Heavy Metals Toxicity: Mechanism, Health Effects, and Therapeutic Interventions

ABSTRACT

Heavy metals (HMs), such as chromium, arsenic, cadmium, mercury, and lead, constitute a class of environmental pollutants with significant toxicity that pose a serious threat to human health. This review provides a comprehensive overview of the biochemical properties of HMs, and their effects at the cellular, molecular, and genetic levels. HMs exert their toxic effects by interfering with various intracellular biochemical processes, including enzyme activity, protein synthesis, and energy metabolism. Furthermore, they can disrupt the integrity of cell membranes and affect cellular signaling, leading to cellular dysfunction and death. At the molecular and genetic levels, HMs can cause DNA damage and induce gene mutations, thereby affecting genetic transmission and expression. Then, the effects of HMs on the nervous system, kidneys, cardiovascular system, reproduction, and cancer risk are discussed. Therapeutic strategies, such as chelation therapy, antioxidants and free radical scavengers, supportive therapy, and prevention and reduction of exposure, have been shown to mitigate the toxic effects of HMs. Last, based on the current findings on the mechanisms of HMs, future research directions are prospected. Through multidisciplinary cooperation and integrated interventions, it is expected that the health risks posed by HMs can be alleviated. Future research needs to further elucidate the mechanisms of HMs toxicity, develop more effective treatments, and strengthen preventive and control measures.

Heavy metals exert a wide range of effects at the cellular, molecular, and genetic levels, leading to neurological damage, renal dysfunction, cardiovascular disease, reproductive developmental abnormality, immune system abnormality, and increased risk of cancer by interfering with biomolecule function, signaling pathways, inducing oxidative stress, and inhibiting enzyme activity, among other mechanisms. Therapeutic interventions for heavy metals include chelation therapy, antioxidant application, supportive therapy, and exposure reduction strategies aimed at mitigating the toxic effects of heavy metals. Future research is needed to further elucidate the mechanisms of toxicity, develop more effective therapeutic approaches, and strengthen environmental management and public health education in order to minimize the risks of heavy metals to human health.

1. Introduction

Heavy metals (HMs) have long been regarded as important environmental pollutants due to their toxicity and persistence in ecosystems. Historically, the adverse effects of HMs on human health and the environment have been documented for centuries. For example, the dangers of lead (Pb) poisoning were known in ancient Rome, and mercury (Hg) toxicity had been observed in populations consuming contaminated fish [1, 2]. In Japan, Hg poisoning has also sparked widespread global concern about the toxicity of HMs [3]. The use of traditional medicine with certain HMs‐based drugs, such as cinnabar and realgar, has also triggered the investigation of HMs toxicity. Cinnabar, the main component is HgS, is used in traditional medicine for its purported calming effects on the nervous system and other therapeutic purposes [4, 5, 6, 7].

With the rapid development of modern industrialization and urbanization, the problem of HMs pollution is becoming serious. Various factors, including industrial emissions, agricultural activities, mining extraction, and atmospheric deposition, have led to widespread contamination of soil, water, and air with HMs, such as chromium (Cr), arsenic (As), cadmium (Cd), Hg, and Pb [8]. These metals can accumulate through the food chain and pose a serious threat to human health through a variety of pathways, including intake, inhalation, and dermal contact [9]. Current research focuses on understanding the mechanisms of HMs toxicity, assessing their health effects, and developing effective alleviation and prevention strategies.

The serious problem of HMs pollution and its widespread impact on human health highlights the necessity of a comprehensive analysis of the biochemical properties and toxicity mechanisms of HMs. This process not only fills gaps in our existing knowledge, but also promotes the development of therapeutic and preventive strategies. Additionally, it provides an important basis for the formulation of public health policies and the guidance for future research directions. Given the complexity and multidisciplinary nature of the HMs pollution problem, this review was conceived with the objective of integrating and organizing the latest research findings on the mechanisms of HMs toxicity, health effects, and intervention strategies. By systematically summarizing the sources, pollution pathways, toxicity mechanisms, and effects of HMs on different organ systems, this review not only enhances the understanding of HMs pollution problems, but also promotes interdisciplinary cooperation and the formulation of more effective pollution prevention strategies and health protection measures. Furthermore, this review aims to reveal the shortcomings in existing research and propose potential avenues for future investigation, with the aim of offering inspiration and guidance for subsequent scientific studies, so as to better address the global challenges posed by HMs pollution.

Here, this review introduces HMs definition, classification, sources, and their pollution pathways. Next, the mechanisms underlying HMs toxicity are explored in detail, including their interactions with biomolecules, induction of oxidative stress (OS), inhibition of enzyme activities, and interference with metabolic pathways. Subsequently, the effects of HMs on different organ systems and their roles in the development of diseases are analyzed. Then, current treatment strategies and preventive measures are discussed. Finally, the key findings of the review are summarized, and future research directions are prospected.

2. Heavy Metals

2.1. Definition and Classification of HMs

HMs can be defined as metals with atomic number over 20 and a density exceeding 5 g/cm³. These metals can cause chronic toxicity when they accumulate to a certain extent in the human body [10, 11]. Moreover, HMs can be classified into four categories based on their environmental and biological impacts. Category (I): highly toxic HMs, including Pb, Hg, and Cd, pose significant threats to human health and the ecological environment, and their use and emissions should be strictly controlled. Category (II): moderately toxic HMs, including Cr, cobalt, and manganese, which are harmful to human health and the ecological environment, necessitating monitoring. Category (III): low‐toxicity HMs, including copper (Cu), zinc (Zn) and iron, pose relatively less harmful to human health and the ecosystem, but can also have an impact on the environment if accumulated excessively. Category (IV): trace HMs, including molybdenum (Mo), vanadium (V), antimony (Sb), and so on, although minimal risk to human health and the ecosystem environment, also require monitoring and controlling.

2.2. Sources and Ways of HMs Pollution

The sources and ways of HMs pollution are crucial topics in environmental science, with four main categories identified. Category (I): Industrial emissions are the main sources of HMs pollution. With the rapid development of industrialization and urbanization, the potential impact of HMs pollution on the environment and human health is increasingly a matter of public concern [12]. Category (II): Agricultural practices where pesticides and fertilizers use contribute to HMs contamination of soils, affecting their distribution in the soil [13]. Category (III): Mining activities,  mining and smelting activities release large quantities of toxic and harmful HMs into the soil, causing serious soil HMs pollution [14]. Category (IV): Atmospheric deposition, where HMs in the atmosphere can enter soil and water through aerosol deposition [15].

Correspondingly, there are three main ways in which HMs affect human health. Category (I): Soil pollution: soil is the main conduit for HMs pollution. Once HMs infiltrate the soil via different routes, they will affect the growth of microorganisms and plants and enter the human body through the food chain, and after accumulating to a certain extent, they will damage multiple organs and systems, and threaten human health. Category (II): Water pollution: when HMs enter water environments through industrial wastewater and agricultural drainage, affecting water quality and human safety. Category (III): Atmospheric pollution: HMs enter the atmosphere mainly through industrial emissions and traffic exhaust and then enter the human body through the respiratory system or affect soil and water through deposition.

In summary, HMs are derived from diverse sources, including industrial emissions, agricultural activities, and natural geological processes, and these pollutants ultimately enter the human body through the food chain, drinking water, and direct exposure, causing multisystemic harm health effects.

3. Mechanism of HMs Toxicity

HMs exert toxic effects through multiple mechanisms, mainly including interactions with biomolecules, induction of OS and reactive oxygen species (ROS) production, inhibition of enzymatic activity, and interference with metabolic pathways. These mechanisms are correlated and lead to cellular dysfunction and damage. Binding of HMs to proteins and nucleic acids directly impaired their function, while ROS production further exacerbated cellular damage. In addition, HMs inhibited the activity of key enzymes, which could lead to metabolic and intracellular homeostatic disorders. In‐depth understanding of these mechanisms and their interrelationships is essential for elucidating the toxicological properties of HMs.

3.1. Biochemistry of HMs

3.1.1. Interaction with Biomacromolecule

Biomacromolecules, including proteins, nucleic acids, and polysaccharides, are the basic substances of living organisms and perform important functions in the body [16, 17]. Hexavalent Cr (VI) had the potential to disrupt chromatin structure through direct oxidation and the formation of Cr–DNA complexes, a process that triggered the DNA damage response and facilitated the chromatin structural adjustments necessary for DNA repair mechanisms [18]. As interferes with protein function by binding to cysteine residues in proteins and forming complexes with thiols that produce toxic effects [19, 20, 21]. Interestingly, one mechanism by which HMs ions interfered with protein function is through ionic mimicry, wherein they could minic other ions, which is known as. For example, Cd could mimic native metal ions, such as calcium and Zn, by competing with protein binding sites, potentially altering protein structure and function [22]. Similarly, Hg could interact with sulfur groups in proteins, resulting in protein structural changes and function loss, which could lead to OS [23]. Additionally, Pb (II) could bind to sulfhydryl groups in proteins, leading to alterations in protein structure and function. Specially, the enzyme δ‐aminolevulinic acid dehydratase (ALAD) contained a Zn(II)–Cys3 site that could be replaced by Pb [24]. These mechanisms reveal the potential hazards posed by HMs to organisms and highlight their disruptive effects on the normal functions of biomacromolecules.

3.1.2. OS and ROS

Humans are primarily exposed to two oxidation states of Cr: trivalent Cr (Cr (III)) and Cr (VI). Notably, ROS were generated during the reduction of Cr (VI) to Cr (III), leading to OS and DNA damage. Furthermore, Cr (VI) was often present in the environment as the chromate anion. Due to its structural similarity to sulfate, it could enter the cells via the cellular sulfate transporter protein. Once inside the cells, Cr (VI) reacted with ascorbic acid and thiols, such as glutathione (GSH), producing hydrogen peroxide (H₂O₂) and free radicals, triggering OS, and causing damage to lipids, proteins, and DNA [25]. Likewise, under physiological conditions, As predominantly exists in the As (III) and pentavalent As (V), with As (III) exhibiting higher toxicity. As (III) could be oxidized to As (V) by redox reactions, and the methylation process was a crucial step in As metabolism, generating intermediates and potentially ROS. In addition, As (V) could be reduced back to As (III), leading to ROS generation and OS [26]. Cd‐induced OS was associated with its activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase (NOX), an enzyme complex found in a wide range of cell types that primarily facilitated the transfer of electrons from reduced NADPH to oxygen molecules, resulting in the production of ROS [27]. Chronic exposure to Hg increased extracellular glutamate levels, potentially due to enhanced glutamate release and/or decreased uptake, culminating in the overproduction of free radicals, such as nitric oxide (NO) [28]. Furthermore, Pb could directly stimulate the production of ROS, including mono‐linear oxygen (¹O₂), H₂O₂, and hydroxyl radical (OH⁻) [29]. These observations indicated that HMs, such as Cr, As, Cd, Hg, and Pb, share the common property of generating ROS and triggering OS through distinct mechanisms, which might ultimately lead to cellular damage and a variety of health issues.

