella et al., 2011). In fact, it has been observed that AuNPs administered by ingestion to Drosophila were equally distributed along various organs and tissues, causing a strong reduction in lifespan and fertility of flies (Pompa et al., 2011b), and disorder in gene expression (Vecchio et al., 2012b) and metabolism (Wang et al., 2012). However, the most striking result obtained during the analysis of the effects induced by AuNPs in Drosophila was the discovery of aberrant phenotypes in the untreated progeny derived from flies fed with nanoparticles (Vecchio et al., 2012a). Ironically, just as in 1910 T.H. Morgan obtained the first white-eyed mutant, the first gene mutation induced by nanomaterials in Drosophila is represented by an aberration, once again, in the fly’s eye (Vecchio et al., 2012a). Unfortunately, in this case, the aberrations induced by nanomaterials in the organism of Drosophila confirm the suspect that this new materials can interact with genetic heritage inducing mutations in living organisms (Singh et al., 2009). Apart from AuNPs, Drosophila was successfully applied as model organism to investigate the toxicity of several ENMs, such as silver nanoparticles (Ahamed et al., 2010; Armstrong et al., 2013; Demir et al., 2011; Gorth et al., 2011; Panacek et al., 2011; Posgai et al., 2011), silica nanoparticles (Barandeh et al., 2012; Pandey et al., 2013), carbon-based nanomaterials (de Andrade et al., 2014; Ghosh et al., 2011; Leeuw et al., 2007; Liu et al., 2009), quantum-dots (Brunetti et al., 2013; Galeone et al., 2012; Parvin et al., 2013), etc. The versatility of Drosophila has allowed its employement for the in vivo quantitative ranking of several types of nanoparticles with different coatings and/or surface chemistries (Pompa et al., 2011a; Vecchio et al., 2013), highlighting the importance of post-synthesis modifications in order to modulate the physico-chemical characteristics of ENMs and, consequently, their toxicity outcomes.

Among all the nanomaterials tested until now, a large part has been shown to induce toxic effects with both in vitro and in vivo approaches, exploiting Drosophila as well as other model organisms. However, the literature data are roughly limited to determine the toxicity or biocompatibility of ENMs, since the available observations are still too general and partially contrasting (in terms of viability, fertility, level of ROS, etc.). For these reasons, we are still far from understanding the molecular mechanisms underlying the interactions between nanomaterials and living matter. The clarification of these mechanisms is of great scientific interest since it would shed light on the interactions at the molecular level when different cells (belonging to tissues and organs of a complex organism) interface with the ENMs. This information is necessary to define in detail the toxicity of nanomaterials and could reveal the presence of different molecular pathways involved in response to the different types of nanomaterials. On the other side, the investigation of the molecular bases of ENMs-living system interaction could be used to develop nanomaterial-based drugs that can modulate specific molecular pathways. In this framework, Drosophila has emerged as a useful whole animal model for drug screening among all the possible non-mammal model organism candidates for drug screenings (Gladstone & Su, 2011; Panacek et al., 2011; Willoughby et al., 2013), since the mutations defining thousands of genes (that are useful for functional analyzes of molecular pathways) have been isolated and are nowadays available in several Drosophila stock centers around the world (Rasmuson-Lestander, 1995).

Currently, Drosophila is being established as an interesting model organism for the risk assessment and toxicological classification of nanomaterials as well. Future research in the field of nanomedicine aiming at the discovery of new drug formulations for the treatment of diseases that still lack of appropriate or definitive therapies will also profit from this particular exploitation of Drosophila. Now it is the time to profit from the peculiar features of this powerful scientific tool in a new multidisciplinary context and, once again, the collaboration between humans and flies could lead to the achievement of fundamental scientific discoveries and technological advances.