Potentially toxic elements (PTE), such as lead (Pb), cadmium (Cd), arsenic (As), zinc (Zn), silver (Ag), chromium (Cr), and copper (Cu), occur naturally in metal-rich areas such as ultramafic or karst (1, 2). However, the major sources of exposure are anthropogenic as consequence of industrial and urban development, such as metal processing in mining, petroleum refining and combustion, smelting, other metal-based industrial operations (3, 4), production of chemical-based fertilisers (5), transportation (road and maritime traffic) (6), and even personal care products such as face cosmetics, skin lightening products, and herbal cosmetics (7). Rural areas are not spared, as long-range transboundary emissions can affect even the most remote regions (8, 9).
Humans are mainly exposed through inhalation, ingestion, and/ or skin, and reports associate exposure with varying metabolic changes affecting the heart, kidney, liver, brain, developing foetus, and even the DNA (10–14). PTEs have also been associated with cancer, Parkinson’s disease, and rare autoimmune disorder and/or degenerative diseases (15–17). They can also elicit genotoxic, cytotoxic, and carcinogenic effects (15, 16).
The aim of this paper is to review current knowledge about the sources of emission, human exposure, and mechanisms of toxicity and genotoxicity, as well as the carcinogenic potential of As and Pb, two elements that rank the highest on the Substance Priority List (SPL) issued by the Agency for Toxic Substances and Disease Registry (ATSDR) (18). Despite the efforts to ban or limit their use, both are highly persistent in the environment and continue to pose
Arsenic
Arsenic is a metalloid that occurs naturally in soil and many kinds of rocks (19). It occurs in three major chemical forms. The most common organic As compounds are arsanilic acid (C6H8AsNO3), methylarsonic acid (MMA) (CH3AsO3H2), and dimethylarsinic acid (DMA) (C2H7AsO2) (20–23). In addition to them, there are arsenolipids, predominantly present in fish and seafood. They appear in nine main structural groups, of which arseno-fatty acids (AsFAs) and arseno-hydrocarbons (AsHCs) are of particular interest due to their cytotoxicity, comparable to that of inorganic As (23). Inorganic compounds include arsenic trioxide (As2O3), sodium arsenate (NaAsO2), lead arsenate (PbHAsO4), arsenic trichloride (AsCl3), calcium arsenate (Ca3(AsO4)2), and arsine gas (AsH3).
Arsenic has three ionised states: pentavalent arsenate (AsV+), trivalent arsenite (AsIII+), and arsines (AsIII-), and either of these states can be found in inorganic and organic forms. However, the trivalent or pentavalent states are the most common and mobile (24). The inorganic forms are generally considered more toxic, with trivalent arsenite being most toxic (22).
Humans are exposed to As through contaminated drinking water, medicines, cosmetics, or diet, as shown in Table 1. Upon ingestion or inhalation, inorganic and organic As is readily absorbed in the gastrointestinal tract (≥75 % for AsIII+, AsV+, MMA, and DMA) or lungs, respectively (14). Arsine gas (AsH3) is the most toxic form of As, and inhalation of over 32 mg/m3 is lethal after exposure of more than one hour. With inhalation of 80–160 mg/m3, death occurs in less than an hour, and with inhalation of >800 mg/m3 it is instantaneous (22, 25).
Main sources and routes of exposure of As
Main sources
Sources
Route of exposure
Earth crust
Rocks (e.g., volcanic eruptions), naturally enriched areas (e.g., serpentine areas)
Ingestion/ Inhalation
Dietary sources
Seafood, contaminated water, accumulation in food crops, fruits and grains
Ingestion
Medicinal sources
Arsenic trioxide treatment for acute promyelocytic leukemia Arsenic-based drugs in veterinary medicine
Ingestion
Cosmetics
Skin lightening products and fairness creams
Intradermal
Industrial sources
Pesticide production, wood preservatives, microelectronics production, microwave devices, and lasers
Ingestion/inhalation
Air
Use of pesticides and agrochemicals, industrial sources
Inhalation
However, dermal absorption is less likely (26, 27). Whichever the route, absorbed As is mainly transported by the blood and deposited in the liver, kidney, lungs, skin, and, to a lesser extent, bones and muscles (28, 29). In the body, pentavalent arsenate is reduced to arsenite, which is further methylated in the liver into MMAv and DMAv, which are eliminated in urine and faeces (30, 31). Methylation was previously considered as a detoxification process, as both products are readily excreted by the kidneys. In contrast, recent studies have shown that methylated trivalent arsenite is as toxic, if not even more toxic, than their parent compound or inorganic forms (32–34).
The symptoms of As toxicity depend on the chemical form, exposure route and duration, and individual health. Acute As poisoning can result in nausea, vomiting, erythropenia, leukopenia, and a pricking sensation in the hands and legs. Skin lesions, systemic damage, nasal perforations, and vascular diseases are associated with long-term exposure (13). Chronic toxicity is known as arsenicosis. Chronic arsenicosis can facilitate the development of skin, lung, liver, and bladder cancer (35–37).
Mechanisms of toxicity
The mechanisms of As toxicity and genotoxicity in humans are not yet fully understood. Most toxicologically relevant data originate from in vitro studies. Important to note, As toxicity depends on its chemical form.
Arsenate and phosphate group
Arsenate (pentavalent) is a phosphate analogue with similar chemical structure and properties, which is why it replaces phosphate in several biological reactions. One reaction that has been studied in vitro (22) is glycolysis. In normal glycolysis, glucose is catabolised by phosphates to generate adenosine triphosphate (ATP) (38). Arsenate, however, interrupts ATP generation through a mechanism called arsenolysis (22). During normal glycolysis, phosphate is linked enzymatically to D-glyceraldehyde-3-phosphate to form 1,3-bisphospho-D-glycerate. Arsenate may replace phosphate to form an unstable product 1-arsenato-3-phospho-D-glycerate, which is further hydrolysed into arsenate and 3-phosphoglycerate, bypassing the generation of ATP from 1,3-biphospho-D-glycerate (22, 39). Arsenolysis may also occur during oxidative phosphorylation. In the mitochondria, ATP is synthesised from phosphate and adenosine diphosphate (ADP), but in the presence of arsenate, ADP-arsenate is formed instead (39, 40). The resulting decline in ATP generation can affect the normal functioning of cellular systems.
Arsenite and thiol groups
Arsenite (trivalent) can also diminish ATP generation via its reaction with thiol, that is, sulphydryl, groups (-SH), which have a major role in the activity of certain enzymes, coenzymes, and receptors. Arsenite binding to critical thiol groups in such molecules can interfere with some biochemical reactions and result in cellular toxicity (29, 41). An example that has been studied in vitro is that of pyruvate dehydrogenase, an enzyme in the citric acid cycle. Arsenite’s affinity for thiols, especially dithiols, alters the lipoic acid moiety and consequently inhibits pyruvate dehydrogenase activity (39, 40), which, in turn, can impair cellular respiration and reduce ATP generation (29, 42). Methylated trivalent arsenicals such as MMA3+ have been shown to be even more potent inhibitors of pyruvate dehydrogenase, GSH reductase, and thioredoxin reductase, all of which contain thiol groups (43). Inhibition of these enzymes can alter key redox reactions and may eventually lead to cytotoxicity or even cell death (41, 44).
Arsenic and oxidative stress
Another mechanism of As toxicity is the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that leads to oxidative stress in cells and can result in cellular damage and death (15, 45). Detectable levels of superoxide anion (O2·–), hydrogen peroxide(H2O2), hydroxyl radical (OH), and nitric oxide (NO) have been found in human vascular smooth muscle cells (VSMC) (46, 47), human-hamster hybrid cells (48, 49) and vascular endothelial cells (28) exposed to As. Even at environmentally relevant concentrations or at non-lethal concentrations (below 5 μmol/L), As can still stimulate O2·– and H2O2 generation (50). In addition, it can also affect antioxidant enzymes (such as with GSH, see above) (51, 52).
Arsenolipids
Currently, only a few studies have assessed the potential risk of arsenolipids for human health. Arseno-hydrocarbons (AsHCs) are more toxic than arseno-fatty acids (AsFAs). Arsenolipids also lower the levels of cellular ATP (53–56). The mechanism is unclear but may be related to mitochondrial membrane damage and disrupted mitochondrial function. Studies with Drosophila melanogaster have shown that AsHCs can pass the blood-brain barrier (BBB) and affect development (54, 55). AsHCs can also enter the milk of lactating mothers after ingestion of fish. Exposure via breastmilk has been shown to affect neurodevelopment in infants and can be linked to the attention deficit hyperactivity disorder (ADHD) (53, 56).
Mechanism of genotoxicity
Various forms of As are genotoxic. Even methylated arsenicals, formerly thought to be harmless, can induce chromosome aberrations and are potent DNA-damaging agents (57). Arsenic and arsenic-containing compounds can activate or indirectly cause genetic changes or damage (58–60).
Potential mechanisms of As genotoxicity include ROS generation, chromosome aberrations (chromatid breaks and gaps), sister chromatid exchange, and the induction of micronucleated cells (61, 62). In recent studies, As has been linked to epigenetic modifications through key mechanisms of gene regulation and DNA methylation (63). ROS can react chemically with DNA resulting in the structural damage of chromosomes, which can further lead to cellular transformation and possibly to tumour proliferation (23, 64). Arsenic-induced chromosome aberrations originate from ROS-mediated single- or double-strand DNA breaks. The latter usually arise at sites where there are single-strand breaks nearby, on the opposite DNA strands, or due to endonuclease action (2, 33, 2, 65). If this happens at the late G1 phase or S phase (DNA synthesis) due to insufficient time for repair, chromatid-type or chromosome-type aberrations may occur in the subsequent metaphase (33). In a study by Kligerman et al. (66), MMAIII and DMAIII induced chromosome mutation in mouse lymphoma cells. Structural aberrations can also affect important regions on chromosomes, leading to various detrimental effects. Although the mechanism of alterations is not fully understood, aberrations in the expression of growth control genes are a key step toward carcinogenesis.
Inorganic As has been shown to modulate the expression of transcription factors – proteins controlling the transcription of genetic information from DNA to mRNA – by causing oxidative stress through intracellular redox reactions (17, 67). In response to oxidative stress, certain early response genes are activated to protect against and prevent further damage. The major pathways involved in arsenic-induced ROS are nuclear factor kappa B (NF-κB), tumour suppressor protein (p53) activating protein-1 (AP-1), Nrf2-antioxidant response element (ARE) signalling pathway, microRNAs (miRNAs), mitophagy pathway, tyrosine phosphorylation system, and mitogen-activated protein kinases (MAPKs) (1, 32, 68). Both NF-κB and AP-1 are stress-response transcription factors that regulate the expression of genes involved in cellular antioxidant defence.
At low concentrations and shorter exposure periods, arsenite has been shown to induce both of these transcription factors in normal cells (69, 70).
NF-κB dimers are normally present in the cytoplasm of unstimulated cells, but are inactive due to interaction with specific inhibitors (71). Production of ROS at As levels ranging from 1 to 10 μmol/L stimulates NF-κB (32). Concentrations above 10 μmol/L induce phosphorylation and degradation of NF-κB inhibitors, leading to the release of NF-κB dimers, which then move to the nucleus and induce transcription of target genes (31, 72, 73). Some reports (72, 74) suggest that arsenite can interfere with the DNA binding of NF-κB, although this was observed at physiologically non-relevant concentrations. AP-1, on the other hand, is maintained within the nucleus and is composed of homodimers or heterodimers of Jun and Fos proteins (32). Trivalent methylated arsenicals are potent inducers of AP-1-dependent gene transcription and its regulator proteins (75). Transactivation of AP-1 is achieved through phosphorylation of its activation domain by c-Jun N-terminal kinase (JNK) (75).
The ARE pathway protects cells from oxidative damage thanks to the Nrf2 -induced expression of cytoprotective genes. Nrf2 is regulated by its repressor, kelch-like epichlorohydrin-associated protein 1 (Keap1) (76, 77). In the presence of excess reactive species, cysteine residues in Keap1 are s-alkylated and Nrf2 accumulates and translocates to the nucleus, where it binds to the ARE motif in the promoter region of target genes and antioxidant enzymes (32). Arsenite can impair Nrf2 ubiquitination and activate the Nrf2-induced antioxidant signalling pathway (77). The Nrf2 pathway may play a dual role in As toxicity, depending on the dose, exposure time, and cell types. Exposure of human skin fibroblasts to As2O3 at concentrations ranging from 0 to 10 μmol/L for 24 h upregulated the expression of Nrf2 and its downstream target gene HO-1, which resulted with reduced levels of ROS (78). In human choriocarcinoma JAr cells, As increased oxidative stress with the production of H2O2, leading to an increase in Nrf2/small Maf DNA binding activity and HO-1 expression (79). Similar results have been observed in mouse lymphatic endothelial cells (80).
In addition, As may induce epigenetic modifications by altering DNA methylation. The cell uses DNA methylation as an epigenetic mechanism to control gene expression. Thus, genes can either be expressed or repressed depending on the type of regulatory element in which methylation occurs. Arsenic can either induce hypomethylation or hypermethylation, with the former being more common (81).