3.1.3. Inhibition of Enzyme Activity and Interference of Metabolic Pathways

Urease is a pivotal enzyme involved in nitrogen metabolism, which plays a crucial role in the urea cycle by catalyzing the hydrolysis of urea into ammonia and carbon dioxide. Notably, elevated concentrations of Cr inhibited the activity of urease, and interfered with the normal process of urea decomposition [30]. Exposure to AS (III) also reduced the mRNA and protein expression levels of γ‐glutamylcysteine synthetase (γGCS), leading to reduced synthesis of GSH and impaired cellular antioxidant capacity [31]. Cd exposure significantly diminished the activity of hexokinase of the glycolytic pathway in the cardiac tissue, thereby affecting glucose metabolism and lipid accumulation [32]. Hg interacted with the thiol and selenol groups of the GSH peroxidase that resulted in reduced enzymatic activity [33]. Pb (II) inhibited the activity of ALAD, thereby obstructing heme synthesis and causing hemoglobin deficiency [24]. HMs interfered with the activity of key enzymes across critical metabolic pathways, including nitrogen metabolism, glucose metabolism, antioxidant systems, and heme synthesis, thereby negatively affecting cellular and organismal functions (Figure 1).

FIGURE 1.

The mechanisms of HMs tocicity. Cr: Cr (III) can be oxidized to Cr (VI), which forms Cr–DNA complexes, resulting in DNA and chromosomal damage. Cr (VI) enters cells via sulfate transporters and reacts with ascorbic acid and GSH to produce ROS, causing OS‐induced DNA damage. Furthermore, Cr (VI) inhibits urease activity in nitrogen metabolism, affecting urea hydrolysis. As: Reduction of As(V) to As(III) generates ROS, leading to OS. As (III) binds to the thiol groups in GSH and cysteine, reducing the cellular antioxidant capacity. Additionally, As (III) decreases the mRNA levels of γGCS, which further reduces GSH levels and diminishes the cellular antioxidant capacity. Cd: Cd competes with calcium and zinc binding sites on proteins, thereby disrupting protein function. Cd inhibits hexokinase activity, affecting glucose metabolism, and generates ROS by activating NADPH oxidase activity. Hg: Hg binds to thiol groups in proteins, leading to protein dysfunction and OS. Hg increases glutamate levels, causing excessive production of NO, which further induces OS. Additionally, Hg binds to thiol and selenol groups in glutathione peroxidase, leading to decreased enzymatic activity. Pb: Pb induces ROS production, including ¹O₂, H₂O₂, and OH⁻, leading to OS. Pb binds to the thiol groups in ALAD, inhibiting its function, which further suppresses heme synthesis and reduces hemoglobin levels. γGCS, γ‐glutamylcysteine synthetase; ALAD, δ‐aminolevulinic acid dehydratase; As, arsenic; Cd, cadmium; Cr, chromium; Cys, cysteine; GSH, glutathione; Hb, hemoglobin; Hg, mercury; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; Pb, lead; ROS, reactive oxygen species.

3.2. Effects at the Cellular Level

3.2.1. Cell Membrane Damage

Cr (VI) could alter cell membrane permeability, impair membrane integrity, and decrease the expression of the tight junction proteins, including zonula occludens 1 and occludin, leading to membrane dysfunction [34]. When bound to sphingomyelin (SM), a crucial component of cell membranes, As (V) triggered SM polymerization, and increased membrane permeability [35]. Cd was recognized as a membrane toxicant that was capable of interfering with ion channels and transporter proteins in cell membranes, causing alterations to membrane structure and function [36]. Cell membranes were primary targets of Hg‐induced damage, and Hg could disrupt the physiological phospholipid asymmetry in erythrocytes, and affect ankyrin and flotillin‐2 protein expression, leading to diminished membrane stability and increased fragmentation [37].

3.2.2. Mitochondrial Dysfunction

Exposure to Cr (VI) significantly increased the production of ROS and decreased the mitochondrial membrane potential (MMP), potentially causing abnormal mitochondrial structural changes, such as swelling and vacuoles formation [38]. Chronic As exposure has been shown to significantly decrease the mRNA and protein expression of the mitochondrial transcriptional coactivator peroxisome proliferator‐activated receptor gamma, coactivator 1α and its downstream target nuclear respiratory factors 1 (NRF1), NRF2, and transcription factor A mitochondrial, suggesting mitochondria damage [39]. Cd toxicity primarily raised from its inhibition of the mitochondrial electron transport chain (ETC), with a pronounced sensitivity to complex III, leading to its inhibition by approximately 77% [40]. Methylmercury (MeHg) might increase the release of calcium ions from the mitochondria into the cytoplasm by increasing mitochondrial membrane permeability, which could facilitate pyruvate entry into the mitochondria, thereby exacerbating the toxic effects of MeHg [41]. Pb inhibited the mitochondrial ETC, particularly at complex III, hindering electron flow and consequently diminishing the ability to synthesize adenosine triphosphate (ATP) [42].

3.2.3. Interference with Cellular Signal Transduction

Cr (VI)‐induced OS, lipid accumulation, and glycemic abnormalities were associated with dysregulation of the ROS/Nrf2/heme oxygenase‐1 (HO‐1) signaling pathway [43]. As activated the NF‐κB signaling pathway and enhanced the expression of vascular cell adhesion molecule‐1 triggered by tumor necrosis factor‐α (TNF‐α), subsequently activating proinflammatory cytokines and eliciting cellular inflammatory responses [44]. Cd might induce cellular pyroptosis by provoking mitochondrial OS and activating the cGAS–STING signaling pathway [45]. Hg‐induced OS initiated apoptosis and necrosis by activating the p38 mitogen‐activated protein kinase (MAPK) signaling pathway [46]. Pb exposure activated death receptor pathways, notably the Fas/FasL system, which subsequently triggered the caspase cascade, leading to apoptosis [47].

3.3. Impacts at the Molecular and Genetic Levels

3.3.1. DNA Damage and Genetic Mutations

Both Cr (III) and Cr (VI) significantly induced gene mutations and DNA damage, albeit through distinct mechanism. Cr(III) caused damage by disrupting DNA base stacking patterns and inducing DNA breaks, whereas Cr(VI) altered DNA structural changes by intercalating within the DNA plane [48]. As exposure induces OS, resulting in DNA damage and the inhibition of sensitive Zn finger DNA repair proteins. Although As itself was not a potent mutagen, it could significantly enhance the mutagenic effects of other mutagens, such as ultraviolet radiation and chemicals, a phenomenon known as “synergistic carcinogenesis” [49]. Similarly, low concentrations of Cd significantly increased the risk of genetic mutations and in turn promoted carcinogenesis by inducing OS and inhibiting DNA repair system [50]. MeHg and mercuric chloride (HgCl₂) significantly increased DNA damage, especially affecting mitochondrial DNA and nuclear DNA. Hg was also capable of inhibiting the activity of DNA repair systems, particularly the base excision repair (BER) and nucleotide excision repair (NER) pathways [51]. Likewise, Pb exposure resulted in the reduced expression of DNA repair genes in the BER, NER, and double‐strand break repair pathways [52].

3.3.2. Epigenetic Modifications

Cr (VI) exposure repressed the expression of genes such as O 6‐methylguanine–DNA methyltransferase (DNMT), mutl homolog 1, and semaphorin 4B by inducing hypermethylation of their promoter regions, and these gene downregulation was closely associated with cellular carcinogenesis, impaired DNA repair and metabolic disorders [53, 54, 55]. As (V) and As(III) were important environmental carcinogens that influenced the methylation status of cellular DNA [56]. The metabolism of As in organisms required substantial amounts of S‐adenosylmethionine (SAM), a crucial intracellular methyl donor. Depletion of SAM reduced the availability of methyl groups necessary for DNA methylation, which might lead to gene hypomethylations. This hypomethylation adversely affected gene expression, which in turn increased the risk of disease development [57, 58]. Additionally, As exposure had been shown to cause significant alterations in histone modifications, particularly histone methylation. Specifically, As exposure caused changes in histone H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 27 trimethylation (H3K27me3) levels, that are crucial in the regulating gene expression [59]. Notably, H3K4me3 was typically associated with gene activation, whereas H3K27me3 was linked to gene repression [60, 61]. In mammalian kidneys, Cd exposure decreased DNA methylation levels due to the inhibition of DNMT activity, thereby affecting gene expression [62]. Furthermore, Cd exposure inhibited histone deacetylase (HDAC) activity, leading to increased histone acetylation and altered chromatin structure, which subsequently influenced the gene transcriptional activity [63]. Hg exposure also affected epigenetic modifications and altered gene expression patterns, thereby regulating neurological development [64]. Mechanisms underlying Hg‐induced brain tumors included hypomethylation of specific genes and hypermethylation of CpG sites, which might lead to dysregulated gene expression and tumor development [65]. Chronic Pb exposure resulted in significantly elevated histone acetylation levels in hippocampal tissues, potentially linked to the enzymatic activity of histone acetyltransferase p300. Notably, the transcriptional level of p300 was significantly elevated following high‐dose Pb exposure [66].

