Mitigation of Cadmium Toxicity: History
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Contributor:
Soisungwan Satarug
,
David A. Vesey
,
Glenda C. Gobe

Cadmium (Cd) is an environmental toxicant of public health significance worldwide. Diet is the main Cd exposure source in the non-occupationally exposed and non-smoking populations. Metal transporters for iron (Fe), zinc (Zn), calcium (Ca), and manganese (Mn) are involved in the assimilation and distribution of Cd to cells throughout the body. Due to an extremely slow elimination rate, most Cd is retained by cells, where it exerts toxicity through its interaction with sulfur-containing ligands, notably the thiol (-SH) functional group of cysteine, glutathione, and many Zn-dependent enzymes and transcription factors. The simultaneous induction of heme oxygenase-1 and the metal-binding protein metallothionein by Cd adversely affected the cellular redox state and caused the dysregulation of Fe, Zn, and copper. Experimental data indicate that Cd causes mitochondrial dysfunction via disrupting the metal homeostasis of this organelle. 

  • bilirubin
  • cadmium
  • carbon monoxide
  • glycoly

1. Introduction

The utility of a redox inert metal cadmium (Cd) in many industrial processes, and the use of phosphate fertilizers contaminated with Cd by the agricultural sector have resulted in widespread dispersion of this toxic metal in the environment and subsequently the food chains [1][2][3][4][5]. Volcanic emissions, biomass and fossil fuel combustion, and cigarette smoke are additional sources of environmental Cd pollution [6][7][8][9][10]. Cd in cigarette smoke as a volatile metallic form and oxide (CdO) has a particularly high transmission rate [10][11]. An existence of the nose-to-brain transport route of toxic metals raises the possibility that airborne Cd may enter the central nervous system (CNS) by utilizing a Cd-altered blood–brain barrier [12][13][14].
Foods that are frequently consumed in large quantities, such as rice, potatoes, wheat, leafy salad vegetables, and other cereal crops, form the most significant dietary sources of Cd [15][16][17]. Seafood (shellfish), mollusks, and crustaceans are additional dietary Cd sources [18][19]. Cd enters the body from the gut and lungs via the metal transporters and pathways for zinc (Zn), calcium (Ca), iron (Fe), manganese (Mn), and possibly selenium (Se) [17]. Because of an extremely slow excretion rate, most absorbed Cd is retained in cells, and the cellular content of Cd increases with the duration of exposure (age) [17].
Evidence from epidemiologic and experimental studies suggest that low environmental exposure to Cd may increase the risk of diseases with high prevalence, such as chronic kidney disease (CKD), liver disease, type 2 diabetes, and neurodegenerative disorders [15][16][17][20]. Developing strategies to prevent these chronic ailments is of global importance in the absence of effective chelation therapies to reduce the Cd body burden.

2. Manifestation of Cadmium Toxicity

Population-based studies in many countries and the U.S. general population study known as National Health and Nutrition Examination Survey (NHANES) suggest adverse effects of chronic exposure to Cd extend beyond kidneys and bones.
The hepatoxicity of Cd was seen in both children and adults [21][22][23]. In adults, increases in risk of liver inflammation, NAFLD, and NASH were associated with urinary Cd levels ≥ 0.6 µg/g creatinine [21]. In children, hepatotoxicity of Cd was more pronounced in boys than girls [23]. In NHANES cycles undertaken between 1999 and 2016, reduced eGFR and albuminuria were consistently associated with Cd exposure measures [24][25][26][27][28].

