Materials acquire unique characteristics when the size of the particle is reduced to nanoscale. Nanomaterials (NMs) are a universal set of nanoscale materials having at least one of the dimensions in the nano-range. With having at least one dimension in nanoscale as a common feature, nanoparticles, nanowires, nanosheets, nanotubes, and nanoplates can be stated as the key subsets of NMs (1). The various properties of a nanomaterial (NM), including its melting point, electrical conductivity, magnetic permeability, chemical reactivity and fluorescence, are determined by the particle size (2). Size-reduction of a material to nanoscale enhances its functional aspects and associated technological benefits. Therefore, the use of engineered nanomaterials (ENMs) in the development of advanced technologies for medicine, engineering and natural sciences has significantly increased since the start of the twenty-first century (3). ENMs are being incorporated into our everyday routine as a part of clothing, food, cosmetics, medicines, electronic goods, etc. However, in parallel to the technological advancements, the biosafety issues related to ENMs have also become a matter of apprehension. Whereas, for applications in medicine, ENMs are optimized to enhance their cellular uptake and/or targeting to the desired tissue, an inadvertent exposure to workers may raise health concerns (4, 5). Multiple studies have suggested that unlike their bulk counterparts, the ENMs are highly toxic and may lead to serious human and ecological health risks (6–8). The toxic outcomes of ENM exposure are largely accredited to their small size and increased chemical reactivity, which enhances their permeability to the target tissues which are otherwise not penetrated by larger but chemically identical materials (9). Noticeably, evidence from several research studies indicates functional similarities between the endocrine-disrupting chemicals (EDCs) and ENMs, which supports the view that different types of NMs may be capable of altering the physiological activity of the endocrine system (10–14).

The WHO (World Health Organization) International Programme on Chemical Safety (IPCS) conducts research to understand the basis for the management of chemicals and related risks. According to the IPCS, “a potential endocrine disruptor is an exogenous substance or a mixture, possessing properties that can lead to endocrine disruption in an intact organism, or its progeny, or (sub) populations” (15). Further to add, the EDCs are elements present in our environment, food, and several consumer products that can interfere with synthesis, secretion, transport, metabolism, binding actions and elimination, and mimic the natural hormones. Consequently, this may lead to a deviation from the normal physiological function of the endocrine system to endocrine disruption. The EDCs and endocrine disrupting ENMs (EDENMs) are prevalent in various consumer goods such as agricultural chemicals, notably fertilizers and pesticides (16, 17), therapeutics (18), cosmetics (19, 20), and paints (19). There is accumulating evidence suggesting an increased presence of EDCs and ENMs in the environment, which putatively affects the functioning of the endocrine system, metabolic system and reproductive system (Figure 1). Hence, though the ENMs promise remarkable benefits, their successful application requires investigation of their impact on human health.

Both EDCs and NMs are regularly investigated for adverse impacts on health. Studies conducted to evaluate the effects of EDCs on health have generally reported deleterious outcomes like altered reproductive function in males and females (21–25), increased incidence of breast cancer (26–30), abnormal growth patterns (31–33), neurodevelopmental delays in children (34–36), and changes in immune functions (37–39). Similarly, exposure to NMs is found to be associated with several adverse outcomes such as impaired immune response, inflammation, fibrosis, emphysema, and tumor formation (40–45).

Additionally, EDCs have been reviewed to act as causative agents of metabolic disorders like type 2 diabetes mellitus (T2DM) (46, 47). The prevalence of T2DM has seen a tremendous global upsurge during the last few decades. A report from the International Diabetes Federation (IDF) estimated ~425 million adults (aged between 20 and 79 years) all over the world were living with diabetes in 2017 and predicted that by 2045 this will rise to 629 million. A large number of investigations to define the genetic and environmental bases of T2DM has been done to date but the definite reasons for a rapid increase in diabetes and obesity in the modern world largely remain unclear. Research in the arena increasingly indicates a major role played by environmental chemicals in diabetes and obesity, advocating that the environmental led metabolism disruption could form the “paradox of progress” (48). At present, only a few studies have examined the role of ENMs in the pathogenesis of T2DM. Chevalier and Fénichel reviewed both in vivo and in vitro experimental data along with epidemiological evidence to support an association of EDC exposure to the induction of insulin resistance and/or disruption of pancreatic β-cell function that leads to glucose homoeostasis related metabolic disorders (49). The evidence of ENM mediated alterations in glucose metabolism, insulin resistance and sensitivity, and homeostasis pathways are mostly indirect. The influence of EDENMs on the candidate genes of T2DM and their further impact on various molecular pathways are scarcely defined at present. Herein, we reviewed the recent literature that presented the effects of ENMs on molecular pathways involved in the development of T2DM. We also identified the knowledge gaps and challenges in the research area, which may provide directions for future research.