3.3.3. Regulation of the Cell Cycle and Apoptosis

Cr (VI)‐induced cell cycle arrest was primarily mediated through a p53‐dependent pathway, wherein p53 protein was activated in response to stressors, such as DNA damage, which in turn regulated the expression of cell cycle‐inhibitory genes (e.g., p21 and p27). Concurrently, Cr(VI)‐induced apoptosis predominantly occurred via the mitochondrial pathway, characterized by the downregulation of antiapoptotic proteins (e.g., Bcl‐2 and Bcl‐XL) and the upregulation of proapoptotic proteins (e.g., Bax and Bcl‐XS). [67]. For As, human neuroblastoma cells treatment with As trioxide resulted in cell cycle arrest at the G2/M phase [68]. As increased cellular ROS levels and disrupted MMP, leading to the activation of caspase cascade reaction [69]. Cd induced apoptosis by increasing the Bax/Bcl‐2 ratio, while concurrently caused cell cycle arrest at the S and G2/M phases by upregulating the expression of p53, p21, and p27, and these combined effects led to apoptosis and cell cycle arrest in human astrocytes [70]. Hg exposure significantly reduced the expression of Cyclin D1 and Cyclin E, proteins crucial for the G1 and S phase transitions of the cell cycle, potentially leading to cell cycle arrest [71]. Additionally, Hg interfered with microtubule assembly and cellular energy metabolism by binding to sulfhydryl and selenol groups in proteins, thereby inducing apoptosis [72]. In vitro, study indicated that Pb nitrate (Pb(NO₃)₂) exhibited significant toxic effects on HL‐60 cells. Pb exposure was able to induce DNA damage, leading to cell cycle arrest at the G0/G1 phase and ultimately triggering apoptosis through the activation of caspase‐3 and the induction of nucleosome DNA fragmentation [73].

4. HMs, Mechanism, and Diseases

HMs are closely associated with a wide range of diseases, mainly affecting the nervous system, kidneys, cardiovascular system, reproductive and developmental system, and immune system, and they severely contribute to cancer risk. Of these, neurodegenerative diseases are particularly prominent as the nervous system is highly sensitive to HMs. Kidney damage and cardiovascular diseases are also major health concerns, while reproductive and developmental problems highlight the long‐term effects of HMs. The immune system is also significantly affected by HMs, which may lead to various immune‐related diseases. Also, certain HMs, such as Cr (VI) and Cd are generally recognized as carcinogens. These diseases are interrelated through OS, DNA damage, and cell signaling disruptions. Understanding these diseases and their mechanisms is critical to developing effective therapeutic strategies.

4.1. Nervous System

4.1.1. Cognitive Dysfunction

Cognitive dysfunction, characterized by impairments in memory, attention, language, executive function, perception, and social skills. Numerous HMs, including Pb, Hg, and Cd, could induce OS in the brain. These metals could also generate ROS that overwhelm the body's antioxidant defense, causing oxidative damage to neurons and other brain cells. Additionally, normal cellular function could be disrupted by OS, leading to cognitive impairment [74, 75, 76]. In addition to OS, Cd exposure had been associated with the induction of inflammatory factors, such as TNF‐α, IL‐1β, and IL‐6, which contributed to cognitive dysfunction [77]. Hg exerted neurotoxic effects by hyperactivating N‐methyl‐D‐aspartate (NMDA) receptors, leading to cytoskeletal instability. The NMDA receptor, an ionotropic glutamate receptor, was involved in a variety of physiological processes, including synaptic plasticity, nervous system development, learning, and memory [78, 79]. HMs, including Pb, Cd, MeHg, and As, shared a common binding affinity with NMDA receptors, Na⁺–K⁺–ATPase pumps, biological Ca²⁺, and glutamate neurotransmitters, which might disrupt the balance between ROS and antioxidants in the hippocampal area, ultimately resulting in cognitive dysfunction [80].

4.1.2. Neurodegenerative Diseases

Neurodegenerative diseases are characterized by a gradual and progressive loss of neuronal cell function and structure in specific brain regions, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) [81, 82]. Despite variations in clinical presentation and the specific brain regions affected, these diseases share some common pathological features: abnormal aggregation of proteins. In AD, amyloid beta (Aβ) protein plaques and neurofibrillary tangles (NFTs) serve as characteristic pathological hallmarks [83]. In PD, the aggregation of α‐synuclein (α‐syn) to form Lewy bodies is a defining pathological feature [84]. In ALS, the aberrant aggregation of TDP‐43 is associated with disease progression [85]. HD is associated with polyglutamine repeat expansion of Huntington protein [86]. Furthermore, mitochondrial dysfunction plays an important role in these neurodegenerative diseases, affecting energy metabolism and cell survival [87].

In AD, As exposure could increase the permeability of the blood–brain barrier, facilitating As accumulation in the brain and triggering neuroinflammation. Microglia, as the major immune cells in the central nervous system, are essential for neuroinflammatory responses and immune regulation [88, 89]. Furthermore, microglia activation was associated with impaired learning memory capacity in an As‐exposed mouse model [90, 91]. As exposure could also interfere with the processing of amyloid precursor protein (APP) to Aβ, a central characteristic of AD. Specifically, As elevated APP expression and facilitated the amyloidogenic pathway through activating β‐secretase and progerin [92]. Additionally, As exposure also affected mitochondrial dynamics, DNA repair pathways, and epigenetic alterations, all of which were potential mechanisms contributing to AD [93, 94].

Cd exposure might lead to neuronal death by triggering the mitochondrial apoptotic through multiple neurodegenerative signaling pathways. Research had demonstrated a significant correlation between blood Cd levels and AD mortality in the American elderly population, indicated that elevated blood Cd levels might serve as a significant predictor of increased AD mortality risk [95]. In addition, mice subjected to chronic Cd exhibited significant deterioration in memory and synaptic function. Furthermore, both subacute and chronic Cd exposure increased ROS production and suppressed antioxidant defense systems, including nuclear factor‐erythroid 2‐related factor 2 (Nrf2) and HO‐1. Also, Cd exposure activated the c‐Jun N‐terminal kinase 1 (JNK1) signaling pathway, which might further exacerbate the pathological changes associated with Aβ accumulation in AD [96]. Cd exposure influenced the phosphorylation state of tau protein, a critical step in the formation of NFTs. In AD, abnormal phosphorylation of tau proteins led to their detachment from microtubules, which in turn aggregated the formation of NFTs. Cd promoted the phosphorylation of tau protein through the activation of specific kinases, such as glycogen synthase kinase 3β (GSK‐3β) and cyclin‐dependent kinase 5 (CDK5) [97, 98]. Furthermore, even nontoxic concentrations of Cd could also promote the release of IL‐6 and IL‐8 by activating MAPK phosphorylation and NF‐κB signaling pathways [99].

Patients with AD exhibit elevated levels of Hg in the brain, blood, and tissue, with dental amalgam fillings being a significant exogenous source of brain Hg [100]. Aβ‐induced memory deficits in AD were manifested by Hg's detrimental effects on spatial learning and memory. Hg‐induced mitochondrial dysfunction further exacerbated spatial memory deficits in rats, as evidenced by increased ROS production, disruption of MMP, increased mitochondrial volume, GSH oxidation, and lipid peroxidation, which ultimately resulted in damage to the mitochondrial outer membrane. These alterations not only impaired hippocampal mitochondrial function, but also led to an elevated ADP/ATP ratio and decreased cytochrome c oxidase (complex IV) activity in the rat hippocampus [101].

Early exposure to Pb might cause young rats to exhibit addiction‐like symptoms of AD, with this exposure increasing the expression of APP and β‐secretase 1 (BACE1) in hippocampal and cortical regions, and further contributed to the accumulation of Aβ protein and the development of senile plaques in these regions [102]. Meanwhile, childhood Pb exposure promoted the expression of APP, BACE1, and transcription factor specific protein 1 (Sp1), which further facilitated Aβ deposition [103]. Furthermore, it had been shown that exposure to a mixture of As, Cd, and Pb induced early manifestations of AD‐like pathology in a synergistic manner, dependent on OS and inflammation [104].

In PD, the reduced expression of brain‐derived neurotrophic factor (BDNF) and phosphorylated GSK3β in the striatum of As‐exposed rats implied that dopamine (DA) signaling was affected here, as BDNF via its receptor tropomyosin receptor kinase B activated the PI3K/Akt signaling pathway, which subsequently inhibited GSK‐3β activity [105]. Additionally, decreased expression of pGSK3β might indicated increased GSK‐3β activity, which in turn led to higher expression of α‐Syn [106].

Cd exposure could trigger motor dysfunction, decrease the number of DA neurons, and cause neuropathological changes in midbrain regions.

Using untargeted lipidomic analyses, it had been demonstrated that Cd exposure led to alterations in the lipid composition of the midbrain, notably increasing levels of the proinflammatory sphingolipids, ceramide (Cer), SM, and ganglioside (GM3), and these lipid changes were associated with the development of neuroinflammation [107]. Cd could enter neuronal cells by influencing Zn transporter proteins, including ZIP6 and ZnT3. Mechanically, the upregulation of ZIP6 import proteins and downregulation of ZnT3 export proteins might lead to the accumulation of Cd in neurons, resulting in the accumulation of α‐syn protein and the disruption of neuroplasticity [108, 109].

As previously mentioned, Hg could be released from dental fillings and traversed the BBB to enter the brain, where it was also associated with PD strongly. Mechanically, Hg exhibited a variety of toxic effects, including the production of free radicals, autoimmune inflammation, and the attachment to sulfhydryl‐rich cell membranes in organelles, such as mitochondria, lysosomes, and the Golgi apparatus, all of which had been implicated in the pathogenesis of PD [110]. In addition, Hg had been found in neurons and oligodendrocytes, and usually colocalized with α‐syn [110]. This indicated that Hg was associated with the aggregation of α‐syn and might be involved in Lewy bodies formation.

Pb exposure had been shown to reduce dopaminergic neurotransmission through mitochondrial dysfunction, OS, and increased glial filaments in astrocyte. It readily crossed the BBB and was associated with alterations in various antioxidant enzymes and increased lipid peroxidation [111]. In addition, Pb could also induce OS via the activation of protein kinase C, leading to neurotoxicity [112]. Also, Pb caused hyperphosphorylation of Tau protein along with the accumulation of α‐Syn in the brain, leading to cellular apoptosis and autophagy activation, which contributed to the onset and progression of PD [113]. However, a study for HM detection of blood samples from PD patients found significantly lower Pb levels in PD patients compared with controls [114]. There are few studies on the correlation between Pb and PD, with inadequate sample sizes and a lack of comprehensive mechanistic studies, highlighting the need for further research in this area.

In ALS, Cd was able to penetrate neurons, leading to increased ROS within neurons and a concomitant reduction in their antioxidant defense mechanisms. Furthermore, Cd disrupted neuronal Ca²⁺ homeostasis, interfered with normal mitochondrial function, and activated cell death signaling pathways [115]. Cd exposure resulted in a significant increased expression level of S100A2 gene, which encodes a highly specific regulatory Ca²⁺ binding protein [116]. Elevated intracellular Ca²⁺ level induced MAPK/mTOR activation, cytochrome oxidase subunit (COX‐I/II/III) dysfunction, MMP disruption, cleavage of caspase‐9 and caspase‐3, and OS‐induced elevated ROS levels [117, 118]. Besides calcium, Cd was able to displace Zn in the superoxide dismutase (SOD) enzyme, which caused SOD inactivity and subsequent OS [119].

