Association between Heavy Metals, Metalloids and Metabolic Syndrome: New Insights and Approaches

Abstract

Metabolic syndrome (MetS) is an important public health issue that affects millions of people around the world and is growing to pandemic-like proportions. This syndrome is defined by the World Health Organization (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Moreover, the etiology of MetS is multifactorial, involving many environmental factors, including toxicant exposures. Several studies have associated MetS with heavy metals exposure, which is the focus of this review. Environmental and/or occupational exposure to heavy metals are a major risk, contributing to the development of chronic diseases. Of particular note, toxic metals such as mercury, lead, and cadmium may contribute to the development of MetS by altering oxidative stress, IL-6 signaling, apoptosis, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, and other mechanisms. In this review, we discuss the known and potential roles of heavy metals in MetS etiology as well as potential targeted pathways that are associated with MetS. Furthermore, we describe how new approaches involving proteomic and transcriptome analysis, as well as bioinformatic tools, may help bring about an understanding of the involvement of heavy metals and metalloids in MetS.

Keywords: arsenic; cadmium; diabetes; hypertension; lead; mercury; obesity.

Figure 1

Molecular mechanisms involved in atherogenic effects of Cd exposure. Cd-induced ROS overproduction promotes LDL oxidation and oxLDL internalization by macrophages, resulting in foam cell formation. LDL oxidation is also aggravated by Cd-induced PON1 inhibition. Up-regulated expression of adhesion molecules including ICAM1 and VCAM1 following Cd exposure increases monocyte adhesion and infiltration with their subsequent transformation to foam cells. Proinflammatory effect of Cd also contributes to atherogenesis through promotion of TMAO-induced NF-κB and subsequent NLRP3 inflammasome activation, as well as JAK2/STAT3-dependent M1 macrophage (Mφ) polarization. Finally, Cd-induced alterations of gut microbiota composition along with increased gut wall permeability results in an increase in circulating LPS levels, also promoting proinflammatory signaling. Different colors (pink, grey, blue, yellow) are indicative of distinct pathways for better visualization. Red and blue arrows show the increase and decrease effects.

Figure 2

Molecular mechanisms involved in atherogenic effects of Cd exposure. Cd-induced ROS overproduction promotes LDL oxidation and oxLDL internalization by macrophages, resulting in foam cell formation. LDL oxidation is also aggravated by Cd-induced PON1 inhibition. Up-regulated expression of adhesion molecules including ICAM1 and VCAM1 following Cd exposure increases monocyte adhesion and infiltration, with their subsequent transformation to foam cells. Proinflammatory effect of Cd also contributes to atherogenesis through promotion of TMAO-induced NF-κB and subsequent NLRP3 inflammasome activation, as well as JAK2/STAT3-dependent M1 macrophage (Mφ) polarization. Finally, Cd-induced alterations of gut microbiota composition along with increased gut wall permeability results in an increase in circulating LPS levels, also promoting proinflammatory signaling. Different colors (pink, grey, blue, yellow) are indicative of distinct pathways for better visualization. Red and blue arrows show the increase and decrease effects.

Figure 3

Molecular mechanisms underlying hyperglycemic effects of As exposure. As exposure was shown to induce β-cell dysfunction and death through ferroptosis, resulting in reduced insulin production. Alteration of IR/IRS/PI3K/Akt signaling pathway upon As exposure was shown to inhibit insulin signaling, thus resulting in insulin resistance. As-induced ROS overproduction was also shown to promote NF-κB and MAPK activation with subsequent NLRP3 inflammasome activation and gasdermin D-dependent pyroptosis that is considered as a potential player in the development of both insulin resistance and insulin deficiency. Activation of endoplasmic reticulum (ER) stress upon As exposure also promote inflammasome activation. In addition, recent findings demonstrated that that As-induced β-cell dysfunction may be mediated by up-regulation of miR-29a, miR-146, and miR-209 expression. The effects of the latter are at least partially associated with inhibition of transcriptional factor PDX1 expression. In addition, metalloid-induced miR-191 up-regulation significantly contributes to inhibition of IRS1/PI3K/Akt pathway. Different colors (pink, grey, blue, yellow) are indicative of distinct pathways for better visualization. Red and blue arrows show the increase and decrease effects.

Figure 4

The potential mechanisms (yellow) and targets (orange) of the role of toxic metals in metabolic syndrome and its components (red). Toxic metal exposure results in induction of oxidative and endoplasmic reticulum stress, inflammation, apoptosis, as well as ferroptosis, pyroptosis, impaired autophagy, and epigenetic effects in target tissues. These mechanisms were shown to underlie the impact of heavy metal toxicity on adipogenesis, β-cell functioning, insulin signaling, appetite regulation, carbohydrate and lipid metabolism, atherogenesis, endothelial dysfunction, vascular reactivity, and gut microbiota.