2.1. Cadmium and the Risk of Type 2 Diabetes

Prediabetes and diabetes are defined as fasting plasma glucose ≥ 110 mg/dL and 126 mg/dL, respectively. The number of people with prediabetes and diabetes have reached epidemic proportions globally. The epidemic is attributed to the increasing prevalence of obesity, leading to a search for environmental obesogenic substances. In comparison, a statistically significant inverse association has consistently been observed between Cd exposure and body mass index and other measures of adiposity (Section 3.2). Dietary exposure to Cd is consequently the least expected and least recognized environmental risk factor for diabetes.
Increases in the risks of prediabetes and diabetes among NHANES 1988–1994 participants were associated with urinary Cd levels of 1–2 µg/g creatinine [29]. An increased risk of prediabetes among NHANES 2005–2010 was associated with urinary Cd levels ≥ 0.7 µg/g creatinine after adjustment for covariates [30]. In a risk analysis, the prevalence of type 2 diabetes was likely to be smaller than 5% and 10% at urinary Cd levels of 0.198 and 0.365 μg/g creatinine, respectively [31].
In the Wuhan-Zhuhai prospective cohort study [32], fasting blood glucose levels were found to increase with urinary Cd over a three-year observation period. For each 10-fold increase in urinary Cd, the prevalence of prediabetes rose by 42%. Dose–response relationships between Cd exposure and risks of prediabetes and diabetes were observed in two meta-analyses, [33][34]. In a risk analysis of pooled data from 42 studies, the risks of prediabetes and diabetes increased linearly with blood and urinary Cd; prediabetes risk reached a plateau at urinary Cd of 2 µg/g creatinine, and diabetes risk rose as blood Cd reached 1 µg/L [34].

2.2. An Inverse Relationship between Cadmium Body Burden and Obesity

The relationships between Cd exposure levels and disease shown by associative studies have often been ignored. However, it is important to recognize such associations as they may indicate mechanisms of disease pathogenesis. Thus, reports of an inverse relationship between Cd body burden and obesity provide developmental data that may lead to future significant correlations that define disease pathogenesis and aid in therapy development. Herein researchers report such associative studies that replicate an association observed between Cd and reduced risk of obesity. These data can be interpreted to suggest that Cd may have caused the dysregulation of the cellular intermediary metabolism and that type 2 diabetes associated with Cd is independent of obesity.
Urinary Cd levels were inversely associated with central obesity among participants of NHANES 1999–2002 [35]. Among NHANES 2003–2010 participants, their blood Cd levels were inversely associated with body mass index (BMI) [36]. In another analysis of data from NHANES 2001–2014, participants aged 20–80 years (n = 3982), with urinary Cd levels were not associated with the risk of metabolic syndrome, but they were associated with a decreased risk of abdominal obesity [37]. In a meta-analysis of data from 11 cross-sectional studies, Cd exposure was not associated with an increased risk of metabolic syndrome, but it was associated with dyslipidemia, especially in the Asian population [38].
Urinary Cd was associated with a reduction in risk of obesity by 54% in children and adolescents enrolled in NHANES 1999–2011; an inverse association between urinary Cd and obesity was stronger in the younger age group (6–12 years) than the older age group (13–19 years) [39]. Urinary Cd levels were inversely associated with height and BMI in Flemish children, aged 14–15 years [40].
Similarly, an inverse association between blood Cd and BMI was seen in non-smokers in the Canadian Health Survey 2007–2011 [41]. A negative association between Cd exposure and various measures of obesity were seen in both men and women in a study of the indigenous population of northern Québec, Canada, where obesity was highly prevalent [42].
An inverse association between blood Cd and BMI was noted in a group of Korean men, 40–70 years of age [43]. This Korean population study observed an inverse correlation between fasting blood glucose and urinary Cd excretion levels, and a 1.81-fold increase in risk of diabetes among men who had urinary Cd > 2 μg/g creatinine.
In a Chinese study, urinary Cd excretion rates ≥ 2.95 µg/g creatinine were associated with reduced risk of excessive weight gain and reduced risk of obesity [44]. Higher urinary Cd levels were associated with lower BMI values in a study of residents of Shanghai without workplace exposure to Cd, showing the median urinary Cd excretion of 0.77 μg/g creatinine [45].
Of interest, lower BMI figures were associated with higher Cd accumulation levels in fat tissues in a cohort study in Spain [46]. Furthermore, an increased resistance to insulin and higher plasma insulin levels were seen in smokers whose adipose tissue Cd levels were in the middle tertile, compared to those with adipose tissue Cd levels in the lowest tertile 1 [47].

2.3. Cadmium-Induced Oxidative Stresss and Inflammation

The aforementioned statistically significant inverse relationship between Cd body burden and obesity suggests that an effect of Cd on the risk of diabetes is independent of adiposity and inflammation, accompanying excessive body fats. Indeed, there is evidence that Cd may cause inflammation in adipose tissues in a Swiss autopsy study, Cd accumulation in omentum visceral and abdominal subcutaneous fat tissues were quantified [48]. In an in vitro study using the adipose-derived human mesenchymal stem cells (FC-0034), Cd in the same range found in those postmortem fat tissue samples was found to disrupt cellular Zn homeostasis and to cause an increase in the expression of various pro-inflammatory cytokines [48]. Studies in mice showed that Cd caused the abnormal differentiation of adipocytes, resulting in small adipocytes and a reduction in the secretion of adiponectin [49][50].