TDP‐43, an RNA‐binding protein, plays a crucial role in ALS, and its aberrant aggregation is a major pathological feature of ALS [120]. MeHg was a powerful neurotoxin that caused neurotoxicity and neuronal cell death [121]. It promoted the aggregation of TDP‐43 in the nucleus and the formation of nuclear granules, while simultaneously reduced the availability of free TDP‐43 in the nucleus. In addition, MeHg disrupted TDP‐43 homeostasis in neurons, leading to increased transcriptional levels and enhanced splicing function [122]. Characteristics of MeHg‐induced ALS included oligodendrocyte damage, depletion of myelin basic protein (MBP), and degeneration of white matter, which in turn contributed to the demyelination and motor neuron death [123]. MeHg could also affect the Nrf2/HO‐1 signaling pathway, a potential target for neuroprotection in ALS. Nrf2 overexpression in astrocytes via the glial fibrillary acidic protein (GFAP) promoter reversed motor neuron damage in a mouse model of ALS [121, 124].

For familial‐ALS (f‐ALS), genes associated with f‐ALS include SOD1, transactivation response DNA binding protein, and angiogenin, with approximately 20% of f‐ALS associated with mutations in the Cu/Zn SOD1 gene [125, 126]. Pb weakened the SOD1 gene in rats, suggesting that Pb affected the normal folding process of the SOD1 protein, resulting in unfolded or misfolded SOD1 protein, which subsequently led to motor neuron apoptosis [127]. In addition, reduced activity of the mutant SOD1 protein and its impaired ability to scavenge superoxide radicals led to excessive production of H₂O₂, which triggered the aggregation of superoxide or hydroxyl radicals, and this might elucidate the mechanism by which the SOD1 mutation induced f‐ALS [128].

In HD, Cd accumulated predominantly in the striatum, and cells expressing mutant Huntington protein (mHTT) were more susceptible to cell death upon acute Cd exposure. This exposure synergistically interacted with mHTT to reduce MMP and ATP levels in striatal cells, and the expression of the profusion proteins MFN1 and MFN2 in mitochondria, leading to abnormalities in mitochondrial morphology and function that exacerbated cell death [129]. In addition, Cd activated NOX and produced more ROS, which in turn triggered OS. Notably, heterotrimeric HTT cells interacted with Cd exposure to activate protein kinase C δ (PKCδ), which activated caspase‐9 and caspase‐3‐mediated apoptosis, while simultaneously blocked the overexpression of extracellular signal regulated kinase (ERK) [130] (Figure 2).

FIGURE 2.

HMs affect the pathogenesis of neurodegenerative diseases through various pathways. AD: As increases Aβ production by affecting β‐secretase and APP expression, while also disrupting mitochondrial dynamics and DNA repair. As enters the brain through the BBB, and activates microglia, leading to neuroinflammation. Cd increases Aβ and IL‐6/IL‐8 production by activating the JNK1, P‐MAPK, and NF‐κB signaling pathways, resulting in neuroinflammation. Cd also affects CDK5, GSK‐3β, and Tau protein phosphorylation. Hg acts on mitochondria, causing the destruction of MMP, an increase in the ADP/ATP ratio, and a decrease in complex IV activity, ultimately leading to increased ROS levels. Pb increases the deposition of Aβ by affecting Sp1 expression, activating BACE1 and APP. PD: As reduces BDNF level, affecting the PI3K/AKT signaling pathway, thereby influencing GSK‐3β phosphorylation, which can lead to an increase in α‐syn. Cd affects the balance of zinc through ZIP6/ZnT3 transporters, thereby impacting the expression and aggregation of α‐syn. Additionally, Cd exacerbates neuroinflammation by increasing the levels of proteins related to neuroinflammation, such as Cer, SM, and GM3. Hg crosses the BBB and generates ROS in the brain. It can react with sulfhydryl groups in mitochondria, lysosomes, and the Golgi apparatus, leading to altered or inactivated functions. Hg entry into oligodendrocytes and neurons affect the aggregation of α‐Syn to form Lewy bodies. Pb affects mitochondria, induces ROS production, activates astrocytes, and thereby impeding dopaminergic neurotransmission. Pb activates PKC, increases OS, and promotes the aggregation of α‐Syn, leading to neurotoxicity in dopaminergic neurons. ALS: Cd disrupts calcium ion homeostasis, increases ROS production, activates the MAPK/mTOR signaling pathway, leading to mitochondrial dysfunction, and triggers the activation of apoptotic signaling pathways. Hg affects oligodendrocytes, reduces the level of MBP, causing demyelination, and inhibits the Nrf2/OH‐1 signaling pathway, thereby increasing the expression of TDP43 protein and mRNA in motor neurons. HD: Cd increases ROS production through NADPH oxidation, leading to OS. Additionally, mutated mHTT interacts with Cd to cause collapse of MMP, impairment of energy metabolism, and reduction of MFN1/2 levels. Meanwhile, Cd activates the PKCδ/Caspase‐3/9 signaling pathway, promoting cell death. α‐syn, α‐synuclein; Aβ, amyloid beta; AD, Alzheimer's disease; ADP/ATP, adenosine diphosphate/adenosine triphosphate; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; As, arsenic; BACE1, β‐secretase 1; BBB, blood–brain barrier; BDNF, brain‐derived neurotrophic factor; Cd, cadmium; CDK5, cyclin‐dependent kinase 5; Cer, ceramide; COX, cytochrome c oxidase; DA, dopamine; GFAP, glial fibrillary acidic protein; GM3, ganglioside; GSK‐3β, glycogen synthase kinase 3β; GSK‐3β, glycogen synthase kinase‐3β; HD, Huntington's disease; Hg, mercury; Hg, mercury; IL‐6/IL‐8, interleukin 6/interleukin 8; JNK1, c‐Jun N‐terminal kinase 1; LBs, Lewy body; MAPK, mitogen‐activated protein kinase; MBP, myelin basic protein; MFN1/2, mitofusin 1/2; mHTT, mutant huntingtin; MMP, mitochondrial membrane potential; mTOR, mechanistic target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NF‐κB, nuclear factor kappa B; P‐GSK‐3β, phosphorylated glycogen synthase kinase‐3β; P‐MAPK, phosphorylated mitogen‐activated protein kinase; Pb, lead; PD, Parkinson's disease; PI3K/AKT, phosphoinositol‐3 kinase/protein kinase B; PKCδ, protein kinase c delta; PKC, protein kinase C; ROS, reactive oxygen species; S100A2, S100 calcium binding protein A2; SM, sphingomyelin; Sp1, specific protein 1; TDP‐43, TAR DNA binding protein 43; ZIP6, zinc finger protein 6; ZnT3, zinc transporter 3.

4.2. Kidney Damage ‐ Renal Dysfunction

Renal dysfunction is characterized by impaired kidney function, resulting in the inability to effectively filter blood, excrete waste products, maintain electrolyte balance, and regulate blood pressure.

Cr (VI) is recognized as a toxic Cr in the environment. Clinically, exposure to Cr (VI) led to severe acute renal exhaustion, primarily affecting the epithelial cells of the proximal tubules. In the human immortalized proximal renal tubular epithelial cell line HK‐2, Cr (VI) treatment activated intrinsic and extrinsic apoptosis pathways, as evidenced by the increased expression of cleaved caspase‐8 and caspase‐3 [131].

As, predominantly excreted via the kidneys, could alter protein expression in renal tissues following exposure. Specifically, remarkable changes in the ETC, oxidative phosphorylation, mitochondrial structure, and apoptosis‐related protein expression were observed [132].

Cd accumulated mainly in the tubular cells of the kidney, and upon cell death, Cd was released and appeared in the urine. Within the proximal tubule, Cd was able to bind to molecules such as β2‐microglobulin, albumin, and lipid transport protein‐2, to form complexes. These complexes were internalized via the megalin and cubilin receptors located on proximal tubule cells, which were integral to the endocytosis pathway and responsible for intracellular uptake of Cd complexes [133, 134].

In systemic circulation, two transporter proteins, organic anion transporters 1 and 3 (OAT1 and OAT3), played an important role in the kidneys and are responsible for the transport of organic anions from blood into renal tubular cells. Hg entered the kidney cells via OAT1 and OAT3, where it undergone conversion from organic to inorganic forms by enzymatic or nonenzymatic processes [135, 136, 137]. Inorganic Hg deposition was strongly associated with ROS generation, metallothionein (MT) expression, cell apoptosis, and proximal tubule injury [138].

Pb‐induced pathological changes in the kidneys are mainly characterized by impaired proximal tubular function and might progress to Fanconi syndrome. Pb interacted with renal cell membranes and enzymes, disrupting energy metabolism, calcium homeostasis, glucose regulation, ion transport, and the renin‐angiotensin system [139].

4.3. Cardiovascular System

4.3.1. Cardiovascular Disease

HMs, such as Cr, As, Cd, Hg, and Pb, are environmental pollutants prevalent in air, water, soil, food, and industrial products, and are associated with an elevated risk of cardiovascular disease [140]. As could cause cardiac arrhythmias, and it had been found that As₂O₃ could prolong the cardiac QT interval by inhibiting the processing of the human Ether‐à‐go‐go‐Related Gene protein to block rapid delayed rectifier potassium current (Ikr) in endoplasmic reticulum [141, 142]. Cd (VI) had a quenching effect on tryptophan and tyrosine residues in bovine hemoglobin, and this effect altered its secondary structure. In addition, Cd (VI) induced apoptosis and increased OS in vascular endothelial cells by modulating the p38 MAPK and JNK signaling pathways [143]. Myocardial cell electrophysiological disorder serve as crucial indicator of Cd‐induced myocardial cells injury. These disorders arise from the generation of stimulus electric potentials formed by ionic flow across cell membranes, involving ions include Na⁺, K⁺, and Ca²⁺. In biological systems, Cd existed as Cd²⁺ ions, which share structural similarities with Ca²⁺ ions [144]. Consequently, Cd²⁺ could compete with Ca²⁺ at the myocardial cell membrane, blocking its binding to calcium channel proteins and affecting Ca²⁺ influx, resulting in a decreased intracellular Ca²⁺ concentration and inhibited myocardial contractility [145]. Hg and its compounds damaged the vascular system primarily by triggering OS. Specifically, HgCl₂ induced locally increased angiotensin II secretion, which might increase the activity of cyclooxygenase‐2 (COX‐2) and NOX, leading to ROS production and OS [146, 147, 148].There was an established association between Pb exposure and cardiovascular diseases, wherein chronic Pb exposure regulated NO signaling pathway. Then, NO activated soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), which reduced Ca2+ concentration in vascular smooth muscle cells and promoted vasodilation. However, Pb exposure impaired this pathway by reducing sGC and cGMP, leading to decreased vasodilatory capacity [149].