Methylation of arsenite is necessary for its excretion. However, methyl groups are also required for normal function of DNA methyltransferases (81, 82). Demanelis et al. (63) described two mechanisms of how As impairs DNA methylation: by lowering the expression of DNA methyltransferases 3 and DNA methyltransferases 1 (83–85) and by depleting methyl groups as it is being metabolised and making them unavailable for DNA methyltransferases and DNA methylation.
Genotoxicity of As is a useful property in some cases, for example in antitumor therapy. Arsenic trioxide (As2O3) has shown some potential in the treatment of hypertrophic scars (78). Li et al. (86) reported that varying concentrations of As2O3 significantly inhibited cell proliferation, activation of caspase-3 (mediator of cell death), and JNk activation (86) in hepatocellular carcinoma (HepG2) cells. Antiproliferative effects of As on hepatocellular carcinoma have been studied extensively over the years and reported in several papers (87–89). However, recent findings by Chen et al. (90) suggest that hypoxic hepatocellular carcinoma cells develop resistance against As2O3 due to upregulation of the transcription factor HIF-1α. Similar antitumor effects of As2O3 have been observed in glioma cells, in which As exerts anti-tumour effects via apoptosis and autophagy (91–93). While this is promising, the use of As for treatment calls for great caution, because normal cells respond differently to As exposure, and further studies are needed to ensure high target specificity and eliminate adverse effects.
Mechanism of carcinogenicity
The International Agency for Research on Cancer (IARC) classifies inorganic As as a group I carcinogen (63). Potential mechanisms of As carcinogenicity include genotoxicity, tumour production, co-carcinogenesis, cell proliferation, altered DNA methylation, ROS production and oxidative stress (94), and production of dimethyl arsenate (DMAv), which at extremely high concentrations is carcinogenic in rat bladder (95, 96).
Lead
Lead (Pb) is a widely used element due to its softness, malleability, ductility, poor conductibility, and resistance to corrosion. Its extensive use has brought about human exposure in various ways, mainly through environmental pollution. For many years now, it has been banned in petrol, paint, and several other applications, but being a non-biodegradable element, it persists in the environment, and is easily accumulated in all ecosystems. Pb is highly toxic (4, 97, 98), especially for the nervous system development in children. In 2017, the Institute for Health Metrics and Evaluation (IHME) estimated that Pb exposure accounted for 1.06 million deaths and 24.4 million disability-adjusted life years (DALYs) worldwide due to long-term effects on health (99). Table 2 shows the main sources and routes of human exposure.
Main sources and route of exposure of Pb
Main sources
Sources
Route of exposure
Earth crust
Naturally enriched areas (e.g., black shale areas)
Ingestion and dermal contact
Dietary sources
Contaminated food, lead accumulated in plants (e.g., urban agriculture), game hunting meat
Ingestion
Medicinal sources
Some traditional medicines
Ingestion
Cosmetics
Lipstick, Nail polish
Intradermal (organic forms only)
Industrial sources
Lead-based paints, mining and smelting, lead acid battery production, solder and glassware production, recycling activities
Ingestion/Inhalation
Recreational activities
Use of indoor firearms, recreational shooting activities and/or fishing activities
Inhalation, dermal contact, ingestion
Air
Combustion of lead-based gasoline, tobacco smoke, leaded aviation fuel
Inhalation
Drinking water
Lead pipes
Ingestion
Soil
Contaminated soil
Ingestion (mainly in children)
Ingestion and inhalation dominate, while absorption through the skin is minimal and mostly concerns organic tetraethylated and tetramethylated Pb. When Pb-contaminated food, water, or soil is ingested, it is easily absorbed by the digestive system (100). When inhaled from polluted air, it is directly absorbed through the lungs (smaller particles) or cleared by the mucociliary transport (larger particles) only to be swallowed and absorbed in the gastrointestinal tract (28).
Absorbed Pb is transported by the blood to soft (e.g., liver, kidney, brain, spleen, ovary, and prostate) and mineralising (bone, teeth) tissues. Its elimination takes about 30–40 days from the first and about 10–20 years from the second (99, 100).
Lead has no physiological function in the human body but impairs multiple biochemical processes, and affects the renal, reproductive, and nervous (especially in children) systems (101, 102).
Until 2012, having a blood Pb level of 10 μg/dL or above was considered “level of concern” in children. Since 2012, the US Centers for Disease Control has lowered this threshold to 5 μg/dL (103–105). This reference value was then also adopted for adults by the National Institute for Occupational Safety and Health (NIOSH) in 2015 (106). According to the World Health Organization (WHO), there is no safe blood Pb concentration. Flannery and Middleton (107) have recently published an extensive report regarding blood Pb levels in children and adverse effects associated with reference values. Table 3 summarises symptoms of Pb toxicity, depending on its concentration in blood.
Symptoms of Pb toxicity at different blood lead concentrations [adapted from Rehman et al. (103)]
Acute Toxicity
Mild toxicity (40–60 μg/dL)
Moderate toxicity (60–100 μg/dL)
Severe toxicity (>100 μg/dL)
Metallic taste
Myalgia
Arthralgia (especially nocturnal)
Lead palsy (wrist or foot drop)
Abdominal pain
Paraesthesia
Muscular exhaustibility
A bluish black lead line on gums (Barton's line)
Constipation or diarrhoea
Fatigue
Tremor
Lead colic (intermittent severe abdominal cramps)
Vomiting
Irritability
Headache
Lead encephalopathy
Hyperactivity or lethargy
Abdominal discomfort
Diffuse abdominal pain
Ataxia
Anorexia, metallic taste, vomiting
Behavioural changes
Constipation
Convulsions and coma
Weight loss
Hypertension
Mechanisms of toxicity
The mechanisms of Pb toxicity include oxidative imbalance (that could lead to oxidative stress), interference with enzymes, and various phenomena at the molecular level, including single nucleotide polymorphisms and epigenetic modifications, while recent studies also report changes in regulatory RNA or microRNA (miRNA) molecules (108, 109). Oxidative stress, however, is considered the major mechanism of Pb-induced toxicity.
Lead and oxidative stress
Lead induces oxidative stress via the generation of ROS [such as hyperoxides (HO2·), singlet oxygen, and hydrogen peroxide (H2O2)] and depletion of intrinsic antioxidants that counter ROS (110–112).
Pb leads to the generation of ROS mostly by inhibiting δ-aminolevulinic acid dehydratase, which catalyses porphobilinogen (PBG) formation (113, 114). This, in turn, results in the accumulation of of δ-aminolevulinic acid (ALA) through the negative feedback loop. ALA is a potent neurotoxin associated with neurological damage and the inhibition of Na+, K+-ATPase, and adenylate cyclase activities (115, 116). Increased ALA levels generate free ROS, especially H2O2 and superoxide radicals. These radicals cause lipid peroxidation and, by interaction with oxyhaemoglobin, they contribute to further generation of hydroxyl radicals (117). These, in turn, oxidise haemoglobin and impair oxygen transport to tissues. Hydroxyl radicals can also trigger red blood cell lysis (117).
Lead and thiol groups
Under normal circumstances, intrinsic antioxidants rise to mitigate ROS effects (118, 119). However, Pb can impair glutathione, one of the body’s main antioxidants, as it binds covalently with the thiol group in glutathione, glutathione reductase (GR), glutathione peroxidase (GPX), and glutathione-S-transferase (110, 119). A similar mechanism has been reported for other antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) (120). Along with inactivating these enzymes through covalent binding, Pb replaces zinc ions, which are important cofactors for their activity (110, 121).
In this sense, SOD, GPX, and CAT levels inversely correlate with increased blood Pb levels (122). For example, Kshirsagar et al. (123) reported that a 458 % increase in blood Pb (p<0.001) in occupationally exposed individuals was accompanied by a 50.4 % decrease in SOD (p<0.001) and a 34.33 % decrease in CAT (p<0.001) levels compared to non-exposed individuals.
Another enzyme whose activity is impaired by Pb is glucose-6-phosphate dehydrogenase (G6PD), which also contains numerous thiol groups. It supplies cells with nicotinamide adenine dinucleotide phosphate (NADP). Its reduced form, NADPH, serves as a donor of reducing equivalents in the antioxidant system. Since red blood cells lack other NADPH-producing enzymes, their survival depends on NADPH supplied by G6PD. Animal studies report varying effects of Pb on G6PD but all point to three possible and concurrent mechanisms of action. The first involves higher demand for NADPH and, ultimately, higher G6PD activity in red blood cells in response to increased ROS (124, 125 ). The second involves G6PD inhibition due to a formation of a Pb and thiol group complexes in the enzyme (126, 127). This, however, is more likely to occur in vitro than in vivo. The third involves glutathione depletion, which in turn increases the demand for NADPH (121, 128).
Altogether, Pb exposure may both increase or decrease G6PD activity, depending on concentration, duration of exposure, and the integrity of the cellular antioxidant system (118, 129).
Lead and ions
Another significant mechanism of Pb toxicity is substitution of divalent cations vital for biological processes like Ca2+, Mg2+, Fe2+, Zn2+ and monovalent cations like Na+ (110, 121). Pb2+, for example, can replace Ca2+ at binding sites and activate or inhibit them, depending on its level (121, 130). This effect is the most prominent in the nervous system. After replacing Ca2+, Pb can cross the BBB and accumulate in astroglial cells (110, 121). The neurotoxic effect on immature astroglial cells is particularly pronounced, as they play an important role in the development of BBB (131).
Mechanism of genotoxicity
Several studies using different Pb-containing compounds in various biological systems have provided evidence of direct or indirect interaction between Pb and genetic material. Genotoxic effects observed in vitro and in animal and human studies range from the production of free radicals, inhibition of DNA repair to DNA double-strand breaks, chromosome aberrations, sister chromatid exchange (SCE), and increased micronucleus (MN) frequency (132, 133).
Recent studies have linked increased Pb levels to chromosome aberrations and sister chromatid exchange (SCE). Das and De (134) reported chromatid breaks as the main aberration in 100 patients with high blood Pb levels. Other chromosome abnormalities observed include chromosome breaks and dicentrics (109, 134). Older studies have reported no Pb-related increase in SCE frequency or have attributed an increase in that parameter to tobacco use in research subjects (135, 136). However, there are several recent studies (137–139) that associate Pb-exposure with an increase in SCE frequency.
Another marker of genotoxicity is micronucleation. Micronuclei are formed as a result of chromosome breaks (originated from unrepaired or incorrectly repaired DNA lesions) or mitotic spindle dysfunction. Their formation may be induced by oxidative stress or exposure to clastogens, including Pb (140–142). Balasubramanian et al. (143) reported an increase in MN frequency and DNA damage in workers exposed to Pb compared to the control group, which was related to years of exposure and accumulated genome damage.
Oxidative stress triggered by Pb can induce the formation of 8-hydroxy-2-deoxyguanosine (8-OHdG), which is a molecular marker for DNA oxidative damage. Its concentration in urine was reported to be significantly higher in workers exposed to Pb (144). Higher 8-OHdG levels were also reported in human lymphoblastoid TK6 cells exposed to Pb (145).
Another potential mechanism of Pb genotoxicity is the signalling pathway of the nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 and NF-κB are the two key transcriptional factors that interact to regulate cellular redox status in response to oxidative stress and inflammation, respectively. Pb-induced oxidative stress can disrupt this interaction impairs cell proliferation, cell cycle progression and, eventually, leads to cell death (146). Oxidative stress induced in bovine granulosa cells by Pb concentrations ranging from 1 to 10 μg/mL downregulates both Nrf2 and NF-κB and their downstream genes (147). Similar observations of oxidative stress, including downregulation of Nrf2, inflammation, and apoptosis were made in rat testis (148).
Mechanism of carcinogenicity
The IARC classifies Pb as a group 2A carcinogen (149). Pb-induced carcinogenicity is owed to increased oxidative stress, membrane alterations, impaired cell signalling, and impaired neurotransmission (150). It likely starts with ROS damaging the DNA, disrupting DNA repair and affecting genes that regulate the growth of tumour cells (151).
By inhibiting δ-aminolevulinic acid dehydratase, Pb favours the accumulation of ALA, which triggers ROS production, but also acts as a carcinogen (116). ALA-mediated oxidative DNA damage occurs through the production of 8-OHdG, 8-hydroxyguanine (8-oxo-7,8-dihydroguanine), and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) (116, 152). A number of studies has reported positive correlation between ALA levels and markers of oxidative stress and carcinogenesis (116, 137, 141, 153). Furthermore, hydroxyl radicals (HO•) generated by ALA attack DNA strands and interact with its nucleobases to produce various oxidation products. All DNA nucleobases are susceptible to HO•. The 8-oxodG lesion (HO• interaction with guanine) is the most abundant and is promutagenic (141). Unrepaired 8-oxodG can lead to genomic instability through transversions and the formation of double-strand breaks (116, 154). Furthermore, several studies (155–157) have revealed the epigenetic function of 8-oxodG, and its role in carcinogenesis through gene regulation.
Conclusion
This review sheds new light on the mechanisms of toxicity and genotoxicity of As and Pb. Both PTEs have been proven to affect various metabolic processes and impair the function of some organ systems, cause genetic damage, prevent DNA repair, and consequently promote carcinogenesis and tumour growth.