The probability of exposure to NMs in humans (50, 51) increases not only during production and application of ENMs, but also due to their emergence through several natural processes.

Both natural and anthropogenic NMs enter the human body primarily through the respiratory system, skin and gastrointestinal (GI) tract, with further translocation to different tissues and organs as depicted in Figure 2 (71, 72). Considering the plethora of anthropogenic NMs, many ENMs may not be effectively removed and therefore can accumulate in different organ-systems over a period. Various cell types by which the ENMs are internalized include macrophages (73–75) endothelial cells (76), pulmonary epithelial cells (77–79), the gastrointestinal epithelium (80), blood cells (81), and neurons (82). Depending on their cellular concentration, the nanoscale particulate matter can mediate mutagenesis, damage to cell organelles, and eventually cell death.

A global spike in the production of ENM has been observed in the twenty-first century, which has enhanced the exposure rate among workers and users. At present no occupational exposure level (OEL) for ENM has been defined and the assessment of exposure to ENM is challenging. Several research groups through various experimental models have demonstrated that ENM can elicit toxic responses that may be inferred from abnormalities in various organ-systems (110–113). The extent of toxicity conferred by ENM has been reported to depend upon their physicochemical properties including size, shape, chemical nature, and surface functionalization. The cytotoxic nature of ENM could eventually lead to cell death in a dose-and time-dependent manner (114). On the other hand, some other research studies that conducted short-term experiments on cultured cells and model organisms in order to evaluate the biocompatibility of ENM (115) suggested a low level of cytotoxicity of ENM. These studies advocated a huge potential for in vivo applications of ENM in the form of therapeutic and diagnostic reagents, although the effects related to a long-term exposure remain an unexplored domain at present. The studies on the long-term effects of ENM in vivo hold significant importance in designing and development of next-generation materials, but the mechanisms underlying ENM mediated toxicity in humans are less understood (116), Particularly, whether ENM exposure leads to endocrine-disruption and influences development of T2DM among the exposed subjects remains a topic of investigation.

Contemporary in vitro, in vivo and epidemiological studies link human EDC exposure with obesity, T2DM and metabolic syndrome (47). Endocrine disruptors have a tendency to interact with the cellular receptors either by mimicking the natural hormones (Figure 3A) or by blocking the action of hormones (Figure 3B) (117).

Some studies have revealed the harmful effects of ENMs on endocrine functions, which suggests that ENMs may behave as potential endocrine disruptors, EDENMs (118–121). It is well acknowledged that endocrine disruption can often lead to the onset of metabolic disorders such as T2DM (122). Therefore, it is suggested that the ENM, which reportedly affects endocrine function, may induce T2DM. The EDENMs can behave in a similar fashion as the EDCs (13, 123, 124). The additional aspects of EDENMs over the traditional EDCs are small size, increased surface area and better uptake capability. Such properties of EDENMs enhance their chances of uptake and bioavailability, which further amplifies the deteriorating effect of the material on metabolic homeostasis (125–129) when compared to the other EDCs.

Working on similar ground as that of endocrine disruptors, ENMs may alter the normal metabolic state by affecting glucose homeostasis, leading to T2DM via the two chief mechanisms (Figure 4)—(i) decreasing insulin sensitivity and (ii) impairment of beta (β)-cells, resulting in a deleterious effect on insulin production (130–132).