4.3.2. Effects of Cardiac Function

In a Drosophila model, cardiac direct exposure to Cd induced reversible cardiac arrest and disrupted calcium signaling [150]. Also, CdCl₂ also reduced the expression and phosphorylation levels of the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), adversely affecting the normal transport and utilization of calcium ions, ultimately leading to cardiac contractile dysfunction. This effect was more pronounced in males, whereas females did not exhibit similar changes, suggesting that sex differences might have an important role in Cd toxicity [151]. Early Pb exposure in mice led to offspring with reduced cardiac ejection fraction and increased left ventricular volume, accompanied by abnormal cardiomyocyte sarcomeres development, mitochondrial structural disorders, and impaired mitochondrial function [152]. Additionally, Pb exposure inhibited voltage‐gated calcium channels, impeded channel activation, reduced cardiac contractility, and increased the risk of arrhythmias [153].

4.4. Reproduction and Development

4.4.1. Effects on the Reproductive System

Cr (VI) exposure increased the levels of OS markers, such as malondialdehyde (MDA) and protein carbonyls, while concurrently decreased the activities of antioxidant enzymes (e.g., SOD), in the ovaries of female rats, leading to ovarian dysfunction, adversely affecting follicular development and hormone synthesis [154]. Likewise, Cr (VI) induced OS damage in the male reproductive system by promoting free radical production, elevating MDA levels, and decreasing SOD and CAT activities, which resulted in reduced sperm count, lower viability, and tissue damage in reproductive organs [155]. Furthermore, As exposure during juvenile and puberty stages significantly affected reproductive development in female Sprague–Dawley rats by disrupting the estrous cycle, decreasing the number of primordial follicles and corpus luteum, increasing the number of atretic follicles, decreasing serum levels of estradiol, progesterone, and testosterone, elevating luteinizing hormone and follicle‐stimulating hormone levels, and selectively downregulating proteins associated with steroidogenesis, including follicle‐stimulating hormone receptor, steroidogenic acute regulatory protein, Cytochrome P450 family 17 subfamily A member 1 (CYP17A1), 3β‐hydroxysteroid dehydrogenase  (HSD3B1), and Cytochrome P450 family 19 subfamily A member 1 (CYP19A1) [156]. Cd disrupted spermatogenesis and compromised structural integrity of testicular tissue by inducing OS and DNA damage, and upregulated the expression of epidermal growth factor receptor (EGFR) and its downstream signaling pathways (e.g., p‐AKT, NF‐κB, COX‐2, etc.), which resulted in a decrease in spermatozoa viability and quantity [157]. HgCl₂ exposure exerted significantly toxic to the male reproductive system, primarily through mechanisms involving the testicular immunosuppression and fibrosis, which were related to the inhibition of the CD74 signaling pathway [158]. Pb caused testicular damage, decreased sperm quality, and induced reproductive dysfunction by promoting OS, disrupting mitochondrial function in sperm, decreasing sperm motility, and downregulating steroidogenesis‐related enzymes [159].

4.4.2. Effects on Embryo Development

Cr (VI), exemplified by potassium dichromate, showed significant toxicity to mouse embryos cultured in vitro, mainly by inhibiting blastocyst formation, and inducing OS and apoptosis in embryonic cells [160]. As caused delayed preimplantation embryonic development by inducing redox imbalance, characterized by decreased GSH levels and increased p66Shc levels, and interfered with extracellular amino acid metabolism in the embryo [161]. Additionally, maternal Cd exposure impaired preimplantation embryonic development in mice by inducing OS, interfering with epigenetic modifications, such as elevated levels of HDAC 1 and altered DNA methylation of the H19 gene, and increasing DNA damage, ultimately leading to embryonic death and developmental arrest [162].

4.5. Cancer Risk

4.5.1. Carcinogenicity of HMs

A recognized association exists between HMs and carcinogenicity, the process by which normal cells are transformed into cancerous cells. HMs might contribute to the cancer development through a variety of mechanisms. They could damage DNA and induce genetic mutations, which might lead to cancer. Additionally, HMs also produced ROS and triggered chronic inflammation, which in turn led to OS and DNA damage, further promoting carcinogenesis [163]. In addition, HMs could also alter gene expression patterns through epigenetic changes, such as DNA methylation and histone modifications, leading to abnormal gene expression that derived cancer progression. Moreover, HMs also interfered with signaling pathways involved in cell growth, differentiation, and apoptosis, and disruption of these pathways might promote uncontrolled cell proliferation and evasion of programmed death, both of which are hallmarks of cancer [164].

4.5.2. Associations with Specific Cancer Types

Cr (VI) is a prevalent environmental and industrial pollutant that is strongly associated with an increased incidence of lung cancer. Polycyclic aromatic hydrocarbons (PAHs) from cigarette smoking are the main carcinogens responsible for lung cancer. Cr (VI) exposure had a high proportion of guanine to thymine (G to T) mutations in the p53 gene, which is a hallmark mutation pattern observed in PAHs. In addition, Cr (VI) facilitated the binding of PAHs to the p53 gene in the lungs [165]. Similarly, As exhibited high toxicity and pathogenicity, especially in the lungs [166]. Upon As entered the human body, it undergone a series of reduction, oxidation, and methylation reactions, to transform into carcinogenic substances. Specifically, As (V) was reduced to As (III) in the presence of GSH and thioredoxin (TRX). Subsequently, As (III) was further methylated during in vivo metabolism to produce more carcinogenic As metabolites: trivalent monomethylarsenic acids MMAs (III), pentavalent MMAs (V), and pentavalent dimethylarsenic acids DMAs (V). Alterations triggered by these processes at the genetic and epigenetic levels included the generation of ROS and reactive nitrogen species, modifications in DNA methylation patterns, alterations in miRNA expression, and variations in histone modifications [167]. Chronic Cd exposure in human lung cells in vitro had been shown to exhibit increased invasiveness, colony formation, cell proliferation, downregulation of tumor suppressor genes p16 and SLC38A3, upregulation of oncoproteins K‐RAS and N‐RAS, increased in MT‐1A and MT‐2A, and activation of OS adaptive response genes HO‐1 and HIF‐1A, as well as increased metal transporter genes ZNT‐1, ZNT‐5 and ZIP‐8 expression [168] (Figure 3).

FIGURE 3.

Mechanisms of HMs in the kidney, heart, and cancer. Kidney: Cd binds with albumin, β2‐microglobulin, and lipid transport protein‐2 and is endocytosed via megalin and cubilin receptors on the proximal tubular cells, thereby interfering with the normal metabolic processes of the kidney. Organic Hg interacts with OAT1/3 and is converted into inorganic Hg through enzymatic or nonenzymatic processes, leading to ROS production. Heart: As can prolong the QT interval of the heart. Cd induces vascular endothelial cell apoptosis by activating P38 MAPK or JNK signaling pathway, and competing with Ca²⁺ to inhibit the contractility of myocardium cells. Hg increases the secretion of angiotensin II and causes ROS generation. Pb impairs the NO signaling pathway and reduces the vasodilatory capacity of blood vessels. Lung: Cd regulates the expression of multiple signaling pathways and promotes the occurrence of lung cancer. Cr (VI) promotes the binding of PAHs in cigarettes to the p53 gene in the lung and also increases the mutation of guanine to thymine in the p53 gene. As (V) is reduced to As (III) in the presence of GSH and TRX, which is further metabolized into carcinogens such as MMA (III), MMA (V) and DMA (V), causing lung cancer. As (V), arsenic (V); Cd, cadmium; cGMP, cyclic guanosine monophosphate; COX‐2, cyclooxygenase 2; Cr, chromium; DMA, dimethylarsinate; GSH, glutathione; GSH/TRX, glutathione/thioredoxin; hERG, human ether‐à‐go‐go‐related gene; Hg, mercury; HIF‐1A, hypoxia‐inducible factor‐1A; HO‐1, heme oxygenase‐1; IKR, inward rectifier potassium current; JNK, c‐Jun N‐terminal kinase; MMA, monomethylarsonate; MT‐1A/2A, metallothionein‐1A/2A; MT, metallothionein; NADPH, nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; P38 MAPK, P38 mitogen‐activated protein kinase; p53, tumor protein 53; PAHs, polycyclic aromatic hydrocarbons; ROS/RNS, reactive oxygen species/reactive nitrogen species; sGC, soluble guanylate cyclase; ZNT‐1/ZNT‐5/ZIP‐8, zinc transporter‐1/5/Zinc induced protein‐8.

Cd is a known environmental carcinogen that is strongly associated with the development of breast cancer. Cd, an endocrine disruptor, could promote breast cancer cell proliferation and survival by activating the interaction between estrogen receptor alpha (ERα) and proto‐oncogene c‐jun (c‐Jun) [169]. Alternatively, Cd could also promote breast cancer cell proliferation by binding to the membrane estrogen receptor GPR30 and activating the downstream Erk‐1/2 signaling pathway [170]. Similarly, Pb belongs to a class of metalloestrogens that could activate ERα, thereby triggering estrogen‐like biological effects that promoted cell proliferation and the development of estrogen‐dependent breast cancer. Furthermore, both Cd and Pb affected DNA repair mechanisms, causing DNA damage and increased genetic instability [171]. Interestingly, Cr (II) was able to activate ERα, whereas Cr (III) cannot [172]. For As, it was shown that individuals who are adept at metabolizing inorganic As to (MMA (III)), but less adept at further metabolizing MMA (III) to dimethylarsenic acid (DMA (III)), were at higher breast cancer risk [173]. The impact of Hg on breast cancer breast cancer has been relatively understudied; however, evidence suggests its potential carcinogenic properties. Hg was capable of damaging DNA, and mutations in genes associated with DNA repair (e.g., BRCA1) had been linked to breast cancer development [174, 175].