Both elements are still persistent in the environment, with millions of people at risk of exposure. In this sense, previously implemented strategies for preventing, monitoring, limiting and managing exposures to As, Pb, and other PTEs, heavy metals in particular, should be strictly followed. Engineering solutions can limit most occupational exposures, and it is essential to monitor levels of heavy metals so that such solutions can be implemented. Good occupational hygiene is another effective method of limiting exposure.
Since both As and Pb are highly persistent in the environment, regardless of the fact that their primary sources have been removed, they still may contaminate water, soil, and food crops. To prevent and minimise secondary exposure, effective soil remediation and food monitoring are needed.
This review shows that the knowledge about both PTEs is still insufficient, and that it is necessary to regularly revise the existing concepts and accumulate data relevant for risk assessment. In this regard, it is recommended to focus on findings obtained using various sensitive genotoxicity tests and novel -omics approaches, which could help to better understand the process of carcinogenesis triggered by high levels of exposure to As and Pb.
Vithanage M, Kumarathilaka P, Oze C, Karunatilake S, Seneviratne M, Hseu ZY, Gunarathne V, Dassanayake M, Ok YS, Rinklebe J. Occurrence and cycling of trace elements in ultramafic soils and their impacts on human health: A critical review. Environ Int 2019;131:104974. doi: 10.1016/j.envint.2019.104974VithanageMKumarathilakaPOzeCKarunatilakeSSeneviratneMHseuZYGunarathneVDassanayakeMOkYSRinklebeJOccurrence and cycling of trace elements in ultramafic soils and their impacts on human health: A critical reviewEnviron Int201913110497410.1016/j.envint.2019.10497431376597Open DOISearch in Google Scholar
Wu W, Qu S, Nel W, Ji J. The impact of natural weathering and mining on heavy metal accumulation in the karst areas of the Pearl River Basin, China. Sci Total Environ 2020;734:139480. doi: 10.1016/j. scitotenv.2020.139480WuWQuSNelWJiJThe impact of natural weathering and mining on heavy metal accumulation in the karst areas of the Pearl River Basin, ChinaSci Total Environ202073413948010.1016/j. scitotenv.2020.139480Open DOISearch in Google Scholar
Hanfi MY, Mostafa MYA, Zhukovsky MV. Heavy metal contamination in urban surface sediments: sources, distribution, contamination control, and remediation. Environ Monit Assess 2019;192:32. doi: 10.1007/s10661-019-7947-5HanfiMYMostafaMYAZhukovskyMVHeavy metal contamination in urban surface sediments: sources, distribution, contamination control, and remediationEnviron Monit Assess20191923210.1007/s10661-019-7947-531823021Open DOISearch in Google Scholar
Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. In: Luch A, editor. Molecular, clinical and environmental toxicology. Basel: Springer; 2012. p. 133–64.TchounwouPBYedjouCGPatlollaAKSuttonDJHeavy metal toxicity and the environmentInLuchAeditorMolecular, clinical and environmental toxicology.BaselSpringer2012p.1336410.1007/978-3-7643-8340-4_6414427022945569Search in Google Scholar
Singh A, Chauhan S, Varjani S, Pandey A, Bhargava PC. Integrated approaches to mitigate threats from emerging potentially toxic elements: A way forward for sustainable environmental management. Environ Res 2022;209:112844. doi: 10.1016/j.envres.2022.112844SinghAChauhanSVarjaniSPandeyABhargavaPCIntegrated approaches to mitigate threats from emerging potentially toxic elements: A way forward for sustainable environmental managementEnviron Res202220911284410.1016/j.envres.2022.11284435101398Open DOISearch in Google Scholar
Jeong H, Ryu JS, Ra K. Characteristics of potentially toxic elements and multi-isotope signatures (Cu, Zn, Pb) in non-exhaust traffic emission sources. Environ Pollut 2022;292:118339. doi: 10.1016/j. envpol.2021.118339JeongHRyuJSRaKCharacteristics of potentially toxic elements and multi-isotope signatures (Cu, Zn, Pb) in non-exhaust traffic emission sourcesEnviron Pollut202229211833910.1016/j. envpol.2021.118339Open DOISearch in Google Scholar
Mohiuddin AK. Heavy metals: the notorious daredevils of daily personal care products. Int J Pharm Pharm Res 2019;2:8–18. doi: 10.21694/2642-2980.19008MohiuddinAKHeavy metals: the notorious daredevils of daily personal care productsInt J Pharm Pharm Res2019281810.21694/2642-2980.19008Open DOISearch in Google Scholar
WHO Regional Office for Europe & Joint WHO/Convention Task Force on the Health Aspects of Air Pollution. Health Risks of Heavy Metals from Long-Range Transboundary Air Pollution. Copenhagen: WHO Regional Office for Europe; 2007.WHO Regional Office for Europe & Joint WHO/Convention Task Force on the Health Aspects of Air Pollution. Health Risks of Heavy Metals from Long-Range Transboundary Air Pollution.CopenhagenWHO Regional Office for Europe;2007Search in Google Scholar
Fu X, Zhang H, Feng X, Tan Q, Ming L, Liu C, Zhang L. Domestic and transboundary sources of atmospheric particulate bound mercury in remote areas of China: evidence from mercury isotopes. Environ Sci Technol 2019;53:1947–57. doi: 10.1021/acs.est.8b06736FuXZhangHFengXTanQMingLLiuCZhangLDomestic and transboundary sources of atmospheric particulate bound mercury in remote areas of China: evidence from mercury isotopesEnviron Sci Technol20195319475710.1021/acs.est.8b0673630685968Open DOISearch in Google Scholar
Natasha, Shahid M, Khalid S, Saleem M. Unrevealing arsenic and lead toxicity and antioxidant response in spinach: a human health perspective. Environ Geochem Health 2022;44:487–96. doi: 10.1007/ s10653-021-00818-0NatashaShahid MKhalidSSaleemMUnrevealing arsenic and lead toxicity and antioxidant response in spinach: a human health perspectiveEnviron Geochem Health2022444879610.1007/ s10653-021-00818-0Open DOISearch in Google Scholar
Alina M, Azrina A, Mohd Yunus A, Mohd Zakiuddin S, Mohd Izuan Effendi H, Muhammad Rizal R. Heavy metals (mercury, arsenic, cadmium, plumbum) in selected marine fish and shellfish along the Straits of Malacca. Int Food Res J 2012;19:135–40 [displayed 25 October 2022]. Available at http://www.ifrj.upm.edu.my/19%20(01)%202011/(18)IFRJ-2010-235%20Alina.pdfAlinaMAzrinaAMohdYunus AMohdZakiuddin SMohdIzuan Effendi HMuhammadRizal RHeavy metals (mercury, arsenic, cadmium, plumbum) in selected marine fish and shellfish along the Straits of MalaccaInt Food Res J20121913540[displayed 25 October 2022]. Available athttp://www.ifrj.upm.edu.my/19%20(01)%202011/(18)IFRJ-2010-235%20Alina.pdfSearch in Google Scholar
Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN. Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 2014;7:60–72. doi: 10.2478/intox-2014-0009JaishankarMTsetenTAnbalaganNMathewBBBeeregowdaKNToxicity, mechanism and health effects of some heavy metalsInterdiscip Toxicol20147607210.2478/intox-2014-0009442771726109881Open DOISearch in Google Scholar
Engwa GA, Ferdinand PU, Nwalo FN, Unachukwu MN. Mechanism and health effects of heavy metal toxicity in humans. In: Karcioglu O, Arslan B, editors. Poisoning in the modern world - new tricks for an old dog? London: IntechOpen; 2019. doi: 10.5772/intechopen.82511EngwaGAFerdinandPUNwaloFNUnachukwuMNMechanism and health effects of heavy metal toxicity in humansInKarciogluOArslanBeditorsPoisoning in the modern world - new tricks for an old dog?LondonIntechOpen201910.5772/intechopen.82511Open DOISearch in Google Scholar
Anyanwu BO, Ezejiofor AN, Igweze ZN, Orisakwe OE. Heavy metal mixture exposure and effects in developing nations: an update. Toxics 2018;6(4):65. doi: 10.3390/toxics6040065AnyanwuBOEzejioforANIgwezeZNOrisakweOEHeavy metal mixture exposure and effects in developing nations: an updateToxics2018646510.3390/toxics6040065631610030400192Open DOISearch in Google Scholar
Leonard SS, Bower JJ, Shi X. Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses. Mol Cell Biochem 2004;255:3–10. doi: 10.1023/b:mcbi.0000007255.72746.a6LeonardSSBowerJJShiXMetal-induced toxicity, carcinogenesis, mechanisms and cellular responsesMol Cell Biochem200425531010.1023/b:mcbi.0000007255.72746.a614971640Open DOISearch in Google Scholar
Zhu Y, Costa M. Metals and molecular carcinogenesis. Carcinogenesis 2020;41:1161–72. doi: 10.1093/carcin/bgaa076ZhuYCostaMMetals and molecular carcinogenesisCarcinogenesis20204111617210.1093/carcin/bgaa076751395232674145Open DOISearch in Google Scholar
Fu Z, Xi S. The effects of heavy metals on human metabolism. Toxicol Mech Methods 2020;30:167–76. doi: 10.1080/15376516.2019.1701594FuZXiSThe effects of heavy metals on human metabolismToxicol Mech Methods2020301677610.1080/15376516.2019.170159431818169Open DOISearch in Google Scholar
ARSDR Agency for Toxic Substances and Disease Registry. ATSDR’s Substance Priority List, 2019 [displayed 08 September 2022]. Available at https://www.atsdr.cdc.gov/spl/index.htmlARSDR Agency for Toxic Substances and Disease Registry. ATSDR’s Substance Priority List, 2019[displayed 08 September 2022]. Available athttps://www.atsdr.cdc.gov/spl/index.htmlSearch in Google Scholar
Briffa J. Heavy Metals in Maltese Agricultural Soil. [Master thesis]. Malta: University of Malta; 2020.BriffaJHeavy Metals in Maltese Agricultural Soil. [Master thesis]MaltaUniversity of Malta2020Search in Google Scholar
Chung JY, Yu SD, Hong YS. Environmental source of arsenic exposure. J Prev Med Public Health 2014;47:253–7. doi: 10.3961/jpmph.14.036ChungJYYuSDHongYSEnvironmental source of arsenic exposureJ Prev Med Public Health201447253710.3961/jpmph.14.036418655325284196Open DOISearch in Google Scholar
Matta G, Gjyli L. Mercury, lead and arsenic: impact on environment and human health. J Chem Pharm Sci 2016;9:718–25 [displayed 25 October 2022]. Available at https://jchps.com/issues/Volume%209_Issue%202/jchps%209(2)%2010%20Gagan%20Matta.pdfMattaGGjyliLMercury, lead and arsenic: impact on environment and human healthJ Chem Pharm Sci2016971825[displayed 25 October 2022]. Available athttps://jchps.com/issues/Volume%209_Issue%202/jchps%209(2)%2010%20Gagan%20Matta.pdfSearch in Google Scholar
Kuivenhoven M, Mason K. Arsenic Toxicity. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan [displayed 27 October 2022]. Available at https://www.ncbi.nlm.nih.gov/books/NBK541125/KuivenhovenMMasonKArsenic Toxicity. [Updated 2022 Jun 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan [displayed 27 October 2022].Available athttps://www.ncbi.nlm.nih.gov/books/NBK541125/Search in Google Scholar
Chávez-Capilla T. The need to unravel arsenolipid transformations in humans. DNA Cell Biol 2022;41:64–70. doi: 10.1089/dna.2021.0476Chávez-CapillaT.The need to unravel arsenolipid transformations in humansDNA Cell Biol202241647010.1089/dna.2021.0476878770534941367Open DOISearch in Google Scholar
Sanyal T, Bhattacharjee P, Paul S, Bhattacharjee P. Recent advances in arsenic research: significance of differential susceptibility and sustainable strategies for mitigation. Front Public Health 2020;8:464. doi: 10.3389/fpubh.2020.00464SanyalTBhattacharjeePPaulSBhattacharjeePRecent advances in arsenic research: significance of differential susceptibility and sustainable strategies for mitigationFront Public Health2020846410.3389/fpubh.2020.00464757836533134234Open DOISearch in Google Scholar
Pakulska D, Czerczak S. Hazardous effects of arsine: a short review. Int J Occup Med Environ Health 2006;19:36–44. doi: 10.2478/v10001-006-0003-zPakulskaDCzerczakSHazardous effects of arsine: a short reviewInt J Occup Med Environ Health200619364410.2478/v10001-006-0003-z16881597Open DOISearch in Google Scholar