3. Mitigation of the Cytotoxicity of Cadmium

Owing to its high toxicity and cumulative potential, minimizing the Cd contamination of the food chains and reducing Cd levels in food crops to the lowest achievable levels are essentially preventive public measures. Here, researchers discuss the frontline cellular stress response that may be a complementary measure to mitigate harmful effects of inevitable exposure to such a toxicant as Cd.

3.1. Heme Oxygenase-1 and Heme Oxygenase-2 (HO-1, HO-2)

HO-1 and HO-2 are enzymes involved in the degradation of heme to retrieve Fe for reuse by cells and to generate cytoprotective molecules, carbon monoxide (CO) and biliverdin IXα from which bilirubin is rapidly generated [51][52][53]. The economy of Fe utilization requires the salvaging of Fe, so the bulk of Fe released by the action of HO-1 and HO-2 is reutilized in the synthesis of hemoproteins, such as nitric oxide synthase, various enzymes of the mitochondrial respiratory chain, and the cytochrome P450 super family [54]. In every nucleated cell of the body, heme degradation and de novo biosynthesis of heme are indispensable and simultaneous induction of MT and HO-1 occurs in most nucleated cells of the body in response to Cd exposure [51][52][55][56].

3.2. Products of the Physiologic Heme Degrdation

3.2.1. Bilirubin

Serum bilirubin, a product of normal heme degradation and the catalytic activity of biliverdin XI-α reductase, contributes mostly to the total antioxidant capacity of blood plasma [57][58][59]. Due to its lipophilic properties, bilirubin is a lipid peroxidation chain breaker that protects lipids from oxidation more effectively than the water-soluble antioxidants, such as glutathione [58][59]. The ability of bilirubin to inhibit the oxidation of low-density lipoprotein accounts for the association observed between higher total serum bilirubin levels and lower risks of metabolic syndrome and non-alcoholic liver disease [60]. Of note, recent experimental data show that Cd-activated HO-1 gene and heme degradation did not result in formation of bilirubin [61].

3.2.2. Carbon Monoxide

Synthetic carbon monoxide-releasing molecules (CORM) were used to study effects of CO on mitochondrial biogenesis [62][63][64]. In high doses, CO has anti-inflammatory, anti-apoptotic, and vasodilatory effects and is cardioprotective. In low levels achievable through induction of HO-1 expression, CO increases the generation of reactive oxygen species (ROS) by the mitochondria, presumably through the inactivation of cytochrome C oxidase (COX) [62]. The elevated ROS then activates the PI3K/AKT signaling pathway, causing the inhibition of glycogen synthase kinase 3 β (GSK3β) and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) [65]. CO, p62, and NAD(P)H dehydrogenase quinone 1 (NQO1) are all required for the biogenesis of mitochondria and the removal of mitochondria with severe damage [65][66]. Mitochondrial ROS production is a mechanism that cells use to increase their capacity to adapt to stress [67][68]. Thus, HO-1 induction represents an important cellular stress response mechanism. The repression of this stress response gene is equally important to sustain the cellular redox state.