For other types of cancer, Cd exposure induced malignant cell transformation in prostate epithelial cells mainly by increasing the expression level of the antiapoptotic gene Bcl‐2, which in turn blocked the JNK signaling pathway, and ultimately results in a significant increase in the antiapoptotic capacity of prostate epithelial cells, leading to prostate cancer development [176]. Similarly, the prostate is a target organ for the carcinogenic effects of inorganic As [177]. Chronic As exposure led to the malignant transformation of prostate epithelial cells, manifested by genomic DNA hypomethylation and K‐ras overexpression [178]. In addition, long‐term low‐dose Cd exposure promoted the invasive and metastatic ability of colorectal cancer cells through the unique activation of the EGFR signaling pathway, which is evidenced by persistent EGFR signaling and activation of Akt/mTOR cascade, whereas blocking EGFR eliminated the promotion of Cd on the metastasis of colorectal cancer cells to the liver [179]. Chronic Cr(VI) exposure was found to exacerbate colorectal cancer induced by 1,2‐dimethylhydrazine, with an underlying mechanism involving Cr (VI) induced OS and macrogenomic analyses revealing alterations in gut microbiota composition, with downregulation of the abundance of Firmicutes and Bacteroidetes, remarkable increased abundance of Verrucomicrobia, and decreased levels of certain short‐chain fatty acids generating bacteria [180].

4.6. Immune System

HMs can damage immune cells and influence immune function. In allergic contact dermatitis, Cr (VI) penetrated the skin barrier, was reduced to Cr(III), and subsequently formed immunogenic complexes with skin proteins, which activated antigen‐presenting cells, subsequently triggering a cascade of immune responses involving effector T cells, regulatory T cells, and Tγδ cells, ultimately leading to allergic reactions [181]. Cr exposure could also disrupt the balance of Th1/Th2/Th17 cytokines and regulate the humoral immune response, resulting in the disruption of immune homeostasis, and causing inflammation as well as other adverse outcomes [182]. As exposure had a wide range of toxic effects on the immune system, including the inhibition of T‐cell activation, the alteration in a variety of cytokines (IL‐2, IL‐4, IL‐5, IL‐10, IFN‐γ, and TNF‐α expressions, the effects on leukocyte function and adhesion, and impairment of both humoral and cellular immune responses, which could lead to an increased risk of infection and inflammatory diseases [183]. For Cd, immune cells were both targets of Cd toxicity and effectors of Cd‐induced immune responses and toxic effects [184]. In primary T lymphocytes derived from BALB/c mice, Cd induced immunotoxicity by selectively acting on CD4+ and CD8+ T cells. Of these, CD4+ T cells were more sensitive to Cd‐induced OS and apoptosis, and Cd significantly inhibited Th1 and Th2 cytokines expression in a dose‐dependent manner [185]. Under the context of Hg‐induced inflammation and autoimmune responses, Hg activated innate immune cells (neutrophils and macrophages) and induced the activation of adaptive immune cells (T and B cells), to trigger autoimmune diseases [186]. Among workers with chronic exposed to Pb in battery factories, decreased helper T‐lymphocyte numbers and immunoglobulins (IgG and IgM), and complement proteins (C3 and C4), suggested that Pb exhibited an inhibitory effect on the immune system, thus weakening the body's immune response [187].

5. Therapeutic Intervention

Addressing the toxic effects of HMs requires a comprehensive combination of therapeutic strategies covering chelation therapy, antioxidants and free radical scavengers, supportive care, preventive measures, and emerging therapeutic technologies. Chelation therapy promotes the elimination of HMs from the body through the formation of complexes between chelating agents and HMs. Antioxidants and free radical scavengers are effective in attenuating OS and ROS damage and protecting cells from further damage. Supportive therapy, including nutritional support and symptomatic treatment, can help improve patient prognosis and relieve symptoms. Preventive measures are taken at the source to reduce HMs exposure and reduce health risks through environmental interventions and personal protection. Notably, emerging therapeutic strategies such as nanotechnology, gene therapy, and microbial modulation offer new directions and ideas for the treatment of HMs toxicity and show broad application prospects. Together, these strategies provide comprehensive protection against HMs toxicity.

5.1. Chelation Therapy

5.1.1. Types and Mechanisms of Chelating Agents

HMs, such as Cr, As, Cd, Hg, and Pb, pose significant threats to human health. Chelating agents played an important role in detoxifying these metals, and they are categorized into two main types: mercapto and nonmercapto chelating agents. Mercapto chelators, including agents like bimercaptopropanol (BAL), dimercaptosuccinic acid (DMSA), dimercaptopropanesulfonic acid (DMPS), Monoisoamyl DMSA (MiADMSA), penicillamine (PEN), and lipoic acid (LA), contain sulfhydryl groups that enable them to form stable chelates with HMs [188, 189]. In contrast, nonmercapto chelators, primarily represented by ethylenediaminetetraacetic acid (EDTA), do not contain sulfhydryl groups, but possess multiple carboxyl groups that facilitate chelation with HM ions [190, 191].Chelating mechanism of the aforementioned agents mainly involve: (1) Ligand bond formation, wherein the chelating agent interact with HM ions through its active functional groups, such as sulfhydryl and carboxylic acid group, to form ligand bonds and generate stable chelates, thereby reducing the bioavailability of HMs [192, 193]. (2) Enhanced excretion, as the chelates formed with HMs are usually readily excreted, facilitating the removal of HMs from the body [194].

5.1.2. Clinical Application of Chelation Therapy

The earliest HM chelators were EDTA and BAL, and their clinical use has been limited by the inconvenience of administering, inherent toxicity, and the potential for increased neurotoxicity of certain metals [195]. Notably, DMPS and DMSA, representing a new generation of chelating agents, offered superior safety and therapeutic benefit over BAL in the treatment of As and Hg toxicity, as these agents exhibited a higher therapeutic index, and did not result in the redistribution of toxic metals to the brain [196, 197]. Specifically, BAL, also known as British Anti‐Lewis Aerosol, is to detoxify from As or Hg. Upon interaction with Lewis gas, BAL is able to produce stable and nontoxic As compounds [198]. In the decades following Second World War, BAL was widely used in the detoxification of HMs poisoning with inorganic Hg, As, Sb, gold (Au), and bismuth (Bi) [199]. However, high doses of BAL caused a range of serious adverse effects, including vasoconstriction of small arteries, increased blood pressure, headaches, blurred vision, and numbness in the hands [200]. Due to its high toxicity, nowadays, BAL is only used for a short period of time when the patient's life is threatened or in an emergency situation where is experiencing acute As poisoning. In addition, given its narrow therapeutic range and its propensity to redistribute toxic elements to the brain, BAL had been replaced in most cases by DMSA or DMPS [195]. DMSA, a disulfide compound and an analog of BAL, can specifically bind to Pb, reducing its absorption and retention in the gastrointestinal tract, and subsequently lowering blood Pb concentrations. However, short‐term administration of DMSA, it is easy to free Pb from bone and redistribute it, causing rebound elevation of blood Pb [201]. The hydrophilic properties of DMSA enable considerable absorption in the gastrointestinal tract, thus the oral administration pathway gives it a significant advantage over BAL [202]. Furthermore, DMSA had a large therapeutic window and the lowest toxicity among dithiols [203]. DMPS, another analog of BAL, is not considered an appropriate treatment for Pb poisoning [204]. Whereas, DMPS had shown remarkable efficacy in the field of detoxification of Hg poisoning and had become a critical therapeutic agent for this condition, its effectiveness in the treatment of Pb and As poisoning was limited [205, 206, 207]. MiADMSA is a potential candidate drug that is still in the developmental stage. It had been shown to be effective in experimental animal models of acute and chronic Pb and As poisoning, exerting antioxidant properties, promoting MT synthesis, and also reversing Cd‐induced oxidative damage [208, 209]. Additionally, MiADMSA had no significant effect on maternal and fetal developmental toxicity, which was higher than DMSA but lower than BAL [210, 211]. In summary, the field of chelation therapy has progressed significantly from the early use of EDTA and BAL to the development of safer and more effective chelating agents such as DMSA and DMPS. As research progresses, emerging drug candidates such as MiADMSA offer new hope for improving the treatment of HMs toxicity.

5.1.3. Preclinical Animal Experiments and Clinical Trials

Preclinical experiments serve as a fundamental approach to elucidate the mechanisms underlying the toxicity of HMs and to develop potential therapeutic interventions. By simulating human HMs exposure scenarios in animal models, researchers are able to gain an in‐depth understanding of the effects of HMs on different organ systems and evaluate the efficacy and safety of therapeutic strategies. For example, in high‐dose Pb‐exposed mice, intraperitoneal injection of DMSA significantly reduced Pb levels in the kidney, bone, and brain, which was superior to other well‐known chelating agents such as calcium sodium ethylenediaminetetraacetate (CaNa₂EDTA), Zn sodium ethylenediaminetetraacetate, and the trisodium salt of Zn dimercaptopropionic acid [212]. Additional studies had found that in Pb‐exposed rats, the combination of intraperitoneal DMSA and CaNa₂EDTA was more effective at removing Pb from organs and bones than either drug alone or in combination with other drugs (e.g., DMPS) without causing the redistribution of Pb to other organs [213]. In a study on the prevention of As poisoning in rats, the combination of intraperitoneal DMSA and MiADMSA performed excellently, significantly reducing As‐induced OS and effectively removing As from the blood and liver [214]. In addition, after As exposure in rats, N‐acetylcysteine (NAC) in combination with DMSA significantly reduced OS and removed As from organs [215]. Also, As exposure elevated OS, increased ROS and MDA, and inhibited cholinesterase activity in Swiss white rat brains. Intraperitoneal injection of vitamin E and coenzyme Q10 attenuated oxidative damage, restored cholinesterase activity, and improved brain function by scavenging free radicals and modulating SOD and GSH‐Px activities [216]. In a study of Cd‐induced kidney toxicity in mice, the combination of intraperitoneal injection of DMSA and subcutaneous injection of Zn diethylenetriaminepentaacetate trisodium (ZnDTPA) was more effective than individual use [217]. Notably, certain chelating agents may pose potential risks in the treatment of HMs poisoning. For example, BAL increased the uptake of Hg into the brain tissue of mice, leading to the redistribution of Hg in the brain [218]. Apart from synthetic chelating agents, natural products also showed potential for HMs management. Aqueous extracts of onion and garlic prevented Cd‐induced OS injury in rat kidneys, in addition, garlic extracts reduced Pb concentrations in rat liver, kidney, brain, and bone [219, 220]. Chelation of Pb by oral administration of an alcoholic extract of cilantro significantly reduced Pb deposition in mouse femurs, decreased renal injury, and decreased urinary excretion of δ‐aminolevulinic acid, showing preventive effects against Pb poisoning [221].