Evidence suggesting a role of EDENM exposure in the pathogenesis of T2DM is gradually emerging, but a comprehensive understanding of a wide range of nanomaterials and their effect on candidate gene pathways and other causal factors involved in T2DM remain to be completely deciphered. The fact that ENM can disrupt the endocrine system, which may eventually lead to T2DM, has gathered support from several in vitro, in vivo, and epidemiological studies. Altered glucose metabolism through various molecular mechanisms including insulin resistance, decreased insulin sensitivity, induction of oxidative stress pathways, and altered homeostasis have been reported by numerous laboratory studies that examined the effect of EDENM exposures. On the other hand, a few studies also report a contrasting effect of the same EDENM on T2DM related molecules. Many research groups have come up with a safer application of ENMs by illustrating their ability to work as therapeutics. Particularly, some of the biologically synthesized ENMs (178, 179) were found to possess therapeutic potential against T2DM (180–182). Other non-metallic and metallic NMs for similar applications are also reported (Table 1).

In an interesting study, an increase in cell viability, ATP/ADP ratio and secretion of insulin in response to glucose stimuli in the isolated pancreatic islets when treated with metallic nanoparticles prepared from cerium oxide (CeO₂-NPs) at a concentration of 100 nmol/L, either alone or in combination with 30 nmol/L sodium selenite, was reported (197). These findings could possibly be ascribed to the anti-oxidant potential of CeO₂-NPs, which may exert a different effect on the insulin release. In a similar study, the effect of zinc oxide nanoparticles (ZON) on oxidative stress-mediated pancreatic β-cell death was investigated in rats (RIN5f). The cellular levels of antioxidant factors and the rate of apoptosis were assessed in correlation with ZON uptake. RIN5f cell treatment with ZON (30 and 100 μg/ml) resulted in cytotoxicity, oxidative stress and apoptosis. In contrast, the sub-cytotoxic concentrations (1, 3, 10 μg/ml) protected RIN5f cells from hydrogen peroxide (H₂O₂)-induced oxidative stress by the reducing the cellular levels of ROS, increased SOD activity and GSH, and reduced cell death (198). The findings reported in the above-mentioned studies indicated that nanomaterial-type and size dependencies on the associated cellular toxicity are not precisely explored. An incomplete characterization of ENM may underlie discrepancies observed in available scientific reports. Confusion created from such incomplete explorations demands for the development of a common understanding in the area of ENM characteristics (shape, size, surface area, mass concentration, or a combination of these), which should be a prerequisite to toxic effect determination. This broadens the scope of research to particularly define physicochemical properties of ENM for their sustainable bio-medical applications. Considering this, ENMs for vital bio-medical, pharmaceutical, agricultural, and environmental applications are required to be well characterized for their uptake to various cell/ tissue types, interaction with cellular organelles and cell mechanistic aspects within the intracellular environment (199).

Since in vitro systems do not necessarily mimic the human system, results obtained from such experiments need to be replicated through in vivo studies conducted in different model animals. Additionally, in vivo studies that address potential effects of EDENM on the development of T2DM at a large scale such as a population, a community, or an ecosystem with sufficient power are necessarily required. Further, most of the in vivo studies have been conducted on small rodents, specifically rats, mice and hamsters, which may not be optimum for studying the long-term toxic effects of nanomaterial and makes it difficult to extrapolate the observed results to humans. Experiments by including other model systems, which are more closely related to human systems, like Danio rerio, Daphnia magna, and Caenorhabditis elegans need to be conducted in more numbers. Furthermore, pre-clinical in vitro studies, such as those using blood samples from a control population, can also be conducted for impact-assessment of EDENMs (200). Additional support to the candidate mechanisms underlying EDENM mediated T2DM and identification of novel pathways can be achieved through the application of the “-omics” approach, which at present is virtually lacking. Also, developing high-throughput pre-screening (HTPS) and quantitative structure-activity relationship (QSAR) methods for in silico screening and prediction would be extremely important to comprehend the effect of EDENM (201).

We emphasize the importance of research on safety aspect of ENMs, which would minimize the uncertainties regarding the health and environmental issues surrounding these advance-materials and help in the development of safe applications of nanotechnologies.

PS was the Principal Scientist, involved in conceptualization of the review, study design, data analyses, data compilation, manuscript writing, critical inputs, and finalization of the manuscript. AP contributed toward data analyses, data compilation, manuscript writing, critical inputs, and finalization of the manuscript. SG was involved in data compilation and manuscript writing. All authors have read and approved the final manuscript.