3.3. Role of HO-1, HO-2, and PFKFB4 in the Homeostasis of Blood Glucose

HO-1 and HO-2 are products of two different genes [69]. The promoter of the human HO-1 gene is unique because it contains the GT repeats, not found in rodent or murine species [51][52][53]. The genetic polymorphisms, such as long GT repeats, are associated with an elevated risk for various diseases, type 2 diabetes included [70][71].
Cellular expression of HO-1 is regulated by the transcription factor, including CLOCK, Bmal, and Per, that work together to generate day–night cyclical expression of the genes involved in energy metabolism [72][73][74][75]. Disruption of the diurnal cycle caused obesity in mice [76]. Expression of the HO-1 gene is controlled also by heme (its own substrate), the levels of glucose, oxygen, and shear stress [51][52][77][78].
The catalytic domains of HO-1 and HO-2 are highly homologous, sharing 93% of their amino acid sequences. HO-2, however, contains an additional domain, which has Cys-Pro dipeptide motifs that allows binding of heme and interacting with other proteins that include Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways [79][80][81].
In addition to heme degradation activity, HO-2 has a regulatory role that was unraveled from obese and diabetic mice lacking HO-2 expression. HO-2 deficiency in mice caused neither lethality nor infertility, and HO-2 deficient mice underwent normal development to adulthood when they display the symptomatic spectrum of human type-2 diabetes, hyperglycemia, increased fat deposition, insulin resistance, and hypertension with aging [82][83][84]. The normal development and normal fecundity in the absence of HO-2 expression suggested that HO-1 could compensate for the heme-degradation activity of HO-2. However, HO-1 did not compensate for the anti-diabetogenicity and anti-obesity of HO-2.
In a protein microarray study, HO-2 was linked to the glycolytic pathway through its interaction with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) [85]. In liver, PFKFB4 is the key regulator of glycolysis [86], and a lack of HO-2 expression causes persistent hyperglycemia due to an impaired ability to suppress glucose production. Cd may mimic this effect of HO-2 deficiency, thereby causing hyperglycemia. Both HO-1 and HO-2 are required to prevent a fall of blood glucose during fasting or a rise in blood glucose in a post-absorptive period. HO-2 expression ensures PFKFB4 expression.
In the liver of wild-type mice, lowered glycolysis with enhanced gluconeogenesis could be achieved in fasting state by HO-1 up-regulation plus PFKFB4 down-regulation. In the post-absorptive state, high glycolysis with suppressed gluconeogenesis could be achieved by HO-1 down-regulation plus HO-2 and PFKFB4 up-regulation. HO-1 protein expression levels in the liver of HO-2 knockout mice fell by 35–40% [87]. A possible consequence of a reduction in expression levels of HO-1 is increased susceptibility to oxidative damage. However, such repression of the HO-1 gene expression is an essential metabolic adaptation to safeguard the cellular redox state. This is achieved by utilizing NADPH (H+) for regenerating reduced glutathione (GSH) rather than for heme catabolism [85]. GSH recycling is a mechanism for maintaining cellular redox state. It is central to normal protein folding and cell function.

3.4. Exogenous HO-1 Inducers

Several therapeutic drugs, such as statins (lipid lowering agents), rosiglitazone (anti-diabetic drug), aspirin (anti-inflammatory drug), paclitaxel and rapamycin (anti-cancer drugs), have been shown to induce HO-1 expression. The therapeutic efficacy of these drugs may be attributable, at least in part, to HO-1 induction [59][60].
A wide range of antioxidants from plant foods, such as curcumin, quercetin, tert-butylhydroquinone, and caffeic acid phenethyl ester, are HO-1 inducers, as are catechin (in green tea), α-lipoic acid (in broccoli, spinach), resveratrol (in red wine, grapes), carnosol, sulforaphane (cruciferous vegetable), coffee diterpenes cafestol, and kahweol [81][82][83][88][89][90]. Beneficial effects of consumption of these antioxidants could thus be mediated in part through the induction of HO-1 expression.
Diet high in anti-oxidative and anti-inflammatory nutrients was associated with increased serum bilirubin levels and reduced oxidative stress and systemic inflammation [91]. Green tea consumed in usual amounts was found to increase HO-1 expression [92][93][94]. One of the trials included only non-smoking diabetic subjects who had no history of metabolic complications and did not take regular food supplements [93]. Among 43 subjects, 23 had the long GT repeats (GT repeats ≥ 25; L/L genotype) type of the HO-1 promoter and another 20 had short GT repeats (GT repeats < 25; S/S genotype). According to Western blotting and the comet assay, HO-1 protein levels in circulating lymphocytes were increased by 40%, while the level of the DNA repair enzyme 8-oxoguanine glycosylase (hOGG1) was increased 50% with DNA damage being reduced by 15%. Green tea consumption increased HO-1 protein levels in lymphocytes in both L/L and S/S genotype groups, although the S/S group showed higher HO-1 protein levels at baseline, compared to the L/L group. This trial showed that green tea consumption may reduce cellular DNA damage through induced expression of HO-1.

This entry is adapted from the peer-reviewed paper 10.3390/stresses2030025

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