Zinc:
When evaluating the importance of Zn in the context of cancer, a stimulatory function of this metal for the formation of metallothionein (MTs) is evident. MTs protect cells against oxidative stress, overexpressing themselves in conditions with an increased risk of ROS formation, such as cell proliferation or embryonic development (16).
In most cases, decreased levels of this metal are associated with the development of tumors, i.e., it acts as an antitumor factor (16). Reduced serum Zn levels have been identified in patients suffering from various neoplastic diseases, including head and neck tumors and cancers of the breast, prostate, liver, and lung.
Prostate cancer and its relationship with Zn has been highly studied, the glandular epithelial cells of this gland have the unique ability to accumulate elevated levels of Zn, these levels block the enzyme aconitase, thus accumulating citrate, which is necessary for the formation of prostatic fluid and MT (16, 17). Since the Kreb´s cycle is blocked, there is less energy, slowing down the cell cycle, and thus it is considered to have antiproliferative functions. The ability of prostate cells to accumulate Zn is due to the expression and activity of the zinc uptake transporter, ZIP1, malignant prostate cells show a silencing of ZIP1 gene expression. (15, 16). It is noteworthy that in the context of the central nervous system (CNS), increased Zn levels in the adult population have been associated with malignant gliomas (18).
Cadmium:
Cd does not have an essential function for human biology as other metals such as Cu or Ni and has an approximate half-life of 10 years. Its use resides primarily in the industry as fabrication alloys, plastics, pigments, and rechargeable batteries. Cd fumes, leaking sewage to crops and cigarettes are the main exposure mechanisms for human beings. Cd has various toxic effects including bone damage by trabecular bone loss and lowering of osteocytes which causes osteoporosis. This was studied and described when inhabitants of the Jinzu river in Japan suffered Cd poisoning naming it as the “Itai-Itai” disease which roughly translates to “it hurts” causing osteomalacia on the population. Cd is also involved in renal toxicity as it damages the glomerulus.
Further insight on Cadmium physiopathology, literature reports the binding and inhibiting of enzymes such as superoxide dismutase, MT, and other antioxidant enzymes, which leads to the accumulation of ROS, causing oxidative stress, DNA and cellular damage and carcinogenesis. Cd has also been reported to cause DNA deletions and mutations directly altering the equilibrium between oncogenes and tumor suppressor genes further leading to cancer. Acute poisoning can be treated with activated charcoal and intestinal wash. Chelation is being studied as a treatment measure but for chronic poisoning it is not recommended (19, 20)
Lead:
Pb has been found naturally in the environment in low concentrations mostly as lead sulfate, yet it has been increasing due to human activity. It has been used in multiple products such as petroleum, pipes, canned food, even in plumbing and tableware since the time of the Roman Empire, and since industrialization it has been on the rise due to human activity with increasing levels since the 20th century thus leading countries have sought strategies to decrease human exposure to Pb. (21)
As for the influence of Pb in cancer, multiple mechanisms have been evidenced. Among them are: base substitutions at G-C sites, deletions similar to ROS-induced DNA damage (Pb increases ROS through mechanisms such as increased heme precursor ALA which in combination with Pb inhibits the enzyme ALAD resulting in increased free radicals and DNA damage), glutathione depletion, ability of Pb to undergo Fenton-type reactions in the presence of hydrogen peroxide causing DNA strand breaks, PKC activation which initiates a signaling pathway leading to regulation of immediate early response genes resulting in a proliferative response, inhibiting nucleotide excision repair and increases the mutagenicity of polycyclic aromatic hydrocarbons and UV rays causing DNA lesions.
Pb is associated with aneuploidy, chromosomal aberrations, micronuclei, sister chromatid exchange and DNA damage. Specifically, Pb has been associated with lung cancer, stomach cancer, renal cancer, and brain and nervous system tumors. However, the IARC (International agency for research on cancer) states that Inorganic lead compounds are potentially carcinogenic to humans and Organic lead compounds are not classifiable as to their carcinogenicity to humans. This relates to limited evidence on the carcinogenicity of inorganic lead to humans and inadequate evidence for organic lead (22)
Nickel:
Nickel (Ni) exposure has increased recently due to over exposure caused by increased industrial processes, the term “bioaccumulation” has been used to emphasize the accumulation of this substance in the human body.
