Role of Endocrine-Disrupting Engineered Nanomaterials in the Pathogenesis of Type 2 Diabetes Mellitus

Abstract

Nanotechnology has enabled the development of innovative technologies and products for several industrial sectors. Their unique physicochemical and size-dependent properties make the engineered nanomaterials (ENMs) superior for devising solutions for various research and development sectors, which are otherwise unachievable by their bulk forms. However, the remarkable advantages mediated by ENMs and their applications have also raised concerns regarding their possible toxicological impacts on human health. The actual issue stems from the absence of systematic data on ENM exposure-mediated health hazards. In this direction, a comprehensive exploration on the health-related consequences, especially with respect to endocrine disruption-related metabolic disorders, is largely lacking. The reasons for the rapid increase in diabetes and obesity in the modern world remain largely unclear, and epidemiological studies indicate that the increased presence of endocrine disrupting chemicals (EDCs) in the environment may influence the incidence of metabolic diseases. Functional similarities, such as mimicking natural hormonal actions, have been observed 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. Disruption of the endocrine system leads to hormonal imbalance, which may influence the development and pathogenesis of metabolic disorders, particularly type 2 diabetes mellitus (T2DM). Evidence from many in vitro, in vivo and epidemiological studies, suggests that ENMs generally exert deleterious effects on the molecular/hormonal pathways and the organ systems involved in the pathogenesis of T2DM. However, the available data from several such studies are not congruent, especially because of discrepancies in study design, and therefore need to be carefully examined before drawing meaningful inferences. In this review, we discuss the outcomes of ENM exposure in correlation with the development of T2DM. In particular, the review focuses on the following sub-topics: (1) an overview of the sources of human exposure to NMs, (2) systems involved in the uptake of ENMs into human body, (3) endocrine disrupting engineered nanomaterials (EDENMs) and mechanisms underlying the pathogenesis of T2DM, (4) evidence of the role of EDENMs in the pathogenesis of T2DM from in vitro, in vivo and epidemiological studies, and (5) conclusions and perspectives.

Keywords: endocrine disruptor; engineered nanomaterial (ENM); epidemiological evidences; in vitro and in vivo studies; insulin resistance; oxidative stress; reduced insulin sensitivity; type 2 diabetes mellitus (T2DM).

Figure 1

A schematic describing different types of endocrine disruptors and the associated endocrine disorders.

Figure 2

A concise overview of affected organs resulting in various pathological states due to the exposure to ENMs as described in the literature (42, 70). The directly and indirectly affected systems are shown by solid and dashed lines respectively.

Figure 3

Effect of endocrine disrupting chemicals on receptor—hormone interaction. (A) Shows the blocking action of EDCs, where it binds to the receptor within the cell and blocks the endogenous hormone from binding. The normal signaling is blocked and the associated organ system (liver and pancreas) fails to respond properly. In (B), the mimicking action of EDCs is depicted. EDCs completely or partially mimic the naturally occurring hormones, thereby interfering with the obvious physiological responses.

Figure 4

Effects of ENM on the gastrointestinal system, leading to the development of T2DM.

Figure 5

Molecular pathways influenced by EDENM, leading to the development of T2DM. (EDENM, endocrine disrupting engineered nanomaterials; T2 DM, Type 2 Diabetes Mellitus; ER, estrogenic receptor; AR, androgenic receptor; PR, progesterone receptor; AhR, aryl hydrocarbon receptor; GPR30, G-protein-coupled receptor for estrogen; IRE-1, inositol-requiring enzyme 1; AKT, alpha serine/threonine kinase; CHOP, CCAAT-enhancer-binding protein homologous protein; JNK, c-Jun N-terminal kinase; GSK 3β, Glycogen synthase kinase 3 beta; IRS-1, Insulin receptor substrate 1). (The green solid arrows show the direct effect of EDENM. The green dashed arrow shows one of the major consequent events later resulting in T2DM, as further described by the blue solid arrows. Black solid arrows point toward the involvement of various receptors resulting in endocrine system disorders. Purple solid arrows infer the T2DM occurrence via various pathways).

Figure 6

Effect of EDENM on various immune cells resulting in enhancement of expression of various pro-inflammatory cytokines (Interleukins, IL-1β, IL-6; TNF-α, Tumor Necrosis Factor-α), immunoglobulin superfamily members—B7/CD28 and chemokines (MCP-1, Monocyte chemoattractant protein-1).