HMs chelators have also demonstrated promising therapeutic effects in clinical trials. A prospective experimental research had shown that sequestration treatment with long‐term, intermittent intravenous CaNa₂EDTA significantly reduced accumulated Pb levels in healthy asymptomatic individuals [222]. Moreover, in a case study involving 17 Pb‐poisoned individuals, intravenous DMSA treatment significantly increased urinary Pb excretion and rapidly relieved neurologic and gastrointestinal symptoms associated with Pb poisoning [223]. In clinical trials conducted in a Au‐mining region of the Philippines, 106 patients with Hg poisoning were treated with 400 mg per day of oral DMPS. Although blood Hg levels did not significantly decrease, urinary Hg excretion increased up to 85‐fold [224]. Currently, the combined treatment strategy for HMs poisoning is still in the exploratory stage in clinical trials. Future research could explore the combined use of antioxidants, vitamins, and chelating agents, based on preclinical animal studies, to evaluate their collective efficacy (Table 1).

TABLE 1.

Animal experiments and clinical trials on the therapy of different heavy metal poisoning.

HMs	Experimental subject	Treatment	Drug delivery pathway	Consequence	References
Pb	Mouse	DMSA	Intraperitoneal injection	Reduced Pb levels in kidneys, bone, and brain	Jones et al. [212]
Pb	Rat	DMSA + CaNa2EDTA	Intraperitoneal injection	Reduced Pb levels in bone and brain	Tandon et al. [213]
As	Rat	DMSA + MiADMSA	Intraperitoneal injection	Reduced oxidative stress and cleared As from blood and liver	Flora et al. [214]
As	Rat	DMSA + NAC	Intraperitoneal injection	Reduced oxidative stress and removed As from organs	Flora et al. [215]
As	Swiss white rat	Vitamin E and coenzyme Q10	Intraperitoneal injection	Reduced oxidative damage and restored cholinesterase activity	Sharma et al. [216]
Cd	Mouse	DMSA + ZnDTPA	Intraperitoneal injection; hypodermic injection	Combination of drugs to alleviate renal toxicity	Eybl et al. [217]
Hg	Mouse	BAL	Intraperitoneal injection	Increased Hg uptake in brain tissue, redistribution of Hg in the brain	Berlin et al. [218]
Cd	Rat	Onion and garlic water extract	Oral	Alleviate renal oxidative stress	Suru et al. [219]
Pb	Rat	Garlic extract	Oral	Reduced Pb concentration in the liver, kidney, brain, and bone	Senapati et al. [220]
Pb	Mouse	Cilantro alcoholic extract	Oral	Reduced Pb deposition in femur, ameliorated Pb‐induced kidney damage	Aga et al. [221]
Pb	Healthy, asymptomatic individuals	CaNa2EDTA	Intraperitoneal injection	Reduced accumulated Pb levels in the body	Petteruti et al. [222]
Pb	Pb‐poisoned individuals	DMSA	Oral	Increased urinary lead excretion and relieved neurological and gastrointestinal symptoms	Bradberry et al. [223]
Hg	Patients in the gold‐mining area	DMPS	Oral	Significantly increased urinary Hg excretion	Drasch et al. [224]

Abbreviations: As, arsenic; BAL, bimercaptopropanol; CaNa₂EDTA, calcium sodium ethylenediaminetetraacetate; Cd, cadmium; DMPS, dimercaptopropanesulfonic acid; DMSA, dimercaptosuccinic acid; Hg, mercury; MiADMSA, monoisoamyl DMSA; NAC, N‐acetylcysteine; Pb, lead; ZnDTPA, zinc diethylenetriaminepentaacetate trisodium.

5.2. Antioxidant and Free Radical Scavenger

5.2.1. The Role of Antioxidants

Antioxidants play a crucial role in mitigating HM toxicity, and they alleviate the oxidative injury and toxic effects through multiple mechanisms. (1) Antioxidants directly neutralized free radicals and prevented them from attacking cell membranes, proteins, and DNA, thereby protecting cells from OS [225]. (2) LA antioxidants were able to form stable complexes with HM ions, reducing their bioavailability and toxicity in the body [226]. (3) Antioxidants activated and regenerated endogenous antioxidants, such as GSH, vitamins C and E, strengthening cellular antioxidant defense mechanisms [227, 228]. (4) Antioxidants mitigated HM‐induced mitochondrial damage, protected mitochondrial function, and reduced ROS generation [229].

5.2.2. Application of Free Radical Scavenger

Clinically, the main free radical scavengers used included a variety of natural and synthetic compounds that act by neutralizing free radicals, reducing OS, and safeguarding cells from damage. These agents were employed not only in the prevention and treatment of diseases associated with OS, such as cardiovascular diseases, cancer, and neurodegenerative diseases, but also played an important role in delaying the aging process and improving overall health. The following are some of the free radical scavengers that are widely used in clinical practice: (1) Vitamin C: a water‐soluble antioxidant that collaborated with vitamin E to protect lipids from peroxidation [230]. (2) GSH: the predominant intracellular antioxidants involved in a variety of biosynthetic and metabolic processes [231]. (3) NAC: an antioxidant containing sulfhydryl groups, which acted as a precursor to GSH, to enhance the antioxidant capacity of cells through multiple mechanisms [232]. (4) Melatonin, the hormone secreted by the pineal gland, was integral to regulate the sleep–wake cycle, and is also widely acknowledged for its powerful antioxidant properties [233]. (5) Natural flavonoids: such as curcumin and resveratrol, had antioxidant activity [234].

5.3. Supportive Treatment

5.3.1. Nutritional Support

Nutritional therapy for HM intervention was a comprehensive strategy used that encompassed multiple aspects. Prior to initiating HM chelation therapy, it is imperative to ensure adequate supplementation of nutrients required for liver detoxification, including essential fatty acids, phospholipids, antioxidants, vitamins, and minerals. Dietary adjustments should be made to minimize the intake of foods that caused allergies or intolerances, while prioritizing clean, organic foods to reduce the sources of toxicity. Propolis extracts and proanthocyanidins might serve as alternative dietary supplements for mitigating Pb and Cd exposure in the body [235]. Intake of specific phytonutrients, including lignans, glucosides, catechins, isoflavones, and ellagic acid, was recommended to enhance liver detoxification mechanisms. Also, increasing the intake of probiotic‐rich foods available in the market, usually found in dairy products such as cheese and yoghurt, as well as certain cereals could be beneficial. Specific probiotics, such as Lactobacillus, was able to scavenge HMs, thereby reducing their detrimental effects by either forming complexes with them or altering their bioavailability [236, 237, 238, 239]. Collectively, these strategies constitute an integrated nutritional therapy plan aimed at alleviating the advance effects of HMs on human health.

5.3.2. Symptomatic Treatment

Symptomatic treatment of HM poisoning involved a series of therapeutic interventions targeting various symptoms and indications caused by HM toxicity, to alleviate clinical symptoms, prevent the progression of the diseases, protect the function of vital organs, and promote patient recovery. For HM through oral intake, emetic and stomach lavage should be performed promptly to eliminate the toxic residues in the stomach. However, for patients experiencing severely poisoning or for whom stomach lavage was ineffective, blood purification techniques such as haemodialysis or peritoneal dialysis should be considered to remove the HM ions from the blood. For symptoms such as nausea and vomiting, antiemetic drugs might be administered, while antispasmodic drugs were appropriate for managing symptoms such as abdominal pain and diarrhea.

5.4. Prevention and Reduction of Exposure

5.4.1. Environmental Interventions

Environmental interventions for HMs include the following specific strategies. Implementing stringent industrial emission standards to curtail the release of HMs from factories and mines [240]. Adoption of advanced waste treatment and recycling technologies to mitigate the risk of HMs entering the environment [241]. Establishment of an environmental monitoring system to regularly assess the levels of HMs in soil, water, and air, for timely detection and intervention [242]. Employment of chemical reagents to transfer HMs from the soil to an aqueous solution, called drenching, to reduce the soil HM content [243]. Using techniques such as phytoextraction, phytovolatilization, phytofiltration, and microbial restoration, to diminish HMs through biological processes in soil and water [244, 245].

5.4.2. Personal Protection and Health Education

Personal protection measures against HMs are multifaceted, covering various aspects from workplace safety and daily habits to diet and health defense. It was important to wear protective gear, including gloves, lab coats, goggles, long trousers, and closed shoes, when handling HMs. These strategies are instrumental in mitigating skin exposure and inhalation of HMs. When performing HM‐related experiments, it is essential to cover laboratory bench with protective mats to prevent any spills or drips, which should subsequently be disposed of as hazardous waste. Moving away from areas with high levels of air pollution and industrial emissions can significantly reduce HM exposure. Air purifiers are advisable when living in urban areas with poor air quality. Sweating is the body's natural way of eliminating toxins, including HMs. Participation in activities such as exercise, saunas, and hot yoga can eliminate toxins through perspiration. Cigarette smoke contains detrimental chemicals, including HMs like Cd and Pb. Thus, quitting smoking and avoiding second‐hand smoke are crucial for significantly reduce HM exposure. Raise public awareness of the hazards of HMs through educational activities to inform individuals about HMs sources, their effects on health, and preventive measures. Strengthen legislation and enforcement of HM pollution, establish a robust policy and regulatory framework, delineating responsibilities, authorities, and regulatory bodies, increase penalties for sources of pollution, and promote the fulfilment of environmental protection obligations by enterprises and individuals.

5.5. Emerging Therapeutic Strategies

Previously, the article mainly discussed the existing treatment strategies for HMs poisoning, including chelation therapy, antioxidants, and free radical scavengers, as well as supportive care and preventive measures. Although these methods can alleviate the symptoms of HMs poisoning at a certain extent, with the development of science and technology and the in‐depth understanding of HMs toxicity, have highlighted the limitations of the traditional treatments. Consequently, there is an urgent need to develop new therapeutic approaches to effectively address the health risks associated with HM poisoning. Here, this section will focus on emerging therapeutic strategies that are expected to provide new directions and ideas for the treatment of HMs poisoning.