The mechanisms in which Ni exposure at high concentrations results in oncogenesis (especially in lung and breast cancer) is clearer by the day and multiple patho-physiological pathways have been established. Firstly, Ni has been described as a Metalloestrogens, a heavy metal that mimics estrogen in the human body. The precise mechanism is still unclear (23), this directly impacts estrogen related tumors such as the ones previously mentioned. Ni binds to the ligand binging domain of the alpha estrogen receptor (ERα) by interacting with amino acids C381 and C477 activating it (24). Additionally, Ni has been proven to play a key role in chromatin remodeling by altering acetylation, methylation and ubiquitination of histone proteins which results in transcription defects of proteins and gene repression (25–33).
Besides the direct role that plays as a metalloestrogen there is evidence to believe that Ni leads to direct DNA damage by inducing hyper condensation of chromatin and forming heterochromatin formation in specific DNA parts which are critical for correct transduction and translation such as tumor repression genes, thus leading to carcinogenesis (34). p53 and p16, key cell cycle regulators, have been proven to be altered and silenced when elevated serum levels of Ni have been found, especially in tumor cells in the breast.
Lastly, as it was proven by Seoane et al. and Epe et al, Ni salts such as NiCl2 and NiSO4 have carcinogenic potential due to the peroxidative estrogen pathways leading that directly interact with tubulin proteins that end up interfering with the microtubule assembly, affecting the spindle fiber formation and therefore, resulting in increased aneuploidy risk (35, 36).
Chromium:
Cr was discovered in 1798 by French chemists and was named for the colors that this material and it´s compounds produce. In its natural form, it is a hard, white, glossy, and brittle metal that has a high melting point (36). Cr can be oxidized into two stable states: hexavalent Chromium (Cr (VI)), its most dangerous and toxic form, and trivalent Cr. Currently Cr has many uses, such as: antirusting agent in water cooling, plating, leather tanning, plays a fundamental role in the production of textiles, dyes, and pigments, and it is also used in the metallurgical industry because of its high heat resistance (37, 38).
At its molecular level, Cr (VI) exists as an oxyanion at physiological levels, it is taken into the cells through an anionic transport system and is then reduced intracellularly by reductants such as ascorbic acid, glutathione and cystine, to trivalent chromium (Cr (III), allowing it to accumulate intracellularly (39). Higher levels of reducing agents will increase the intake of Cr (VI), enhancing its toxic effect in the cells (40, 41). Cr (III) then reacts with intracellular macromolecules, forming ternary complexes with DNA and an intracellular reducer, generating Cr DNA adducts in consequence, which have the potential to be mutagenic via altering DNA sequences during the cell transformation process, leading to a p53 inhibition signal in the cell cycle checkpoint, thus generating apoptotic death (42). Cr (III) also reacts with other cellular components as proteins, producing cytotoxic effects in cells leading to its death (42). On the other hand, Cr (VI) has apoptotic effects secondary to p53 activation, and its reduction to trivalent Cr leads to production of oxygen radicals, activating pathways which inhibit apoptosis (PI3K and AKT) (41).
The first case report of cancer in association with exposure to Chromium was reported in 1890, a 47-year-old worker exposed to chrome pigment developed adenocarcinoma of the left turbinate body (43). Because of Cr wide range of applications, numerous populations have been exposed to it, potentially developing neoplastic diseases (41). Currently, stainless steel welding and Cr pigments manipulation are the most common sources of exposure (45). Cr carcinogenic effect has been associated with lung cancer; in a prospective cohort study published by Gibbs, et al., it was determined that cumulative exposure to hexavalent Cr had a strong dose-effect relationship with lung cancer, while trivalent exposure to Cr was not (46).
In the systematic review published by Seidler et al. aimed to investigate the exposure risk of Cr (VI) and its relationship with lung cancer to determine exposure limits, five studies of two cohorts of Cr production workers from across the United States were followed. The absolute excess risk was found to be acceptable with a Cr (VI) concentration of 0.1 µg/m3, while a concentration higher than 1 µg/m3 was deemed “intolerable” (47). Cr has also been identified in drinking water and related to incidence of gastrointestinal neoplastic lesions (43). In the meta-analysis published by Welling et. al. (48), individual relative risk estimates on stomach cancer and Cr (VI) exposure were identified, with a summary RR of all studies was 1.27 (95% CI: 1.18–1.38) (47, 48). An analysis based on studies that identified the relationship between Cr (VI) exposure and lung cancer was also performed, they concluded that Cr (IV) had a stronger link with stomach cancer in contrast with lung cancer (RR 1.41 (95% CI 1.18–1.69) (48).