Nieuwenhuijsen MJ, Toledano MB, Eaton NE, Fawell J, Elliott P. Chlorination disinfection byproducts in water and their association with adverse reproductive outcomes: a review. Occup Environ Med 2000;57:73–85. doi: 10.1136/oem.57.2.73NieuwenhuijsenMJToledanoMBEatonNEFawellJElliottPChlorination disinfection byproducts in water and their association with adverse reproductive outcomes: a reviewOccup Environ Med200057738510.1136/oem.57.2.73173991010711274Open DOISearch in Google Scholar
Zuzolo D, Cicchella D, Demetriades A, Birke M, Albanese S, Dinelli E, Lima A, Valera P, De Vivo B. Arsenic: Geochemical distribution and age-related health risk in Italy. Environ Res 2020;182:109076. doi: 10.1016/j.envres.2019.109076ZuzoloDCicchellaDDemetriadesABirkeMAlbaneseSDinelliELimaAValeraPDeVivo BArsenic: Geochemical distribution and age-related health risk in ItalyEnviron Res202018210907610.1016/j.envres.2019.10907631901628Open DOISearch in Google Scholar
Briffa J, Sinagra E, Blundell R. Heavy metal pollution in the environment and their toxicological effects on humans. Heliyon 2020;6(9):e04691. doi: 10.1016/j.heliyon.2020.e04691BriffaJSinagraEBlundellRHeavy metal pollution in the environment and their toxicological effects on humansHeliyon202069e0469110.1016/j.heliyon.2020.e04691749053632964150Open DOISearch in Google Scholar
Blessing Ebele O. Mechanisms of arsenic toxicity and carcinogenesis. Afr J Biochem Res 2009;3(5):232–7.Blessing Ebele OMechanisms of arsenic toxicity and carcinogenesisAfr J Biochem Res2009352327Search in Google Scholar
Twaddle NC, Vanlandingham M, Beland FA, Doerge DR. Metabolism and disposition of arsenic species from controlled dosing with dimethylarsinic acid (DMAV) in adult female CD-1 mice. V. Toxicokinetic studies following oral and intravenous administration. Food Chem Toxicol 2019;130:22–31. doi: 10.1016/j.fct.2019.04.045TwaddleNCVanlandinghamMBelandFADoergeDRMetabolism and disposition of arsenic species from controlled dosing with dimethylarsinic acid (DMAV) in adult female CD-1 miceV. Toxicokinetic studies following oral and intravenous administration. Food Chem Toxicol2019130223110.1016/j.fct.2019.04.04531091427Open DOISearch in Google Scholar
Yu H, Liu S, Li M, Wu B. Influence of diet, vitamin, tea, trace elements and exogenous antioxidants on arsenic metabolism and toxicity. Environ Geochem Health 2016;38:339–51. doi: 10.1007/s10653-015-9742-8YuHLiuSLiMWuBInfluence of diet, vitamin, tea, trace elements and exogenous antioxidants on arsenic metabolism and toxicityEnviron Geochem Health2016383395110.1007/s10653-015-9742-826169729Open DOISearch in Google Scholar
Hu Y, Li J, Lou B, Wu R, Wang G, Lu C, Wang H, Pi J, Xu Y. The role of reactive oxygen species in arsenic toxicity. Biomolecules 2020;10(2):240. doi: 10.3390/biom10020240HuYLiJLouBWuRWangGLuCWangHPiJXuYThe role of reactive oxygen species in arsenic toxicityBiomolecules202010224010.3390/biom10020240707229632033297Open DOISearch in Google Scholar
Kligerman A, Tennant A. Insights into the carcinogenic mode of action of arsenic. Toxicol Appl Pharmacol 2007;222:281–8. doi: 10.1016/j.taap.2006.10.006KligermanATennantAInsights into the carcinogenic mode of action of arsenicToxicol Appl Pharmacol2007222281810.1016/j.taap.2006.10.00617118416Open DOISearch in Google Scholar
Ng JC. Environmental contamination of arsenic and its toxicological impact on humans. Environ Chem 2005;2:146–60. doi: 10.1071/EN05062NgJCEnvironmental contamination of arsenic and its toxicological impact on humansEnviron Chem200521466010.1071/EN05062Open DOISearch in Google Scholar
Kitchin KT, Conolly R. Arsenic-induced carcinogenesis - oxidative stress as a possible mode of action and future research needs for more biologically based risk assessment. Chem Res Toxicol 2010;23:327–35. doi: 10.1021/tx900343dKitchinKTConollyRArsenic-induced carcinogenesis - oxidative stress as a possible mode of action and future research needs for more biologically based risk assessmentChem Res Toxicol2010233273510.1021/tx900343d20035570Open DOISearch in Google Scholar
Palma-Lara I, Martínez-Castillo M, Quintana-Pérez JC, Arellano-Mendoza MG, Tamay-Cach F, Valenzuela-Limón OL, García-Montalvo EA, Hernández-Zavala A. Arsenic exposure: a public health problem leading to several cancers. Regul Toxicol Pharmacol 2020;110:104539. doi: 10.1016/j.yrtph.2019.104539Palma-LaraIMartínez-CastilloMQuintana-PérezJCArellano-MendozaMGTamay-CachFValenzuela-LimónOLGarcía-MontalvoEAHernández-ZavalaAArsenic exposure: a public health problem leading to several cancersRegul Toxicol Pharmacol202011010453910.1016/j.yrtph.2019.10453931765675Open DOISearch in Google Scholar
Zhou Q, Xi S. A review on arsenic carcinogenesis: epidemiology, metabolism, genotoxicity and epigenetic changes. Regul Toxicol Pharmacol 2018;99:78–88. doi: 10.1016/j.yrtph.2018.09.010ZhouQXiSA review on arsenic carcinogenesis: epidemiology, metabolism, genotoxicity and epigenetic changesRegul Toxicol Pharmacol201899788810.1016/j.yrtph.2018.09.01030223072Open DOISearch in Google Scholar
Rhodes CE, Denault D, Varacallo M. Physiology, Oxygen Transport. [Updated 2021 Nov 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan [displayed 27 October 2022]. Available at https://www.ncbi.nlm.nih.gov/books/NBK538336/RhodesCEDenaultDVaracalloMPhysiology, Oxygen Transport. [Updated 2021 Nov 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan [displayed 27 October 2022].Available athttps://www.ncbi.nlm.nih.gov/books/NBK538336/Search in Google Scholar
Hughes MF. Arsenic toxicity and potential mechanisms of action. Toxicol Lett 2002;133:1–16. doi: 10.1016/s0378-4274(02)00084-xHughesMFArsenic toxicity and potential mechanisms of actionToxicol Lett200213311610.1016/s0378-4274(02)00084-x12076506Open DOISearch in Google Scholar
Kulshrestha A, Jarouliya U, Prasad G, Flora S, Bisen PS. Arsenic-induced abnormalities in glucose metabolism: biochemical basis and potential therapeutic and nutritional interventions. World J Transl Med 2014;3:96–111. doi: 10.5528/wjtm.v3.i2.96KulshresthaAJarouliyaUPrasadGFloraSBisenPSArsenic-induced abnormalities in glucose metabolism: biochemical basis and potential therapeutic and nutritional interventionsWorld J Transl Med201439611110.5528/wjtm.v3.i2.96Open DOISearch in Google Scholar
Fan C, Liu G, Long Y, Rosen B, Cai Y. Thiolation in arsenic metabolism: a chemical perspective. Metallomics 2018;10:1368–82. doi: 10.1039/c8mt00231bFanCLiuGLongYRosenBCaiYThiolation in arsenic metabolism: a chemical perspectiveMetallomics20181013688210.1039/c8mt00231b30207373Open DOISearch in Google Scholar
Walton FS, Harmon AW, Paul DS, Drobná Z, Patel YM, Styblo M. Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes. Toxicol Appl Pharmacol 2004;198:424–33. doi: 10.1016/j.taap.2003.10.026WaltonFSHarmonAWPaulDSDrobnáZPatelYMStybloMInhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetesToxicol Appl Pharmacol20041984243310.1016/j.taap.2003.10.02615276423Open DOISearch in Google Scholar
Stýblo M, Venkatratnam A, Fry RC, Thomas DJ. Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects. Arch Toxicol 2021;95:1547–72. doi: 10.1007/s00204-021-03028-wStýbloMVenkatratnamAFryRCThomasDJOrigins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospectsArch Toxicol20219515477210.1007/s00204-021-03028-w872888033768354Open DOISearch in Google Scholar
Srivastava S, Flora SJ. Arsenicals: toxicity, their use as chemical warfare agents, and possible remedial measures. In: Gupta RC, editor. Handbook of toxicology of chemical warfare agents. Cambridge: Academic Press; 2020. p. 303–19.SrivastavaSFloraSJArsenicals: toxicity, their use as chemical warfare agents, and possible remedial measuresInGuptaRCeditorHandbook of toxicology of chemical warfare agentsCambridgeAcademic Press2020p.3031910.1016/B978-0-12-819090-6.00021-0Search in Google Scholar
Liu Y, Zhao H, Wang Y, Guo M, Mu M, Xing M. Arsenic (III) and/ or copper (II) induces oxidative stress in chicken brain and subsequent effects on mitochondrial homeostasis and autophagy. J Inorg Biochem 2020;211:111201. doi: 10.1016/j.jinorgbio.2020.111201LiuYZhaoHWangYGuoMMuMXingMArsenic (III) and/ or copper (II) induces oxidative stress in chicken brain and subsequent effects on mitochondrial homeostasis and autophagyJ Inorg Biochem202021111120110.1016/j.jinorgbio.2020.11120132805460Open DOISearch in Google Scholar
Li JX, Shen YQ, Cai BZ, Zhao J, Bai X, Lu YJ, Li XQ. Arsenic trioxide induces the apoptosis in vascular smooth muscle cells via increasing intracellular calcium and ROS formation. Mol Biol Rep 2010;37:1569–76. doi: 10.1007/s11033-009-9561-zLiJXShenYQCaiBZZhaoJBaiXLuYJLiXQArsenic trioxide induces the apoptosis in vascular smooth muscle cells via increasing intracellular calcium and ROS formationMol Biol Rep20103715697610.1007/s11033-009-9561-z19437134Open DOISearch in Google Scholar
Lynn S, Gurr JR, Lai HT, Jan KY. NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. Circ Res 2000;86:514–9. doi: 10.1161/01.res.86.5.514LynnSGurrJRLaiHTJanKYNADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cellsCirc Res200086514910.1161/01.res.86.5.51410720412Open DOISearch in Google Scholar
Liu SX, Athar M, Lippai I, Waldren C, Hei TK. Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity. Proc Natl Acad Sci USA 2001;98:1643–8. doi: 10.1073/pnas.98.4.1643LiuSXAtharMLippaiIWaldrenCHeiTKInduction of oxyradicals by arsenic: implication for mechanism of genotoxicityProc Natl Acad Sci USA2001981643810.1073/pnas.98.4.16432931011172004Open DOISearch in Google Scholar
Tam LM, Wang Y. Arsenic exposure and compromised protein quality control. Chem Res Toxicol 2020;33:1594–604. doi: 10.1021/acs. chemrestox.0c00107TamLMWangYArsenic exposure and compromised protein quality controlChem Res Toxicol202033159460410.1021/acs. chemrestox.0c00107Open DOISearch in Google Scholar
Valko M, Jomova K, Rhodes CJ, Kuča K, Musílek K. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 2016;90:1–37. doi: 10.1007/s00204-015-1579-5ValkoMJomovaKRhodesCJKučaKMusílekKRedox- and non-redox-metal-induced formation of free radicals and their role in human diseaseArch Toxicol20169013710.1007/s00204-015-1579-526343967Open DOISearch in Google Scholar
Ran S, Liu J, Li S. A Systematic review of the various effect of arsenic on glutathione synthesis in vitro and in vivo. Biomed Res Int 2020;2020:9414196. doi: 10.1155/2020/9414196RanSLiuJLiSA Systematic review of the various effect of arsenic on glutathione synthesis in vitro and in vivoBiomed Res Int20202020941419610.1155/2020/9414196741146532802886Open DOISearch in Google Scholar
Singh R, Misra AN, Sharma P. Effect of arsenate toxicity on antioxidant enzymes and expression of nicotianamine synthase in contrasting genotypes of bioenergy crop Ricinus communis. Environ Sci Pollut Res Int 2021;28:31421–30. doi: 10.1007/s11356-021-12701-7SinghRMisraANSharmaPEffect of arsenate toxicity on antioxidant enzymes and expression of nicotianamine synthase in contrasting genotypes of bioenergy crop Ricinus communisEnviron Sci Pollut Res Int202128314213010.1007/s11356-021-12701-733606168Open DOISearch in Google Scholar