5.5.1. Nanotechnology

Nanotechnology has great potential in the treatment of HMs toxicity, where nanoparticles can be engineered to specifically bind and remove HMs from the body [246, 247]. Nanoparticles are characterized by small size, large specific surface area, high surface activity, and could efficiently adsorb and transport HMs. Silicon dioxide nanoparticles were able to adsorb metal ions efficiently due to their large specific surface area and suitable adsorption sites, thus reducing the binding and toxic effects of HMs on biomolecules [248]. In addition, nanomaterials could also form stable complexes with HMs through chemical reactions, facilitating their elimination [249]. Moreover, by surface functionalization (e.g., introduction of carboxyl, amino, or sulfhydryl groups), the adsorption capacity of nanomaterials for HMs (such as Pb, Cd, and Hg) could be significantly enhanced [250]. More importantly, nanotechnology could also achieve targeted therapy by combining nanoparticles with ligands, such as monoclonal antibodies, folic acid, or peptides, to specifically target cells or tissues, thereby improving the therapeutic efficacy [251]. Nanoparticles exhibit significant potential for the adsorption and therapeutic management of HMs. However, challenges persist regarding their biosafety, stability, and how to realize efficient and specific HMs adsorption, necessitating further in‐depth investigation.

5.5.2. Gene Therapy

HMs exposure leads to abnormal gene expression or mutations in cells, which can lead to diseases. Clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9), a breakthrough gene‐editing technology, is emerging as a highly promising tool for gene therapy [252]. Using this technology, it is possible to repair or replace damaged genes and restore normal gene functions [253]. Gene therapy technology regulates gene metabolism, facilitates the detoxification of HMs, and enhances tolerance to HMs [254]. However, the application of these technologies need be executed with stringent precision and safety controls, to avoid potential off‐target effects [255].

5.5.3. Microbiome Regulation

Microbes play a unique and important role in the management of HMs pollution by transforming these metals into less toxic forms through complex biochemical processes, such as oxidation, reduction, methylation, and demethylation. For example, some microbes are able to oxidize the highly toxic As (III) to the less toxic As (V), or reduce the strongly oxidizing Cr (VI) to the less toxic Cr (III), thus effectively reducing the harmful effects of these HMs on the environment and living organisms [256, 257]. In addition, microorganisms could convert HMs into volatile compounds through enzymatic reactions, further reducing their toxicity and bioavailability in soil and water. For instance, the enzyme mercuric reductase (MerA) was able to reduce Hg (II) to volatile monomeric Hg (0), allowing it to escape from the environment, and thus reducing its accumulation in ecosystems. Likewise, As methyltransferases could convert As (V) to volatile methylarsenic compounds that are relatively less toxic and easier to remove from the environment [258, 259]. Interestingly, microorganisms exhibited a unique capacity for HMs adsorption and accumulation, characterized by their cell wall components and intracellular metal‐binding proteins (e.g., MT and phytochelatins) that could efficiently adsorb and accumulate HMs [260]. Besides, extracellular polysaccharides secreted by microorganisms also had significant HMs adsorption capacity [261] (Table 2).

TABLE 2.

Therapeutic intervention strategies of HMs on human diseases.

Therapeutic strategy	Measures	Mechanism of action	Applicable heavy metals	Advantages/disadvantages	Research progress	References
Supportive therapy	Blood purification (dialysis/plasma exchange)	Directly removes free HMs from the blood	Acute Hg, Pb poisoning	A: fast‐acting; D: equipment dependent and costly	For severe cases	/
	Nutritional support (propolis extract, proanthocyanidins, Lactobacillus)	Forms complexes with HMs	Cd, Pb	A: preventative; D: long‐term supplementation required	Supported by epidemiological evidence	Halttunen et al. [238]
Protective measure	Environmental remediation (phytoextraction/chemical drenching)	Soil purification using super‐enriched plants	Cd, As, Pb in soil	A: source control; D: long lead times	Higher costs in promotion	Zhang et al. and Ojha et al. [243, 244]
	Personal protection (masks/gloves)	Reduce occupational exposure (e.g., mining, battery manufacturing)	All heavy metals	A: simple and effective; D: dependent on adherence	Statutorily mandated	/
Emerging technology	Nanomaterials (SiO2)	Adsorption of HMs with high specific surface area or targeted delivery of chelating agents	Pb, Cd, Hg	A: efficient targeting; D: potential biotoxicity	Laboratory stage, safety validation required	Olawade et al. and Xia et al. [250, 251] Samani et al. [248]
	Gene therapy (CRISPR–Cas9)	Repair of HMs‐induced mutations (e.g. p53) or enhancement of detoxification gene expression	As, Cr (VI)	A: potential for eradication; D: technological immaturity, ethical controversy	Basic research phase	Ma et al. [252]
	Microbial remediation (MerA genetically engineered bacteria)	Microbial reduction of Hg2⁺ to Hg⁰ volatilization, or degradation of organic arsenic	Hg, As	A: environmentally friendly; D: limited environmental adaptability	Some of the engineered bacteria have been field tested	Hemmat‐Jou et al and Naguib et al. [258, 259]

Abbreviations: As, arsenic; Cd, cadmium; Cr, chromium; CRISPR–Cas9, clustered regularly interspaced short palindromic repeats associated protein 9; Hg, mercury; Pb, lead; SiO₂, silicon dioxide.

6. Conclusion And Prospect

6.1. Summary of HM Toxicity

HMs exert detrimental effects on organisms through various mechanisms inducing OS, triggering neuroinflammation, interfering with protein homeostasis, and disrupting organelle function. HMs can interact with biological macromolecules such as proteins, enzymes, and nucleic acids, in cells, resulting in their structure and function damage, which consequently affects the normal cellular physiological activities. For example, HMs could enhance ROS production, compromise cellular antioxidant defense, trigger lipid peroxidation, oxidative modification of proteins, and DNA damage, ultimately leading to cellular dysfunction and death. HMs might also interfere with cell signaling pathways, affect the cell cycle and apoptosis processes, as well as disrupt the normal functions of mitochondria and endoplasmic reticulum, further exacerbating cellular damage.

The toxic effects of HMs are particularly pronounced in the neurological system, where they can inflict severe damage to nerve cells, contributing to the development of neurodegenerative diseases. HMs can traverse the BBB, then interfering with the nerve cell functions, destroying cellular structure, affecting the signaling pathway, and triggering pathological protein aggregation, neuroinflammation and increased OS. Over time, the accumulation of HM damage to the nervous system led to progressive degradation of neuronal function and structural integrity. This long‐term cumulative effect eventually precipitated a spectrum of neurodegenerative diseases, including AD, PD, ALS, and HD. These diseases usually manifest with a complex set of symptoms that seriously affect patient's quality of living. AD: the main manifestations are memory loss, delayed thinking, and cognitive decline, which may eventually lead to complete loss of self‐care. PD: the predominantly movement disorders, such as tremors, muscle rigidity, and bradykinesia, accompanied by cognitive decline. ALS: primarily affects the motor neurons, leading to muscle weakness and atrophy, which may eventually affect respiratory function. HD: presents with involuntary dance‐like movements, cognitive deficits, and abnormal mental behaviors, accompanied by depression and anxiety. These symptoms not only cause great disturbance to the daily lives of the patients, but also seriously affect their self‐care, social activities and work ability, which brings a substantial burden on family and society.

The health effects of HMs are multisystemic, long term, and cumulative. These hazards are not limited to a single organ, but may affect multiple physiological systems through intricate biological mechanisms. Specifically, HM damage to the kidneys might lead to metabolic disorders, which in turn affected the cardiovascular system. Toxicity to the reproductive system might affect overall health through endocrine disruption. In addition, the carcinogenic mechanism of HMs involved DNA damage, OS, and immunosuppression at various levels, rendering their impacts on health even more complex and far‐reaching. The effects of HMs on the kidneys, the cardiovascular system, the reproductive system, and cancer, are multifaceted and have long‐term cumulative consequences, requiring enhanced environmental management and public health interventions to reduce the risks to human health caused by HMs.

6.2. Implications for Public Health and Environmental Protection

HMs exert a profound and critical impact on public health and environmental protection. From the environmental protection perspective, HMs pollution is detrimental in numerous ways. Within water systems, industrial wastewater emissions, mining, and other events cause large quantities of HMs such as Hg, Cd, and Pb into rivers, lake, and ocean. These not only alter the chemical properties of water and affect the habitat of aquatic organisms, leading to the death or mutation of fish and other aquatic organisms, but also enter the food chain through bioaccumulate in aquatic organisms, posing potential threats to human health. In soil, the use of HM‐containing pesticides and fertilizers in agriculture and the accumulation of industrial waste residues have caused the HMs concentrations exceeding permissible limits, further destroying the soil structure, reducing soil fertility, affecting nutrients and water absorption by plant roots, and resulting in a reduction in crops yields and quality. Additionally, these HMs may also accumulate in plants and further enter the human body through food consumption. In the atmosphere, metal refining, vehicle exhaust emissions, etc. will release Pb, Hg and other HMs. They can remain suspended in the air, to reduce air quality, and can enter the human body via breathing. Long‐term deposition of these HMs in the lung organs can damage to the respiratory system.

From a public health perspective, the threat posed by HMs to human health warrants serious attention. The neurological system is particularly susceptible to the detrimental effects of HMs. Specifically, Pb could affect the intellectual development of children, leading to cognitive decline, learning disabilities, and other problems, and will also lead to neurasthenia and memory loss in adults; Hg could damage to the brain and nervous system, triggering vision loss, limb coordination disorders, and so on. The immune system was also compromised by HMs. For instance, Cd might interfere with the normal function of the immune system, making people more susceptible to infectious diseases, and reducing the body's resistance. Furthermore, HMs had an adverse effect on the reproductive system. Both Pb and Hg could pass through the placental and blood‐testis barriers, and affect the formation and development of reproductive cells, which might lead to infertility and fetal abnormalities, posing a serious threat to human reproduction and offspring health.

Collectively, to protect public health and the environment, it is imperative to implement effective strategies to deal with HMs. On the one hand, it is necessary to strengthen environmental supervision, strictly control the emission of HMs from industrial enterprises, promote cleaner production technologies, and minimize the generation and release of HMs in the manufacturing processes. On the other hand, it is essential to elevate the public awareness regarding the hazards of HMs, advocate environmentally sustainable lifestyles, reduce the use and disposal of HMs‐containing products, and ensure proper garbage classification and recycling. Implementing these comprehensive strategies will effectively mitigate the threat to the environment and human health posed by HMs pollution and to foster sustainable development.

Author Contributions

All authors contributed to the writing of the manuscript and the design of the figures and tables. All the authors participated in the design of the figures and tables. F.Z., Y.F.C., Y.J.Z., and C.C. contributed to the writing of the manuscript. All authors have read and approved the final manuscript

Conflicts of Interest

The authors declare no conflicts of interest.

Ethics Statement

The authors have nothing to report.

Data Availability Statement

The authors have nothing to report.