Mercury:
The Hg is not a heavy metal needed for regular physiological functioning. Human Hg exposure comes chemically via inorganic (Elemental, mercurous, mercuric) or organic (methyl, ethyl, phenyl, etc.) presentation. Inorganic exposure comes primarily from vaporization of dental amalgams, coal burning or mining. Organic Hg comes primarily from sea food ingestion. Scaling up the food chain, bigger predators consume and concentrate larger quantities of Hg to finally being ingested by humans. The Hg has an affinity for sulfhydryl or thiol functional organic chemistry groups, disrupting tertiary protein structure via disulfide bonds. Hg poisoning can affect any cell inside the human body, but it has a high affinity for the nervous system (49, 50).
The Hg has various proposed mechanisms for carcinogenesis. It has been proposed that Hg causes inhibition of the Glutathione peroxidase and Thioredoxin reductase which mediate ROS neutralization, lacking this mechanism leads to indirect DNA damage. High concentrations of Hg also inhibit Gap Junction Intercellular Communications (GJIC), which mediate adjacent cellular communication and homeostasis. Furthermore, Hg has been shown to diminish immune cytokines and interleukins, having immunosuppressive properties. The prior mechanisms have also been documented to produce epigenetic modifications detrimental to normal cellular homeostasis leading to carcinogenesis (51). Chelating Hg with dimercaprol is the treatment of choice, and the prognosis depends on its concentration.
Arsenic:
As compounds are pharmacokinetics depending on As. forms whereas soluble forms are satisfactorily absorbed in the respiratory tract and gastrointestinal tract in the form of organic and inorganic As. Much of the inorganic forms that are absorbed undergoes a methylation phase in the liver leading to the formation of monomethylarsonic which is further methylated enzymatically into dimethylarsinic acids, these are then excreted in the urine together with the rest of residues of inorganic As, 66% of the absorbed amount is excreted in the urine within two to three days (52). Several steps happen for the adequate As. excretion, process in which S-adenosylmethionine (SAM) enzyme action is fundamental, a universal donor of methyl groups which methylates As. thus facilitating its excretion (53).
Circulating As binds to sulfhydryl groups present in keratinized tissue and after cessation of exposure, hair, nails, and skin, where they present the characteristic white lines of discoloration across the nails, called Mees lines (52). As. compounds are present in the body in an inorganic trivalent (As. III) and inorganic pentavalent (As. V) form. As. III is 2–10 times more toxic due to its binding to thiol or sulfhydryl groups on proteins which can inactivate over 200 enzymes, on the other hand, As. V main toxicity is due to its capability to replace phosphate (54).
Carcinogenesis pathway of As. are still uncertain, but multiple mechanisms have been identified, being the most important oxidative stress as well as chromosomal abnormalities, altered DNA repair, epigenetic alterations, hyper and hypomethylation pathways, alteration in growth factors, cell proliferation factors, and suppression of tumor suppressor genes (54).
Oxidative stress comes specially from As. methylated form, which induces ROS production in spleen and liver which accumulates in various tissues, leading to cell death via abnormal gene expression and lesions of cellular components, causing cell apoptosis (55). Radical oxygen species production is caused by the mitochondrial inhibition of oxidative phosphorylation, inhibiting oxidation of pyruvate and beta-oxidation of fatty acids (54).
Intracellularly, arsenate (pentavalent inorganic arsenic) competes with inorganic phosphate, which instead of going into oxidative phosphorylation, induces an earlier reaction to give 1-arsenium-3-phosphoglycerate, which spontaneously hydrolyzes to 3-phosphoglycerate without forming ATP, leading to the formation of radical oxygen species (56). These oxygen species cause Fenton-type reactions and depletion of cell antioxidants like glutathione, which break the normal cell redox state causing formation of peroxides and free radicals that damage all cell components including proteins, lipids, and DNA (53). The persistent damage causes oxidative stress with over activation of apoptotic mechanism. This chronic cell-death ends up in a desensitization process of apoptosis, making cells more resistant to these mechanisms, allowing cancer cells to persist.