Askevold JE. Arsenic and ADHD-Perinatal exposure to Arsenic species in breastmilk and ADHD in adolescents [Project thesis]. Oslo: Faculty of Medicine, University of Oslo; 2022 [displayed 27 October 2022]. Available at https://www.duo.uio.no/bitstream/handle/10852/94054/1/Kappe-Arsenic-og-ADHD.pdfAskevoldJEArsenic and ADHD-Perinatal exposure to Arsenic species in breastmilk and ADHD in adolescents [Project thesis]. Oslo: Faculty of Medicine, University of Oslo; 2022 [displayed 27 October 2022].Available athttps://www.duo.uio.no/bitstream/handle/10852/94054/1/Kappe-Arsenic-og-ADHD.pdfSearch in Google Scholar
Meyer S, Schulz J, Jeibmann A, Taleshi MS, Ebert F, Francesconi KA, Schwerdtle T. Arsenic-containing hydrocarbons are toxic in the in vivo model Drosophila melanogaster. Metallomics 2014;6:2010–4. doi: 10.1039/c4mt00249kMeyerSSchulzJJeibmannATaleshiMSEbertFFrancesconiKASchwerdtleTArsenic-containing hydrocarbons are toxic in the in vivo model Drosophila melanogasterMetallomics201462010410.1039/c4mt00249k25292248Open DOISearch in Google Scholar
Niehoff AC, Schulz J, Soltwisch J, Meyer S, Kettling H, Sperling M, Jeibmann A, Dreisewerd K, Francesconi KA, Schwerdtle T, Karst U. Imaging by elemental and molecular mass spectrometry reveals the uptake of an arsenolipid in the brain of Drosophila melanogaster. Anal Chem 2016;88:5258–63. doi: 10.1021/acs.analchem.6b00333NiehoffACSchulzJSoltwischJMeyerSKettlingHSperlingMJeibmannADreisewerdKFrancesconiKASchwerdtleTKarstUImaging by elemental and molecular mass spectrometry reveals the uptake of an arsenolipid in the brain of Drosophila melanogasterAnal Chem20168852586310.1021/acs.analchem.6b0033327098356Open DOISearch in Google Scholar
Xue XM, Xiong C, Yoshinaga M, Rosen B, Zhu YG. The enigma of environmental organoarsenicals: insights and implications. Crit Rev E nv iron Sc i Te c h no l 2 0 2 2 ; 5 2 : 3 8 3 5 – 6 2 . do i : 10.1080/10643389.2021.1947678XueXMXiongCYoshinagaMRosenBZhuYGThe enigma of environmental organoarsenicals: insights and implications. Crit Rev E nv iron Sc i Te c h no l 2 0 2 2 ; 5 2 : 3 8 3 5 – 6 2 .do i : 10.1080/10643389.2021.1947678Search in Google Scholar
Mac Monagail M, Morrison L. Arsenic speciation in a variety of seaweeds and associated food products. Compr Anal Chem 2019;85:267–310. 10.1016/bs.coac.2019.03.005MacMonagail MMorrisonLArsenic speciation in a variety of seaweeds and associated food productsCompr Anal Chem20198526731010.1016/bs.coac.2019.03.005Open DOISearch in Google Scholar
Flora SJ. Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med 2011;51:257–81. doi : 10.1016/j.freeradbiomed.2011.04.008FloraSJArsenic-induced oxidative stress and its reversibilityFree Radic Biol Med20115125781doi: 10.1016/j.freeradbiomed.2011.04.00810.1016/j.freeradbiomed.2011.04.00821554949Search in Google Scholar
Liu G, Song Y, Li C, Liu R, Chen Y, Yu L, Huang Q, Zhu D, Lu C, Yu X, Xiao C, Liu Y. Arsenic compounds: the wide application and mechanisms applied in acute promyelocytic leukemia and carcinogenic toxicology. Eur J Med Chem 2021;221:113519. doi: 10.1016/j. ejmech.2021.113519LiuGSongYLiCLiuRChenYYuLHuangQZhuDLuCYuXXiaoCLiuYArsenic compounds: the wide application and mechanisms applied in acute promyelocytic leukemia and carcinogenic toxicologyEur J Med Chem202122111351910.1016/j. ejmech.2021.113519Open DOISearch in Google Scholar
Martin EM, Fry RC. Environmental influences on the epigenome: exposure- associated DNA methylation in human populations. Annu Rev Public Health 2018;39:309–33. doi: 10.1146/annurev-publhealth-040617-014629MartinEMFryRCEnvironmental influences on the epigenome: exposure- associated DNA methylation in human populationsAnnu Rev Public Health2018393093310.1146/annurev-publhealth-040617-01462929328878Open DOISearch in Google Scholar
Nuta O, Bouffler S, Lloyd D, Ainsbury E, Sepai O, Rothkamm K. Investigating the impact of long term exposure to chemical agents on the chromosomal radiosensitivity using human lymphoblastoid GM1899A cells. Sci Rep 2021;11:12616. doi: 10.1038/s41598-021-91957-yNutaOBoufflerSLloydDAinsburyESepaiORothkammKInvestigating the impact of long term exposure to chemical agents on the chromosomal radiosensitivity using human lymphoblastoid GM1899A cellsSci Rep2021111261610.1038/s41598-021-91957-y820914234135387Open DOISearch in Google Scholar
Patlolla AK, Todorov TI, Tchounwou PB, van der Voet G, Centeno JA. Arsenic-induced biochemical and genotoxic effects and distribution in tissues of Sprague-Dawley rats. Microchem J 2012;105:101–7. doi: 10.1016/j.microc.2012.08.013PatlollaAKTodorovTITchounwouPBvander Voet GCentenoJAArsenic-induced biochemical and genotoxic effects and distribution in tissues of Sprague-Dawley ratsMicrochem J2012105101710.1016/j.microc.2012.08.013350091323175155Open DOISearch in Google Scholar
Demanelis K, Argos M, Tong L, Shinkle J, Sabarinathan M, Rakibuz-Zaman M, Sarwar G, Shahriar H, Islam T, Rahman M, Yunus M, Graziano JH, Broberg K, Engström K, Jasmine F, Ahsan H, Pierce BL. Association of arsenic exposure with whole blood DNA methylation: an epigenome-wide study of Bangladeshi adults. Environ Health Perspect 2019;127(5):057011. doi: 10.1289/EHP3849DemanelisKArgosMTongLShinkleJSabarinathanMRakibuz-ZamanMSarwarGShahriarHIslamTRahmanMYunusMGrazianoJHBrobergKEngströmKJasmineFAhsanHPierceBLAssociation of arsenic exposure with whole blood DNA methylation: an epigenome-wide study of Bangladeshi adultsEnviron Health Perspect2019127505701110.1289/EHP3849679153931135185Open DOISearch in Google Scholar
Tam LM, Price NE, Wang Y. Molecular mechanisms of arsenic-induced disruption of DNA repair. Chem Res Toxicol 2020;33:709–26. doi: 10.1021/acs.chemrestox.9b00464TamLMPriceNEWangYMolecular mechanisms of arsenic-induced disruption of DNA repairChem Res Toxicol2020337092610.1021/acs.chemrestox.9b00464707803631986875Open DOISearch in Google Scholar
Moura DJ, Péres VF, Jacques RA, Saffi J. Heavy metal toxicity: oxidative stress parameters and DNA repair. In: Gupta D, Sandalio L, editors. Metal toxicity in plants: perception, signaling and remediation. Berlin, Heidelberg: Springer; 2012. p. 187–205 doi: 10.1007/978-3-642-220814_9MouraDJPéresVFJacquesRASaffiJHeavy metal toxicity: oxidative stress parameters and DNA repairInGuptaDSandalioLeditorsMetal toxicity in plants: perception, signaling and remediation.Berlin, HeidelbergSpringer2012p.18720510.1007/978-3-642-220814_9Open DOISearch in Google Scholar
Kligerman AD, Doerr CL, Tennant AH, Harrington-Brock K, Allen JW, Winkfield E, Poorman-Allen P, Kundu B, Funasaka K, Roop BC, Mass MJ, DeMarini DM. Methylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: induction of chromosomal mutations but not gene mutations. Environ Mol Mutagen 2003;42:192–205. doi: 10.1002/em.10192KligermanADDoerrCLTennantAHHarrington-BrockKAllenJWWinkfieldEPoorman-AllenPKunduBFunasakaKRoopBCMassMJDeMariniDMMethylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: induction of chromosomal mutations but not gene mutationsEnviron Mol Mutagen20034219220510.1002/em.1019214556226Open DOISearch in Google Scholar
Renu K, Saravanan A, Elangovan A, Ramesh S, Annamalai S, Namachivayam A, Abel P, Madhyastha H, Madhyastha R, Maruyama M, Balachandar V, Valsala Gopalakrishnan A. An appraisal on molecular and biochemical signalling cascades during arsenic-induced hepatotoxicity. Life Sci 2020;260:118438. doi: 10.1016/j.lfs.2020.118438RenuKSaravananAElangovanARameshSAnnamalaiSNamachivayamAAbelPMadhyasthaHMadhyasthaRMaruyamaMBalachandarVValsalaGopalakrishnan AAn appraisal on molecular and biochemical signalling cascades during arsenic-induced hepatotoxicityLife Sci202026011843810.1016/j.lfs.2020.11843832949585Open DOISearch in Google Scholar
Tchounwou PB, Centeno JA, Patlolla AK. Arsenic toxicity, mutagenesis, and carcinogenesis - a health risk assessment and management approach. Mol Cell Biochem 2004;255:47–55. doi: 10.1023/b:mcbi.0000007260.32981.b9TchounwouPBCentenoJAPatlollaAKArsenic toxicity, mutagenesis, and carcinogenesis - a health risk assessment and management approachMol Cell Biochem 2004255475510.1023/b:mcbi.0000007260.32981.b914971645Open DOISearch in Google Scholar
Nasrollahzadeh A, Bashash D, Kabuli M, Zandi Z, Kashani B, Zaghal A, Mousavi SA, Ghaffari SH. Arsenic trioxide and BIBR1532 synergistically inhibit breast cancer cell proliferation through attenuation of NF-κB signaling pathway. Life Sci 2020;257:118060. doi: 10.1016/j.lfs.2020.118060NasrollahzadehABashashDKabuliMZandiZKashaniBZaghalAMousaviSAGhaffariSHArsenic trioxide and BIBR1532 synergistically inhibit breast cancer cell proliferation through attenuation of NF-κB signaling pathwayLife Sci202025711806010.1016/j.lfs.2020.11806032645343Open DOISearch in Google Scholar
Wei M, Liu J, Xu M, Rui D, Xu S, Feng G, Ding Y, Li S, Guo S. Divergent effects of arsenic on NF-κB signaling in different cells or tissues: a systematic review and meta-analysis. Int J Environ Res Public Health 2016;13(2):163. doi: 10.3390/ijerph13020163WeiMLiuJXuMRuiDXuSFengGDingYLiSGuoSDivergent effects of arsenic on NF-κB signaling in different cells or tissues: a systematic review and meta-analysisInt J Environ Res Public Health201613216310.3390/ijerph13020163477218326821040Open DOISearch in Google Scholar
Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009;1(4):a000034. doi: 10.1101/cshperspect.a000034OeckinghausAGhoshSThe NF-κB family of transcription factors and its regulationCold Spring Harb Perspect Biol200914a00003410.1101/cshperspect.a000034277361920066092Open DOISearch in Google Scholar
Jin W, Xue Y, Xue Y, Han X, Song Q, Zhang J, Li Z, Cheng J, Guan S, Sun S, Chu L. Tannic acid ameliorates arsenic trioxide-induced nephrotoxicity, contribution of NF-κB and Nrf2 pathways. Biomed Pharmacother 2020;126:110047. doi: 10.1016/j.biopha.2020.110047JinWXueYXueYHanXSongQZhangJLiZChengJGuanSSunSChuLTannic acid ameliorates arsenic trioxide-induced nephrotoxicity, contribution of NF-κB and Nrf2 pathwaysBiomed Pharmacother202012611004710.1016/j.biopha.2020.11004732146384Open DOISearch in Google Scholar
Karin M, Delhase M. The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling. Semin Immunol 2000;12:85–98. doi: 10.1006/smim.2000.0210KarinMDelhaseMThe IκB kinase (IKK) and NF-κB: key elements of proinflammatory signallingSemin Immunol200012859810.1006/smim.2000.021010723801Open DOISearch in Google Scholar
Chen F, Shi X. Signaling from toxic metals to NF-κB and beyond: not just a matter of reactive oxygen species. Environ Health Perspect 2002;110(Suppl 5):807–11. doi: 10.1289/ehp.02110s5807ChenFShiXSignaling from toxic metals to NF-κB and beyond: not just a matter of reactive oxygen speciesEnviron Health Perspect2002110Suppl 58071110.1289/ehp.02110s5807124125012426136Open DOISearch in Google Scholar
Medda N, De SK, Maiti S. Different mechanisms of arsenic related signaling in cellular proliferation, apoptosis and neo-plastic transformation. Ecotoxicol Environ Saf 2021;208:111752. doi: 10.1016/j.ecoenv.2020.111752MeddaNDeSKMaitiSDifferent mechanisms of arsenic related signaling in cellular proliferation, apoptosis and neo-plastic transformationEcotoxicol Environ Saf202120811175210.1016/j.ecoenv.2020.11175233396077Open DOISearch in Google Scholar
He X, Ma Q. NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. Mol Pharmacol 2009;76:1265–78. doi: 10.1124/mol.109.058453HeXMaQNRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activationMol Pharmacol20097612657810.1124/mol.109.058453278472819786557Open DOISearch in Google Scholar
