Heavy metals, naturally occurring elements in the Earth’s crust, pose significant environmental and public health concern due to their pervasive nature and toxicity upon anthropogenic release. Owing to their relatively high density (exceeding 4 g/cm³ or five times that of water), these metallic elements can exert toxic effects even at low concentrations. While some are essential at low concentrations, such as trivalent chromium—which plays some essential biological roles, the overwhelming evidence indicates that the detrimental impacts of heavy metals far outweigh any presumed advantages1.
Though naturally occurring components of the Earth’s crust, heavy metals such as aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), lead (Pb), and mercury (Hg) are now reported to be deposited in excess into the environment by anthropogenic activities such as mining, industrial processes, and agricultural practices. After their dissemination, they persistent and endure for centuries or even millennia in places like floodplains and riverine sediments. Exposure to heavy metals in humans can occur via multiple routes, including the ingestion of contaminated food and water, inhalation of polluted air, and dermal absorption. Upon their systemic entry, these metals exert widespread disruptive effects on numerous biological processes, affecting homeostatic and regulatory mechanisms that govern cellular function.
Common mechanisms of heavy metal toxicity
While each heavy metal has its own distinct toxicological profile, several overarching mechanisms of harm are commonly observed1.
Reactive oxygen species (ROS) generation and oxidative stress
A common mechanism of heavy metal toxicity is the generation of ROS. Metals like arsenic, cadmium, mercury, lead, and chromium contribute directly to increased ROS production through redox cycling. However, some metals that are not directly redox-active do so indirectly. For instance, cadmium can displace essential redox-active metals like iron and copper from metalloproteins, increasing the pool of catalytic metals available for reactions that generate ROS. Such overwhelming production of ROS compromises cellular integrity and eventually leads to lipid peroxidation, protein carbonylation, and DNA damage.
Dysregulation of antioxidant mechanisms and enzyme inactivation
Heavy metals also steadily compromise the body’s endogenous antioxidant defense systems. Critical antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, along with cellular antioxidants like reduced glutathione, commonly contain thiol groups. Heavy metals, particularly arsenic, cadmium, mercury, lead, and chromium, have a high affinity for these thiol groups and bind to them. This, in turn, inhibits the activity of these vital protective molecules, making cells vulnerable to oxidative damage and impairing mitochondrial function.
Carcinogenesis
It is now well known that heavy metals have carcinogenic potential. In addition to direct DNA damage induced by ROS, these metals also interfere with regulatory proteins involved in cell cycle progression, DNA synthesis and repair, and the processes of apoptosis and necrosis. For example, cadmium and arsenic dysregulate the activity of key transcription factors such as nuclear factor kappa B (NF-κB) and p53. This impairs the expression of protective genes and promotes uncontrolled cellular proliferation and tumor growth. Cr(VI)-induced carcinogenesis, on the other hand, occurs through chromosomal instability, often a consequence of defective DNA repair.
Epigenetic Alterations
Heavy metals are capable of inducing epigenetic modifications, which means they can trigger heritable changes in gene expression without causing alterations to the underlying DNA sequences. Lead, arsenic, mercury, cadmium, and chromium, for example, are known to induce alterations in DNA methylation patterns and induce histone modifications. Research is ongoing to find the precise mechanism governing these processes, but ROS generation often serves as a common event. This likely contributes to increased expression of proto-oncogenes and the silencing of tumor suppressor genes. These epigenetic shifts contribute significantly to the long-term health consequences, including carcinogenesis.
Unique toxicological signatures of heavy metals
Beyond these commonalities, each heavy metal also presents unique toxicological signatures:
- Aluminum (Al): It is implicated in neurotoxic behavior which results from its role in the induction of ROS generation. It is also involved in the aggregation and precipitation of amyloid-β protein, triggering the onset of neurodegenerative diseases.
- Cadmium (Cd): Its tight binding to metallothionein makes it have a long biological half-life due to which it preferentially accumulates in the kidneys, causing renal tubular disorders and electrolyte imbalances.
- Arsenic (As): It is a potent inhibitor of key enzymes in metabolic pathways like glycolysis, thereby disrupting cellular energy production, ATP, which in turn affects cardiomyocytes, leading to cell death.
- Mercury (Hg): One of its potent forms, methylmercury, is highly neurotoxic, owing to its ability to cross the blood-brain barrier and cause neuronal loss. Mercury compounds can also disrupt calcium homeostasis and neurotransmission.
- Lead (Pb): The mode of action depends on how it mimics essential divalent metal ions like calcium (Ca²⁺) and zinc (Zn²⁺) and interferes with myriad Ca²⁺- and Zn²⁺-dependent cellular functions. This includes affecting the cardiovascular system and heme synthesis through the inhibition of aminolevulinic acid dehydratase.
- Chromium (Cr): Hexavalent chromium is known to be highly toxic due to its ability to undergo reduction inside cells. This in turn helps in the generation of reactive intermediates that cause oxidative damage and DNA lesions.
Heavy metals: catalysts of antimicrobial resistance (AMR)
In addition to their harmful effects on human health, heavy metals play a hidden role in fueling the global issue of antimicrobial resistance2. The diminished efficacy of antimicrobial drugs against microbial pathogens, is observed to be significantly exacerbated by the pervasiveness of heavy metals in diverse environments.
The microbial communities face a potent selective pressure in the presence of heavy metal contamination. This causes bacteria to evolve mechanisms to survive in metal-polluted environments, in addition to resistance to antibiotics. This dangerous epidemiological linkage is primarily driven by two critical mechanisms:
- Co-resistance: This mechanism involves the co-localization of genes responsible for resistance to both antibiotics and heavy metals. The co-localization happens on shared mobile genetic elements (MGEs), such as transposons, plasmids, and integrons. Bacteria select these MGEs to survive in heavy metal contaminated sites, and as a consequence sometimes inadvertently acquire the linked antibiotic resistance genes (ARGs) via horizontal gene transfer (HGT) from different bacterial species. HGT facilitates the rapid dissemination of both metal and antibiotic resistance traits across environmental and clinical microbiomes.
- Cross-resistance: This mechanism is relevant when bacteria develop overarching resistance against both antibiotics and heavy metals due to them sharing similar biochemical pathways or cellular targets. So, exposure to heavy metals leads to upregulation of these efflux pumps, conferring resistance to multiple antibiotics even when direct antibiotic selective pressure—as prevalent in a hospital—was absent.
Microplastics: unforeseen amplifiers in the resistance nexus
The complexity and severity of the escalating threat of AMR aided by heavy metals are further amplified by the ubiquitous environmental presence of microplastics3. These minute plastic fragments provide an ideal, stable substratum for microbial colonization, which leads to the formation of plastisphere—a region containing the intricate microbial community encased in rich and diverse biofilms. Given that microplastics have a strong capacity for adsorption, the microplastic surface in the vicinity of the plastisphere accumulates mixed pollutants, including heavy metals, disinfectants, and residual antibiotics, creating a highly conducive environment for co-selection. Even in the absence of adsorbed antibiotics, exposure to some heavy metals like cadmium, can induce the activation of transmembrane efflux pump systems facilitating cross-resistance.
The combination of heavy metal pollution, microplastic accumulation, and AMR bacteria proliferation therefore presents a complex challenge to environmental management and global public health. A comprehensive, interdisciplinary approach, guided by the principles of One Health and necessitating global collaboration, is imperative to safeguard both our ecosystems and future therapeutic efficacy4.