Heavy metal associated health hazards: An interplay of oxidative stress and signal transduction

Highlights

• Redox homeostasis is a key to healthy/normal cellular function.

• Chromium, cadmium arsenic, and lead toxicity are mediated by oxidative stress.

• Heavy metal-ROS-signal transduction leads to the risk of developing diseases.

• NF-κB, NRF2, JAK-STAT, JNK and FOXO are the key partner of heavy metal-induced ROS.

Abstract

Heavy metal-induced cellular and organismal toxicity have become a major health concern in biomedical science. Indiscriminate use of heavy metals in different sectors, such as, industrial-, agricultural-, healthcare-, cosmetics-, and domestic-sectors has contaminated environment matrices and poses a severe health concern. Xenobiotics mediated effect is a ubiquitous cellular response. Oxidative stress is one such prime cellular response, which is the result of an imbalance in the redox system. Further, oxidative stress is associated with macromolecular damages and activation of several cell survival and cell death pathways. Epidemiological as well as laboratory data suggest that oxidative stress-induced cellular response following heavy metal exposure is linked with an increased risk of neoplasm, neurological disorders, diabetes, infertility, developmental disorders, renal failure, and cardiovascular disease. During the recent past, a relation among heavy metal exposure, oxidative stress, and signaling pathways have been explored to understand the heavy metal-induced toxicity. Heavy metal-induced oxidative stress and its connection with different signaling pathways are complicated; therefore, the systemic summary is essential. Herein, an effort has been made to decipher the interplay among heavy metals/metalloids (Arsenic, Chromium, Cadmium, and Lead) exposures, oxidative stress, and signal transduction, which are essential to mount the cellular and organismal response. The signaling pathways involved in this interplay include NF-κB, NRF2, JAK-STAT, JNK, FOXO, and HIF.

Introduction

The interaction between the environment and the biological system has been established as a crucial factor for organismal health. Indiscriminate uses of pesticides, dyes, heavy metals, plastics, detergents, and cosmetics for various purposes, are enough to promote ecological and biological imbalance, which could pose severe threats to human health. Metals and metalloids, generally and collectively called heavy metals, are elements with high atomic weight and five times higher densities than water. Heavy metals are naturally produced by processes such as weathering of rocks, soil erosion, forest fire, and volcanic eruption (Tchounwou et al., 2012). Besides, residing in the earth’s crust, heavy metals are present naturally in water bodies by run-off along with streams. Volcanic eruption and forest fire also add heavy metals to the air. Although heavy metals are being added to the environment through the natural processes, various anthropogenic activities increase the concentration of environmental heavy metals in large quantities (Fig. 1). This excessive increase in heavy metal concentration in environmental compartments results in the contamination of these compartments. Industries, such as metal processing, mining, smelting, foundries, coal burning, petroleum, nuclear power plants, textiles, microelectronics, plastics, wood processing, paper processing, and pharmaceuticals, add heavy metals through the waste dump, discharge as well as through smokes. Agricultural applications, such as fertilizers, pesticides, and manures mainly contaminate soil and groundwater, and domestic outputs through sewage and burning of fuel add heavy metals into the air, soil, and water (Tchounwou et al., 2012; Wang et al., 2015a). Besides being present in different environmental compartments, heavy metals are also present in the living organisms in trace quantities and play significant roles in a variety of biological processes. For example, copper (Cu) exists nearly in all the tissues and is essential for various metabolic reactions; iron (Fe) plays a vital role in oxygen transport and nucleic acid synthesis; zinc (Zn) has regulatory and structural importance. Likewise, molybdenum (Mo) acts as a cofactor for sulphite oxidase, xanthine oxidase, aldehyde oxidase, and is essential for body growth (Bhattacharya et al., 2016b). Selenium (Se), cobalt (Co), and chromium (Cr) have a role in antioxidant defence systems, synthesis of vitamin B12, and glucose metabolism, respectively (Table 1) (Anderson, 1997; Rayman, 2012; Bhattacharya et al., 2016b). Apart from having biological importance, heavy metals have several applications in different sectors, such as industrial, agricultural, healthcare, cosmetics, pharmaceuticals as well as domestic purposes (Tchounwou et al., 2012; Wang et al., 2015a).