He X, Wang L, Szklarz G, Bi Y, Ma Q. Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway. J Pharmacol Exp Ther 2012;342:81–90. doi: 10.1124/jpet.112.194142HeXWangLSzklarzGBiYMaQResveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathwayJ Pharmacol Exp Ther2012342819010.1124/jpet.112.194142469640022493042Open DOISearch in Google Scholar
Zhong L, Hao H, Chen D, Hou Q, Zhu Z, He W, Sun S, Sun M, Li M, Fu X. Arsenic trioxide inhibits the differentiation of fibroblasts to myofibroblasts through nuclear factor erythroid 2-like 2 (NFE2L2) protein and the Smad2/3 pathway. J Cell Physiol 2019;234:2606–17. doi: 10.1002/jcp.27073ZhongLHaoHChenDHouQZhuZHeWSunSSunMLiMFuXArsenic trioxide inhibits the differentiation of fibroblasts to myofibroblasts through nuclear factor erythroid 2-like 2 (NFE2L2) protein and the Smad2/3 pathwayJ Cell Physiol201923426061710.1002/jcp.2707330317545Open DOISearch in Google Scholar
Massrieh W, Derjuga A, Blank V. Induction of endogenous Nrf2/small maf heterodimers by arsenic-mediated stress in placental choriocarcinoma cells. Antioxid Redox Signal 2006;8:53–9. doi: 10.1089/ars.2006.8.53MassriehWDerjugaABlankVInduction of endogenous Nrf2/small maf heterodimers by arsenic-mediated stress in placental choriocarcinoma cellsAntioxid Redox Signal2006853910.1089/ars.2006.8.5316487037Open DOISearch in Google Scholar
Wang L, Kou MC, Weng CY, Hu LW, Wang YJ, Wu MJ. Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways. Arch Toxicol 2012;86:879–96. doi: 10.1007/s00204-012-0845-zWangLKouMCWengCYHuLWWangYJWuMJArsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathwaysArch Toxicol2012868799610.1007/s00204-012-0845-z22488045Open DOISearch in Google Scholar
Eckstein M, Eleazer R, Rea M, Fondufe-Mittendorf Y. Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis. Rev Environ Health 2017;32:93–103. doi: 10.1515/reveh-2016-0025EcksteinMEleazerRReaMFondufe-MittendorfYEpigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesisRev Environ Health2017329310310.1515/reveh-2016-002527701139Open DOISearch in Google Scholar
Thomas DJ. Arsenic methylation - Lessons from three decades of research. Toxicology 2021;457:152800. doi: 10.1016/j.tox.2021.152800ThomasDJArsenic methylation - Lessons from three decades of researchToxicology202145715280010.1016/j.tox.2021.15280033901604Open DOISearch in Google Scholar
Cheng TF, Choudhuri S, Muldoon-Jacobs K. Epigenetic targets of some toxicologically relevant metals: a review of the literature. J Appl Toxicol 2012;32:643–53. doi: 10.1002/jat.2717ChengTFChoudhuriSMuldoon-JacobsKEpigenetic targets of some toxicologically relevant metals: a review of the literatureJ Appl Toxicol2012326435310.1002/jat.271722334439Open DOISearch in Google Scholar
Mukhopadhyay P, Greene RM, Pisano MM. Cigarette smoke induces proteasomal-mediated degradation of DNA methyltransferases and methyl CpG-/CpG domain-binding proteins in embryonic orofacial cells. Reprod Toxicol 2015;58:140–8. doi: 10.1016/j. reprotox.2015.10.009MukhopadhyayPGreeneRMPisanoMMCigarette smoke induces proteasomal-mediated degradation of DNA methyltransferases and methyl CpG-/CpG domain-binding proteins in embryonic orofacial cellsReprod Toxicol201558140810.1016/j. reprotox.2015.10.009Open DOISearch in Google Scholar
Pogribna M, Hammons G. Epigenetic effects of nanomaterials and nanoparticles. J Nanobiotechnology 2021;19:2. doi: 10.1186/s12951-020-00740-0PogribnaMHammonsGEpigenetic effects of nanomaterials and nanoparticlesJ Nanobiotechnology202119210.1186/s12951-020-00740-0778933633407537Open DOISearch in Google Scholar
Li H, He J, Ju P, Zhong X, Liu J. Studies on the mechanism of arsenic trioxide-induced apoptosis in HepG2 human hepatocellular carcinoma cells. Chin J Clin Oncol 2008;5:22–5. doi: 10.1007/s11805-008-0022-6LiHHeJJuPZhongXLiuJStudies on the mechanism of arsenic trioxide-induced apoptosis in HepG2 human hepatocellular carcinoma cellsChin J Clin Oncol2008522510.1007/s11805-008-0022-6Open DOISearch in Google Scholar
Cai X, Yu L, Chen Z, Ye F, Ren Z, Jin P. Arsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1. Cancer Biomark 2020;28:221–30. doi: 10.3233/cbm-190490CaiXYuLChenZYeFRenZJinPArsenic trioxide-induced upregulation of miR-1294 suppresses tumor growth in hepatocellular carcinoma by targeting TEAD1 and PIM1Cancer Biomark2020282213010.3233/cbm-190490Open DOISearch in Google Scholar
Jing-Jing Z, Xiao-Jie C, Wen-Dong Y, Ying-Hui W, Hang-Sheng Z, Hong-Yue Z, Zhi-Hong Z, Bin-Hui W, Fan-Zhu. Fabrication of a folic acid-modified arsenic trioxide prodrug liposome and assessment of its anti-hepatocellular carcinoma activity. Dig Chin Med 2020;3:260–74. doi: 10.1016/j.dcmed.2020.12.005Jing-JingZXiao-JieCWen-DongYYing-HuiWHang-ShengZHong-YueZZhi-HongZBin-HuiW Fan-ZhuFabrication of a folic acid-modified arsenic trioxide prodrug liposome and assessment of its anti-hepatocellular carcinoma activityDig Chin Med202032607410.1016/j.dcmed.2020.12.005Open DOISearch in Google Scholar
Zhang F, Duan J, Song H, Yang L, Zhou M, Wang X. Combination of canstatin and arsenic trioxide suppresses the development of hepatocellular carcinoma. Drug Dev Res 2021;82:430–9. doi: 10.1002/ ddr.21766ZhangFDuanJSongHYangLZhouMWangXCombination of canstatin and arsenic trioxide suppresses the development of hepatocellular carcinomaDrug Dev Res202182430910.1002/ ddr.21766Open DOISearch in Google Scholar
Chen Y, Li H, Chen D, Jiang X, Wang W, Li D, Shan H. Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance by upregulating HIF-1α expression. Dig Dis Sci 2022;67:3806–16. doi: 10.1007/s10620-021-07202-zChenYLiHChenDJiangXWangWLiDShanHHypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance by upregulating HIF-1α expressionDig Dis Sci20226738061610.1007/s10620-021-07202-z34383201Open DOISearch in Google Scholar
Fang Y, Zhang Z. Arsenic trioxide as a novel anti-glioma drug: a review. Cell Mol Biol Lett 2020;25:44. doi: 10.1186/s11658-020-00236-7FangYZhangZArsenic trioxide as a novel anti-glioma drug: a reviewCell Mol Biol Lett2020254410.1186/s11658-020-00236-7751762432983240Open DOISearch in Google Scholar
Siddique R, Khan S, Bai Q, Li H, Ullah MW, Xue M. Arsenic Trioxide-based nanomedicines as a therapeutic combination approach for treating gliomas: a review. Curr Nanosci 2021;17:406–17. doi: 10.217 4/1573413716999201207142810SiddiqueRKhanSBaiQLiHUllahMWXueMArsenic Trioxide-based nanomedicines as a therapeutic combination approach for treating gliomas: a reviewCurr Nanosci2021174061710.217 4/1573413716999201207142810Open DOISearch in Google Scholar
Sönksen M, Kerl K, Bunzen H. Current status and future prospects of nanomedicine for arsenic trioxide delivery to solid tumors. Med Res Rev 2021;42:374–98. doi: 10.1002/med.21844SönksenMKerlKBunzenHCurrent status and future prospects of nanomedicine for arsenic trioxide delivery to solid tumorsMed Res Rev2021423749810.1002/med.2184434309879Open DOISearch in Google Scholar
Genchi G, Lauria G, Catalano A, Carocci A, Sinicropi MS. Arsenic: a review on a great health issue worldwide. Appl Sci 2022;12(12):6184. doi: 10.3390/app12126184GenchiGLauriaGCatalanoACarocciASinicropiMSArsenic: a review on a great health issue worldwideAppl Sci20221212618410.3390/app12126184Open DOISearch in Google Scholar
Gamboa-Loira B, Cebrián ME, Franco-Marina F, López-Carrillo L. Arsenic metabolism and cancer risk: a meta-analysis. Environ Res 2017;156:551–8. doi: 10.1016/j.envres.2017.04.016Gamboa-LoiraBCebriánMEFranco-MarinaFLópez-CarrilloLArsenic metabolism and cancer risk: a meta-analysisEnviron Res2017156551810.1016/j.envres.2017.04.01628433864Open DOISearch in Google Scholar
Nurchi VM, Djordjevic AB, Crisponi G, Alexander J, Bjørklund G, Aaseth J. Arsenic toxicity: molecular targets and therapeutic agents. Biomolecules 2020;10(2):235. doi: 10.3390/biom10020235NurchiVMDjordjevicABCrisponiGAlexanderJBjørklundGAasethJArsenic toxicity: molecular targets and therapeutic agentsBiomolecules202010223510.3390/biom10020235707257532033229Open DOISearch in Google Scholar
Wani A, Ara A, Usmani JA. Lead toxicity: a review. Interdiscip Toxicol 2015;8:55–64. doi: 10.1515/intox-2015-0009WaniAAraAUsmaniJALead toxicity: a reviewInterdiscip Toxicol20158556410.1515/intox-2015-0009496189827486361Open DOISearch in Google Scholar
Çelebi H, Gök G, Gök O. Adsorption capability of brewed tea waste in waters containing toxic lead(II), cadmium(II), nickel(II), and zinc(II) heavy metal ions. Sci Rep 2020;10(1):17570. doi: 10.1038/s41598-020-74553-4ÇelebiHGökGGökOAdsorption capability of brewed tea waste in waters containing toxic lead(II), cadmium(II), nickel(II), and zinc(II) heavy metal ionsSci Rep20201011757010.1038/s41598-020-74553-4756778633067532Open DOISearch in Google Scholar
World Health Organization. Lead poisoning [displayed 5 September 2022]. Available at https://www.who.int/news-room/fact-sheets/detail/lead-poisoning-and-healthWorld Health OrganizationLead poisoning [displayed 5 September 2022].Available athttps://www.who.int/news-room/fact-sheets/detail/lead-poisoning-and-healthSearch in Google Scholar
Charkiewicz AE, Backstrand JR. Lead toxicity and pollution in Poland. Int J Environ Res Public Health 2020;17(12):4385. doi: 10.3390/ijerph17124385CharkiewiczAEBackstrandJRLead toxicity and pollution in PolandInt J Environ Res Public Health20201712438510.3390/ijerph17124385734517532570851Open DOISearch in Google Scholar
Rehman K, Fatima F, Waheed I, Akash MSH. Prevalence of exposure of heavy metals and their impact on health consequences. J Cell Biochem 2018;119:157–84. doi: 10.1002/jcb.26234RehmanKFatimaFWaheedIAkashMSHPrevalence of exposure of heavy metals and their impact on health consequencesJ Cell Biochem20181191578410.1002/jcb.2623428643849Open DOISearch in Google Scholar
Samarghandian S, Shirazi FM, Saeedi F, Roshanravan B, Pourbagher-Shahri AM, Khorasani EY, Farkhondeh T, Aaseth JO, Abdollahi M, Mehrpour O. A systematic review of clinical and laboratory findings of lead poisoning: lessons from case reports. Toxicol Appl Pharmacol 2021;429:115681. doi: 10.1016/j.taap.2021.115681SamarghandianSShiraziFMSaeediFRoshanravanBPourbagher-ShahriAMKhorasaniEYFarkhondehTAasethJOAbdollahiMMehrpourOA systematic review of clinical and laboratory findings of lead poisoning: lessons from case reportsToxicol Appl Pharmacol202142911568110.1016/j.taap.2021.11568134416225Open DOISearch in Google Scholar
Papanikolaou NC, Hatzidaki EG, Belivanis S, Tzanakakis GN, Tsatsakis AM. Lead toxicity update. A brief review. Med Sci Monit 2005;11(10):RA329–36. PMID: 16192916PapanikolaouNCHatzidakiEGBelivanisSTzanakakisGNTsatsakisAMLead toxicity update.A brief review. Med Sci Monit20051110RA32936PMID: 16192916Search in Google Scholar
Centers for Disease Control and Prevention. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention - Report of the Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for Disease Control and Prevention, 2012 [displayed 28 October 2022]. Available at http://www.cdc.gov/nceh/lead/acclpp/final_document_030712.pdfCenters for Disease Control and PreventionLow Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention - Report of the Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for Disease Control and Prevention, 2012 [displayed 28 October 2022].Available athttp://www.cdc.gov/nceh/lead/acclpp/final_document_030712.pdfSearch in Google Scholar
Raymond J, Brown MJ. Childhood blood lead levels in children aged <5 years - United States, 2009–2014. MMWR Surveill Summ 2017;66:1–10. doi: 10.15585/mmwr.ss6603a1RaymondJBrownMJChildhood blood lead levels in children aged <5 years - United States, 2009–2014MMWR Surveill Summ20176611010.15585/mmwr.ss6603a1589831328103215Open DOISearch in Google Scholar