Mutation induction pathways inhibit DNA repair and cause chromosomal aberrations, leading to chromosome instability due to breaks in DNA chains that cause impairment of production of DNA repairing proteins (53). Arsenic clastogenic effect induces chromosome disruption, leading to sections of chromosomes being deleted (54). This pathological pathway correlates with other significant carcinogenic mechanisms, such as epigenetic alterations in which DNA alterations happen because of hindering chromatin accessibility cell cycle regulators that affect gene transcription and splicing of pre-mRNA leading to the formation of anomalous proteins (57). These changes happen secondary to Arsenics capability to make modifications in non-coding RNAs, RNA molecules that do not translate into proteins and play a key role in DNA sequencing of RNA genes such as microRNA, a regulator of protein synthesis of mRNA, Piwi-interacting RNA, involved in the epigenetic and post-transcriptional silencing of gene expression involved in tumor formation and carcinogenesis (53).
Arsenic mediated epigenetic changes also induce DNA hyper-and hypomethylation, promote changes in gene coding, expression and silencing of specific genes during cellular differentiation. In the As. excretion process, causes depletion of S-adenosylmethionine enzymes because of its use on the metalation processes of arsenic species which reduces the amount of available methyl group donors, this happens when As. levels reach higher than 500 ug/L (53). This enzyme depletion leads to hypomethylation of gene region inducing aberrant gene expression, and tumor formation (54). On the other side, As. induced hypermethylation, after its exposure causes silencing of P53 causing decreased expression of p21 and P16, tumor suppressor genes (58). Gene methylation also induces interspersed nuclear elements-1 (LINE-1) and histone modification, which activate histone kinases pathways such as the nuclear mitogen and stress-activated protein kinase 1 (MSK1), that activate c-fos and c-jun, proto-oncogenes that form AP-1 transcription factor linked to carcinogenesis (58)
Table 2
summarizes for each individual heavy metal source of exposure and concatenates with the most common cancers reported and other diseases.
Reference | Heavy Metal | Source of exposure | Specific Cancer | Other Diseases related with exposure |
Lelièvre P. et al. Shanbhag VC. Et al. (14–15) | Copper | Contaminated food and water sources | Bladder, Colorectal, Breast | Cardiomyopathy, Diabetes |
Franklin RB, et al. Ho E, et al. Hrabeta J, et al. (16–18) | Zinc | Contaminated water | Decreased levels: head and neck tumors and cancers of the breast, prostate, liver, and lung. Increased levels: Medulloblastoma, malignant gliomas. | Acute respiratory illnes |
Koons AL. Et al. Rafati Rahimzadeh M. et al. (19–20) | Cadmium | Rechargeable batteries, cigarettes, indirect crop poisoning | Lung, prostate, and renal cancer | Osteomalacia, Kidney damage, cardiovascular disease |
Asenjo S. Et al. International agency for research on cancer. (21–22) | Lead | Mining, smelting, glass manufacturing, welding, battery fabrication | Lung, brain and nervous system, stomach, renal | Nephropathy, anemia, cardiovascular dysfunction, impaired bone, and tooth development, disturbed calcium metabolism |
Kasprzak KS. El al. Epe B. El al.(34–36) | Nickel | Inhalation as a product of mining, contact exposure, smelting of metals | Lung, Breast | Contact dermatitis, Cardiac valve rejection, intrauterine dispositive rejection, orthopedic implant rejection |
Costa. M. Seidler A. El al. (43,47) | Chromium | Antirust agent in water cooling, plating, leather tanning, being a fundamental part in the production of textiles, dyes, and pigments | Lung, sinus, Stomach. | Pulmonary sensitizing, severe dermatitis, skin ulcers. |
Posin SL. Et al. Zefferino R. El al. (49–51) | Mercury | Mining, Dental amalgamates, sea food diet | Colorectal, Lung | Neurological, Gastrointestinal and Kidney malfunction |
Kim HS, Et al, Rodwell VW, Et al, Kasper DL, Et al, Tchounwou PB, Et al (54–58) | Arsenic | Time and dose dependent on drinking water, air inhalation and smoking, and occidental diet. More exposure in workers in vineyards, ceramics, glassmaking, smelting, refining of metallic ores, pesticide manufacturing and application, wood preservation, and semiconductor manufacturing | Bladder, skin, liver, prostate, kupfer cell, lung, colon, gastric, kidney, nasopharyngeal, pancreatic cancer, and non-Hodgkin’s lymphoma | Skin lesions, cardiovascular disease, reproductive defects, neurological injuries, β-thalassemia, oculomotor apraxia and diabetes mellitus |
Source: self-elaboration |