With the increased use and widespread distribution in the environment, heavy metal toxicants pose a threat to organismal health. Accumulated pieces of evidence suggest that in the biological system, heavy metals cause toxicity through interaction with a large number of defined and undefined cellular components and processes. Heavy metal exposure causes cellular toxicity, which could be promulgated at an organismal level in terms of developmental defects, behaviour alteration, reproductive abnormalities, and reduction in life span (Hallauer et al., 2016; Zhao et al., 2017; Yang et al., 2020). However, route and pattern of exposure, accumulation, and metabolism, target and non-target organ toxicity can differ from the effects of toxicants in different organisms/systems. Several cellular pathways get activated, which try to mitigate cellular damage and maintain cellular and organismal homeostasis (Fulda et al., 2010; Hotamisligil and Davis, 2016).

During normal cellular metabolism, formation of reactive oxygen species (ROS) is a common phenomenon, which is tightly regulated by the cellular antioxidant system. Several enzymatic [Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx)], and non-enzymatic (glutathione) antioxidants are prominent to maintain redox homeostasis by controlling the generation of ROS. SOD, CAT, and GPx are the components of the first line of defence against oxidative stress. SOD is a metalloenzyme, who’s active centre is occupied by Cu and Zn, sometimes, manganese (Mn) or Fe. SOD catalyzes the dismutation of superoxide radicals into oxygen (O₂) and hydrogen peroxide (H₂O₂). CAT and GPx act on H₂O₂ to decompose it into the water (H₂O) and O₂. An imbalance between antioxidant defence and ROS in favour of the overproduction of free radicals leads to a condition of oxidative stress. Elevated oxidative stress is associated with damages to cellular macromolecules, destabilization of cellular events, such as cell division, cell cycle, immune response, and an increase in cell death (Hrycay and Bandiera, 2015; Canli et al., 2017; Habtemariam, 2019; Elzagallaai et al., 2020). Recent evidences indicate that the increased oxidative stress is one of the prime causes for the pathogenesis of several health adversities, such as cancer, diabetes, neurodegeneration, asthma, inflammation, development, and reproductive disorders (Wang et al., 2017c; Choudri and Charabi, 2019; Habtemariam, 2019). The imbalance in cellular redox homeostasis is one of the prime outcomes of heavy metal exposure and also a centre of heavy metal associated toxicity (Tchounwou et al., 2012).

The vital role of ROS in regulating the signaling pathways associated with various stress conditions has been evident. ROS could be an upstream activator or a downstream effector of different cellular signaling, which depends on the nature of stress. However, the interplay between the ROS and signaling pathway is complicated and sometimes controversial due to the multi-factorial eukaryotic system. In toxicology, the interaction between ROS and cellular signaling is a determining factor for the xenobiotic response. Depending on the condition, ROS interact with cell survival or cell death pathways at the transcriptional or translational level. Deciphering the heavy metal-induced cellular and organismal response due to the interaction between ROS and signal transduction is a centre of research since the past decade. Among the heavy metals/metalloids, Chromium (Cr), Cadmium (Cd), Arsenic (As), and Lead (Pb) are considered as priority hazards for the public health due to their presence in different environmental compartments, ubiquitous human exposure, and severe toxicity even at a low level. Direct or indirect ROS generation, reduced glutathione (GSH) depletion, and inhibition of the activity of antioxidant defence enzymes are well-known mechanisms for metal-induced toxicities (Soudani et al., 2011; Jozefczak et al., 2012; Zhang et al., 2020). The involvement of different signaling pathways in heavy metal-induced pathological processes has been documented. For example, malignant transformation of human bronchial epithelial cells was due to hedgehog signaling upon hexavalent (Cr⁶⁺) exposure to these cells (Li et al., 2020). A motor deficit in the corpus striatum of rat upon Cd exposure is associated with cAMP-dependent PKA/DARRP-32/PP1α and non-canonical β-arrestin/AKT/GSK-3β signaling (Gupta et al., 2018). Disruption of insulin signaling by As leads to diabetes mellitus (Martin et al., 2017). In this article, we focus on the interplay among heavy metal (Cr, Cd, As and Pb) exposures, ROS, and various cell signaling proteins/pathways in regulating cellular response.