Dignam T, Kaufmann RB, LeStourgeon L, Brown MJ. Control of lead sources in the United States, 1970–2017: Public health progress and current challenges to eliminating lead exposure. J Public Health Manag Pract 2019;25(Suppl 1):S13–22. doi: 10.1097/phh.0000000000000889DignamTKaufmannRBLeStourgeonLBrownMJControl of lead sources in the United States, 1970–2017: Public health progress and current challenges to eliminating lead exposureJ Public Health Manag Pract201925Suppl 1S132210.1097/phh.0000000000000889Open DOISearch in Google Scholar
Flannery BM, Middleton KB. Updated interim reference levels for dietary lead to support FDA’s Closer to Zero action plan. Regul Toxicol Pharmacol 2022;133:105202. doi: 10.1016/j.yrtph.2022.105202FlanneryBMMiddletonKBUpdated interim reference levels for dietary lead to support FDA’s Closer to Zero action planRegul Toxicol Pharmacol202213310520210.1016/j.yrtph.2022.10520235690180Open DOISearch in Google Scholar
Lubos E, Loscalzo J, Handy DE. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2011;15(7):1957–97. doi: 10.1089/ars.2010.3586LubosELoscalzoJHandyDEGlutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunitiesAntioxid Redox Signal201115719579710.1089/ars.2010.3586315911421087145Open DOISearch in Google Scholar
Mitra P, Sharma S, Purohit P, Sharma P. Clinical and molecular aspects of lead toxicity: An update. Crit Rev Clin Lab Sci 2017;54:506–28. doi: 10.1080/10408363.2017.1408562MitraPSharmaSPurohitPSharmaPClinical and molecular aspects of lead toxicity: An updateCrit Rev Clin Lab Sci2017545062810.1080/10408363.2017.140856229214886Open DOISearch in Google Scholar
Flora G, Gupta D, Tiwari A. Toxicity of lead: A review with recent updates. Interdiscip Toxicol 2012;5(2):47–58. doi: 10.2478/v10102-012-0009-2FloraGGuptaDTiwariAToxicity of lead: A review with recent updatesInterdiscip Toxicol201252475810.2478/v10102-012-0009-2348565323118587Open DOISearch in Google Scholar
Obeng-Gyasi E. Lead exposure and oxidative stress - A life course approach in US adults. Toxics 2018;6(3):42. doi: 10.3390/toxics6030042Obeng-GyasiE.Lead exposure and oxidative stress - A life course approach in US adultsToxics2018644210.3390/toxics6030042616111730071602Open DOISearch in Google Scholar
Jiang X, Xing X, Zhang Y, Zhang C, Wu Y, Chen Y, Meng R, Jia H, Cheng Y, Zhang Y, Su J. Lead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female mice. Ecotoxicol Environ Saf 2021;207:111231. doi: 10.1016/j.ecoenv.2020.111231JiangXXingXZhangYZhangCWuYChenYMengRJiaHChengYZhangYSuJLead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female miceEcotoxicol Environ Saf202120711123110.1016/j.ecoenv.2020.11123132916527Open DOISearch in Google Scholar
Gurer-Orhan H, Sabır HU, Özgüneş H. Correlation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workers. Toxicology 2004;195:147–54. doi: 10.1016/j.tox.2003.09.009Gurer-OrhanHSabırHUÖzgüneşHCorrelation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workersToxicology20041951475410.1016/j.tox.2003.09.00914751670Open DOISearch in Google Scholar
La-Llave-León O, Méndez-Hernández EM, Castellanos-Juárez FX, Esquivel-Rodríguez E, Vázquez-Alaniz F, Sandoval-Carrillo A, García-Vargas G, Duarte-Sustaita J, Candelas-Rangel JL, Salas-Pacheco JM. Association between blood lead levels and delta-aminolevulinic acid dehydratase in pregnant women. Int J Environ Res Public Health 2017;14(4):432. doi: 10.3390/ijerph14040432La-Llave-LeónOMéndez-HernándezEMCastellanos-JuárezFXEsquivel-RodríguezEVázquez-AlanizFSandoval-CarrilloAGarcía-VargasGDuarte-SustaitaJCandelas-RangelJLSalas-PachecoJMAssociation between blood lead levels and delta-aminolevulinic acid dehydratase in pregnant womenInt J Environ Res Public Health201714443210.3390/ijerph14040432540963328420209Open DOISearch in Google Scholar
Andrade V, Mateus ML, Batoréu, MC, Aschner M, Dos Santos AM. Urinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganese. Neurotoxicology 2013;38:33–41. doi: 10.1016/j.neuro.2013.06.003AndradeVMateusMLBatoréuMCAschnerMDosSantos AMUrinary delta-ALA: a potential biomarker of exposure and neurotoxic effect in rats co-treated with a mixture of lead, arsenic and manganeseNeurotoxicology201338334110.1016/j.neuro.2013.06.003377078523764341Open DOISearch in Google Scholar
Ibrahem S, Hassan M, Ibraheem Q, Arif K. Genotoxic effect of lead and cadmium on workers at wastewater plant in Iraq. J Environ Public Health 2020;2020:9171027. doi: 10.1155/2020/9171027IbrahemSHassanMIbraheemQArifKGenotoxic effect of lead and cadmium on workers at wastewater plant in IraqJ Environ Public Health20202020917102710.1155/2020/9171027739742532774395Open DOISearch in Google Scholar
Sridevi SK, Umamaheswari S. Human exposure to lead, mechanism of toxicity and treatment strategy - a review. J Clin Diagnostic Res 2020;14(12):LE01–5. doi: 10.7860/JCDR/2020/45615.14345SrideviSKUmamaheswariSHuman exposure to lead, mechanism of toxicity and treatment strategy - a reviewJ Clin Diagnostic Res20201412LE01–510.7860/JCDR/2020/45615.14345Open DOISearch in Google Scholar
Patra R, Rautray AK, Swarup D. Oxidative stress in lead and cadmium toxicity and its amelioration. Vet Med Int 2011;2011:457327. doi: 10.4061/2011/457327PatraRRautrayAKSwarupDOxidative stress in lead and cadmium toxicity and its ameliorationVet Med Int2011201145732710.4061/2011/457327308744521547215Open DOISearch in Google Scholar
Wyparło-Wszelaki M, Wąsik M, Machoń-Grecka A, Kasperczyk A, Bellanti F, Kasperczyk S, Dobrakowski M. Blood magnesium level and selected oxidative stress indices in lead-exposed workers. Biol Trace Elem Res 2021;199:465–72. doi: 10.1007/s12011-020-02168-xWyparło-WszelakiMWąsikMMachoń-GreckaAKasperczykABellantiFKasperczykSDobrakowskiMBlood magnesium level and selected oxidative stress indices in lead-exposed workersBiol Trace Elem Res20211994657210.1007/s12011-020-02168-x774656232372126Open DOISearch in Google Scholar
Adeyemi WJ, Abdussalam TA, Abdulrahim A, Olayaki LA. Elevated, sustained, and yet reversible biotoxicity effects of lead on cessation of exposure: Melatonin is a potent therapeutic option. Toxicol Ind Health 2020;36:477–86. doi: 10.1177/0748233720937199AdeyemiWJAbdussalamTAAbdulrahimAOlayakiLAElevated, sustained, and yet reversible biotoxicity effects of lead on cessation of exposure: Melatonin is a potent therapeutic optionToxicol Ind Health2020364778610.1177/074823372093719932643556Open DOISearch in Google Scholar
Virgolini MB, Aschner M. Molecular mechanisms of lead neurotoxicity. Adv Neurotoxicol 2021;5:159–213. doi: 10.1016/bs.ant.2020.11.002VirgoliniMBAschnerMMolecular mechanisms of lead neurotoxicityAdv Neurotoxicol2021515921310.1016/bs.ant.2020.11.002827693634263090Open DOISearch in Google Scholar
Jangid AP, Shekhawat V, Pareek H, Yadav D, Sharma P, John P. Effect of lead on human blood antioxidant enzymes and glutathione. Int J Biochem Res Rev 2016;13(1):1–9.JangidAPShekhawatVPareekHYadavDSharmaPJohnPEffect of lead on human blood antioxidant enzymes and glutathioneInt J Biochem Res Rev20161311910.9734/IJBCRR/2016/26992Search in Google Scholar
Kshirsagar MS, Patil JA, Patil A. Increased blood lead level induces oxidative stress and alters the antioxidant status of spray painters. J Basic Clin Physiol Pharmacol 2020;31(2):20180229. doi: 10.1515/jbcpp-2018-0229KshirsagarMSPatilJAPatilAIncreased blood lead level induces oxidative stress and alters the antioxidant status of spray paintersJ Basic Clin Physiol Pharmacol20203122018022910.1515/jbcpp-2018-022931926081Open DOISearch in Google Scholar
Sadhu HG, Amin BK, Parikh DJ, Sathawara NG, Mishra U, Virani BK, Lakkad BC, Shivgotra VK, Patel S. Poisoning of workers working in small lead-based units. Indian J Occup Environ Med 2008;12:139–41. doi: 10.4103/0019-5278.44697SadhuHGAminBKParikhDJSathawaraNGMishraUViraniBKLakkadBCShivgotraVKPatelSPoisoning of workers working in small lead-based unitsIndian J Occup Environ Med2008121394110.4103/0019-5278.44697279674420040974Open DOISearch in Google Scholar
Sirati-Sabet M, Asadikaram G, Ilghari D, Gheibi N, Torkman F, Abdolvahabi Z, Khabbaz F. The effect of lead on erythrocyte glucose-6-phosphate dehydrogenase activity in rats. Biotech Health Sci 2014;1(1):e19192. doi: 10.17795/bhs-19192Sirati-SabetMAsadikaramGIlghariDGheibiNTorkmanFAbdolvahabiZKhabbazFThe effect of lead on erythrocyte glucose-6-phosphate dehydrogenase activity in ratsBiotech Health Sci201411e1919210.17795/bhs-19192Open DOISearch in Google Scholar
Flora S, Mittal M, Mehta A. Heavy metal induced oxidative stress and its possible reversal by chelation therapy. Indian J Med Res 2008;128:501–23. PMID: 19106443FloraSMittalMMehtaAHeavy metal induced oxidative stress and its possible reversal by chelation therapyIndian J Med Res200812850123PMID: 19106443Search in Google Scholar
Lachant NA, Tomoda A, Tanaka KR. Inhibition of the pentose phosphate shunt by lead: a potential mechanism for hemolysis in lead poisoning. Blood 1984;63:518–24. doi: 10.1182/blood.V63.3.518.518LachantNATomodaATanakaKRInhibition of the pentose phosphate shunt by lead: a potential mechanism for hemolysis in lead poisoningBlood1984635182410.1182/blood.V63.3.518.518Open DOISearch in Google Scholar
Moniuszko-Jakoniuk J, Jurczuk M, Brzóska MM. Evaluation of glutathione-related enzyme activities in the liver and kidney of rats exposed to lead and ethanol. Pharmacol Rep 2007;59(Suppl 1):217–25.Moniuszko-JakoniukJJurczukMBrzóskaMMEvaluation of glutathione-related enzyme activities in the liver and kidney of rats exposed to lead and ethanolPharmacol Rep200759Suppl 121725Search in Google Scholar
Dobrakowski M, Pawlas N, Kasperczyk A, Kozłowska A, Olewińska E, Machoń-Grecka A, Kasperczyk S. Oxidative DNA damage and oxidative stress in lead-exposed workers. Hum Exp Toxicol 2017;36:744–54. doi: 10.1177/0960327116665674DobrakowskiMPawlasNKasperczykAKozłowskaAOlewińskaEMachoń-GreckaAKasperczykSOxidative DNA damage and oxidative stress in lead-exposed workersHum Exp Toxicol2017367445410.1177/096032711666567427596070Open DOISearch in Google Scholar
Simons T. Lead-calcium interactions and lead toxicity. In: Baker PF, editor. Calcium in drug actions. Handbook of experimental pharmacology. Vol 83. Berlin, Heidelberg: Springer; 1988. p. 509–25. doi: 10.1007/978-3-642-71806-9_24SimonsTLead-calcium interactions and lead toxicityInBakerPFeditorCalcium in drug actions. Handbook of experimental pharmacology. Vol 83.Berlin, HeidelbergSpringer1988p.5092510.1007/978-3-642-71806-9_24Open DOISearch in Google Scholar
Rădulescu A, Lundgren S. A pharmacokinetic model of lead absorption and calcium competitive dynamics. Sci Rep 2019;9:14225. doi: 10.1038/s41598-019-50654-7RădulescuALundgrenSA pharmacokinetic model of lead absorption and calcium competitive dynamicsSci Rep201991422510.1038/s41598-019-50654-7677516931578386Open DOISearch in Google Scholar
García-Lestón J, Méndez J, Pásaro E, Laffon B. Genotoxic effects of lead: an updated review. Environ Int 2010;36:623–36. doi: 10.1016/j. envint.2010.04.011García-LestónJMéndezJPásaroELaffonBGenotoxic effects of lead: an updated reviewEnviron Int2010366233610.1016/j. envint.2010.04.011Open DOISearch in Google Scholar
Sachdeva C, Thakur K, Sharma A, Sharma KK. Lead: tiny but mighty poison. Indian J Clin Biochem 2018;33:132–46. doi: 10.1007/s12291-017-0680-3SachdevaCThakurKSharmaASharmaKKLead: tiny but mighty poisonIndian J Clin Biochem2018331324610.1007/s12291-017-0680-3589146229651203Open DOISearch in Google Scholar
Das U, De M. Chromosomal study on lead exposed population. Int J Hum Genet 2013;13:53–8. doi: 10.1080/09723757.2013.11886197DasUDeMChromosomal study on lead exposed populationInt J Hum Genet20131353810.1080/09723757.2013.11886197Open DOISearch in Google Scholar
Pinto D, Ceballos JM, García G, Guzmán P, Del Razo LM, Vera E, Gómez H, García A, Gosebatt ME. Increased cytogenetic damage in outdoor painters. Mutat Res 2000;467:105–11. doi: 10.1016/s1383-5718(00)00024-3PintoDCeballosJMGarcíaGGuzmánPDelRazo LMVeraEGómezHGarcíaAGosebattMEIncreased cytogenetic damage in outdoor paintersMutat Res20004671051110.1016/s1383-5718(00)00024-310838197Open DOISearch in Google Scholar
Rajah T, Ahuja Y. In vivo genotoxic effects of smoking and occupational lead exposure in printing press workers. Toxicol Lett 1995;76:71–5. doi: 10.1016/0378-4274(94)03200-9RajahTAhujaYIn vivo genotoxic effects of smoking and occupational lead exposure in printing press workersToxicol Lett19957671510.1016/0378-4274(94)03200-97701519Open DOISearch in Google Scholar
Duydu Y, Süzen HS. Influence of δ-aminolevulinic acid dehydratase (ALAD) polymorphism on the frequency of sister chromatid exchange (SCE) and the number of high-frequency cells (HFCs) in lymphocytes from lead-exposed workers. Mutat Res 2003;540:79–88. doi: 10.1016/s1383-5718(03)00172-4DuyduYSüzenHSInfluence of δ-aminolevulinic acid dehydratase (ALAD) polymorphism on the frequency of sister chromatid exchange (SCE) and the number of high-frequency cells (HFCs) in lymphocytes from lead-exposed workersMutat Res2003540798810.1016/s1383-5718(03)00172-412972060Open DOISearch in Google Scholar
Palus J, Rydzynski K, Dziubaltowska E, Wyszynska K, Natarajan AT, Nilsson R. Genotoxic effects of occupational exposure to lead and cadmium. Mutat Res 2003;540:19–28. doi: 10.1016/S1383-5718(03)00167-0PalusJRydzynskiKDziubaltowskaEWyszynskaKNatarajanATNilssonRGenotoxic effects of occupational exposure to lead and cadmiumMutat Res2003540192810.1016/S1383-5718(03)00167-012972055Open DOISearch in Google Scholar
Wiwanitkit V, Suwansaksri J, Soogarun S. White blood cell sister chromatid exchange among a sample of Thai subjects exposed to lead: lead-induced genotoxicity. Toxicol Environ Chem 2008;90:765–8. doi: 10.1080/02772240701712758WiwanitkitVSuwansaksriJSoogarunSWhite blood cell sister chromatid exchange among a sample of Thai subjects exposed to lead: lead-induced genotoxicityToxicol Environ Chem200890765810.1080/02772240701712758Open DOISearch in Google Scholar
Bonassi S, Znaor A, Ceppi M, Lando C, Chang WP, Holland N, Kirsch-Volders M, Zeiger E, Ban S, Barale R, Bigatti MP, Bolognesi C, Cebulska-Wasilewska A, Fabianova E, Fucic A, Hagmar L, Joksic G, Martelli A, Migliore L, Mirkova E, Scarfi MR, Zijno A, Norppa H, Fenech M. An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis 2007;28:625–31. doi: 10.1093/carcin/bgl177BonassiSZnaorACeppiMLandoCChangWPHollandNKirsch-VoldersMZeigerEBanSBaraleRBigattiMPBolognesiCCebulska-WasilewskaAFabianovaEFucicAHagmarLJoksicGMartelliAMiglioreLMirkovaEScarfiMRZijnoANorppaHFenechMAn increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humansCarcinogenesis2007286253110.1093/carcin/bgl17716973674Open DOISearch in Google Scholar
Celik A, Öğenler O, Çömelekoğlu Ü. The evaluation of micronucleus frequency by acridine orange fluorescent staining in peripheral blood of rats treated with lead acetate. Mutagenesis 2005;20:411–5. doi: 10.1093/mutage/gei055CelikAÖğenlerOÇömelekoğluÜThe evaluation of micronucleus frequency by acridine orange fluorescent staining in peripheral blood of rats treated with lead acetateMutagenesis200520411510.1093/mutage/gei05516135535Open DOISearch in Google Scholar
Nersesyan A, Kundi M, Waldherr M, Setayesh T, Mišík M, Wultsch G, Filipic M, Mazzaron Barcelos GR, Knasmueller S. Results of micronucleus assays with individuals who are occupationally and environmentally exposed to mercury, lead and cadmium. Mutat Res Rev Mutat Res 2016;770:119–39. doi: 10.1016/j.mrrev.2016.04.002NersesyanAKundiMWaldherrMSetayeshTMišíkMWultschGFilipicMMazzaronBarcelos GRKnasmuellerSResults of micronucleus assays with individuals who are occupationally and environmentally exposed to mercury, lead and cadmiumMutat Res Rev Mutat Res20167701193910.1016/j.mrrev.2016.04.00227894681Open DOISearch in Google Scholar
Balasubramanian B, Meyyazhagan A, Chinnappan AJ, Alagamuthu KK, Shanmugam S, Al-Dhabi NA, Mohammed Ghilan AK, Duraipandiyan V, Valan Arasu M. Occupational health hazards on workers exposure to lead (Pb): A genotoxicity analysis. J Infect Public Health 2020;13:527–31. doi: 10.1016/j.jiph.2019.10.005BalasubramanianBMeyyazhaganAChinnappanAJAlagamuthuKKShanmugamSAl-DhabiNAMohammedGhilan AKDuraipandiyanVValanArasu MOccupational health hazards on workers exposure to lead (Pb): A genotoxicity analysisJ Infect Public Health2020135273110.1016/j.jiph.2019.10.00531786007Open DOISearch in Google Scholar
Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2’-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2009;27:120–39. doi: 10.1080/10590500902885684ValavanidisAVlachogianniTFiotakisC8-hydroxy-2’-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesisJ Environ Sci Health C Environ Carcinog Ecotoxicol Rev2009271203910.1080/1059050090288568419412858Open DOISearch in Google Scholar
Liu X, Wu J, Shi W, Shi W, Liu H, Wu X. Lead induces genotoxicity via oxidative stress and promoter methylation of DNA repair genes in human lymphoblastoid TK6 cells. Med Sci Monit 2018;24:4295–304. doi: 10.12659/msm.908425LiuXWuJShiWShiWLiuHWuXLead induces genotoxicity via oxidative stress and promoter methylation of DNA repair genes in human lymphoblastoid TK6 cellsMed Sci Monit201824429530410.12659/msm.908425Open DOISearch in Google Scholar
Buha A, Baralić K, Djukic-Cosic D, Bulat Z, Tinkov A, Panieri E, Saso L. The role of toxic metals and metalloids in Nrf2 signaling. Antioxidants 2021;10(5):630. doi: 10.3390/antiox10050630BuhaABaralićKDjukic-CosicDBulatZTinkovAPanieriESasoLThe role of toxic metals and metalloids in Nrf2 signalingAntioxidants202110563010.3390/antiox10050630814298933918986Open DOISearch in Google Scholar
Aglan HS, Gebremedhn S, Salilew-Wondim D, Neuhof C, Tholen E, Holker M, Schellander K, Tesfaye D. Regulation of Nrf2 and NF-κB during lead toxicity in bovine granulosa cells. Cell Tissue Res 2020;380:643–55. doi: 10.1007/s00441-020-03177-xAglanHSGebremedhnSSalilew-WondimDNeuhofCTholenEHolkerMSchellanderKTesfayeDRegulation of Nrf2 and NF-κB during lead toxicity in bovine granulosa cellsCell Tissue Res20203806435510.1007/s00441-020-03177-x32185525Open DOISearch in Google Scholar
Alotaibi MF, Al-Joufi F, Abou Seif HS, Alzoghaibi MA, Djouhri L, Ahmeda AF, Mahmoud AM. Umbelliferone inhibits spermatogenic defects and testicular injury in lead-intoxicated rats by suppressing oxidative stress and inflammation, and improving Nrf2/HO-1 signaling. Drug Des Devel Ther 2020;14:4003–19. doi: 10.2147/dddt.s265636AlotaibiMFAl-JoufiFAbouSeif HSAlzoghaibiMADjouhriLAhmedaAFMahmoudAMUmbelliferone inhibits spermatogenic defects and testicular injury in lead-intoxicated rats by suppressing oxidative stress and inflammation, and improving Nrf2/HO-1 signalingDrug Des Devel Ther20201440031910.2147/dddt.s265636Open DOISearch in Google Scholar
World Health Organization, International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Inorganic and Organic Lead Compounds. Vol. 87. Inorganic and Organic Lead, 2006 [displayed 28 October 2022]. Available at https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono87.pdfWorld Health Organization, International Agency for Research on CancerIARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Inorganic and Organic Lead Compounds. Vol. 87. Inorganic and Organic Lead, 2006 [displayed 28 October 2022].Available athttps://monographs.iarc.who.int/wp-content/uploads/2018/06/mono87.pdfSearch in Google Scholar
Wallace DR, Djordjevic AB. Heavy metal and pesticide exposure: A mixture of potential toxicity and carcinogenicity. Curr Opin Toxicol 2020;19:72–9. 10.1016/j.cotox.2020.01.001WallaceDRDjordjevicABHeavy metal and pesticide exposure: A mixture of potential toxicity and carcinogenicityCurr Opin Toxicol20201972910.1016/j.cotox.2020.01.001Open DOISearch in Google Scholar
Chen QY, DesMarais T, Costa M. Metals and mechanisms of carcinogenesis. Annu Rev Pharmacol Toxicol 2019;59:537–54. doi: 10.1146/annurev-pharmtox-010818-021031ChenQYDesMaraisTCostaMMetals and mechanisms of carcinogenesisAnnu Rev Pharmacol Toxicol2019595375410.1146/annurev-pharmtox-010818-021031634846530625284Open DOISearch in Google Scholar
Fraga CG, Onuki J, Lucesoli F, Bechara EJ, Di Mascio P. 5-Aminolevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2’-deoxyguanosine in DNA. Carcinogenesis 1994;15:2241–4. doi: 10.1093/carcin/15.10.2241FragaCGOnukiJLucesoliFBecharaEJDiMascio P5-Aminolevulinic acid mediates the in vivo and in vitro formation of 8-hydroxy-2’-deoxyguanosine in DNACarcinogenesis1994152241410.1093/carcin/15.10.22417955060Open DOISearch in Google Scholar
Xu X, Liao W, Lin Y, Dai Y, Shi Z, Huo X. Blood concentrations of lead, cadmium, mercury and their association with biomarkers of DNA oxidative damage in preschool children living in an e-waste recycling area. Environ Geochem Health 2018;40:1481–94. doi: 10.1007/s10653-017-9997-3XuXLiaoWLinYDaiYShiZHuoXBlood concentrations of lead, cadmium, mercury and their association with biomarkers of DNA oxidative damage in preschool children living in an e-waste recycling areaEnviron Geochem Health20184014819410.1007/s10653-017-9997-328623427Open DOISearch in Google Scholar
Gorini F, Scala G, Cooke MS, Majello B, Amente S. Towards a comprehensive view of 8-oxo-7,8-dihydro-2’-deoxyguanosine: highlighting the intertwined roles of DNA damage and epigenetics in genomic instability. DNA Repair 2021;97:103027. doi: 10.1016/j.dnarep.2020.103027GoriniFScalaGCookeMSMajelloBAmenteSTowards a comprehensive view of 8-oxo-7,8-dihydro-2’-deoxyguanosine: highlighting the intertwined roles of DNA damage and epigenetics in genomic instabilityDNA Repair20219710302710.1016/j.dnarep.2020.103027792603233285475Open DOISearch in Google Scholar
Cogoi S, Ferino A, Miglietta G, Pedersen EB, Xodo LE. The regulatory G4 motif of the Kirsten ras (KRAS) gene is sensitive to guanine oxidation: implications on transcription. Nucleic Acids Res 2018;46:661–76. doi: 10.1093/nar/gkx1142CogoiSFerinoAMigliettaGPedersenEBXodoLEThe regulatory G4 motif of the Kirsten ras (KRAS) gene is sensitive to guanine oxidation: implications on transcriptionNucleic Acids Res2018466617610.1093/nar/gkx1142577846229165690Open DOISearch in Google Scholar
Fleming AM, Ding Y, Burrows CJ. Oxidative DNA damage is epigenetic by regulating gene transcription via base excision repair. Proc Natl Acad Sci USA 2017;114:2604–9. doi: 10.1073/pnas.1619809114FlemingAMDingYBurrowsCJOxidative DNA damage is epigenetic by regulating gene transcription via base excision repairProc Natl Acad Sci USA20171142604910.1073/pnas.1619809114534762628143930Open DOISearch in Google Scholar
Giorgio M, Dellino GI, Gambino V, Roda N, Pelicci PG. On the epigenetic role of guanosine oxidation. Redox Biol 2020;29:101398. doi: 10.1016/j.redox.2019.101398GiorgioMDellinoGIGambinoVRodaNPelicciPGOn the epigenetic role of guanosine oxidationRedox Biol20202910139810.1016/j.redox.2019.101398692634631926624Open DOISearch in Google Scholar
