Heavy Metal Pollution: Cancer's Environmental Trigger?

Heavy metal pollution is a serious environmental problem that affects human health. Heavy metals such as lead, mercury, cadmium, chromium, and arsenic are considered to be the primary toxic heavy metals to human health. These metals can enter the human body through contaminated food and water, occupational exposure, and environmental pollution. Exposure to heavy metals has been linked to an increased risk of various cancers, including kidney, lung, liver, skin, and gastric cancer.

The mechanisms by which heavy metals cause cancer are not yet fully understood, but several potential mechanisms have been proposed. One mechanism is the disruption of the gastric mucosal barrier, which can increase the vulnerability of the gastric mucosa to damage. Heavy metals can also induce the generation of reactive oxygen species (ROS), which can cause oxidative stress and damage to DNA and cellular components. Additionally, heavy metals may inhibit DNA repair processes or cause inefficient lesion repair. Heavy metals can also induce gene abnormalities and the expression of pro-inflammatory chemokines and microRNAs, which can promote tumorigenesis.

The prevention and treatment of heavy metal poisoning typically involve the use of chelating agents, which help to remove the metals from the body. However, chelation therapy may have toxic side effects, and there is a need for the development of less toxic alternatives. Reducing exposure to heavy metals is crucial, and this can be achieved through public health strategies, improved detection of environmental contaminants, and control of heavy metal pollution and emissions.

Heavy metals can disrupt the gastric mucosal barrier, leading to inflammation, tissue damage, and dysplastic lesions in the stomach glandular epithelium

Heavy metals such as lead, cadmium, mercury, chromium, and arsenic are considered to be the primary toxic heavy metals to human health. Exposure to these heavy metals can lead to an increased risk of gastric cancer.

There are four main potential mechanisms by which heavy metals induce gastric cancer:

• Disruption of the gastric mucosal barrier: heavy metals can decrease mucosal thickness, mucus content, and basal acid output, thereby affecting the function of E-cadherin and inducing reactive oxygen species (ROS) damage.
• Reactive oxygen species: heavy metals can directly or indirectly induce ROS generation and cause gastric mucosal and DNA lesions, which subsequently alter gene regulation, signal transduction, and cell growth, ultimately leading to carcinogenesis.
• Ineffective DNA repair: heavy metals can inhibit DNA damage repair or cause inefficient lesion repair.
• Gene abnormalities: heavy metals may induce other gene abnormalities, including the expression of proinflammatory chemokine interleukin-8 (IL-8) and microRNAs, which promotes tumorigenesis.

In addition, heavy metals can also affect the gut barrier and gut microbiota, leading to gastrointestinal (GI)-related disorders such as inflammatory bowel disease (IBD).

Heavy metals induce reactive oxygen species (ROS), which can cause oxidative stress and damage to cell structures, lipids, membranes, proteins, and nucleic acids

Heavy metals can induce reactive oxygen species (ROS), which can cause oxidative stress and damage to cell structures, lipids, membranes, proteins, and nucleic acids.

Heavy metals are highly reactive and can bind to parts of your cells, preventing your organs from functioning properly. Heavy metals can enter your body through ingestion of contaminated food, inhalation of polluted air, or absorption through the skin.

Heavy metals can induce reactive oxygen species (ROS), which can cause oxidative stress and damage to cell structures, lipids, membranes, proteins, and nucleic acids. ROS are highly reactive and can be formed by biological systems or as by-products of oxygen metabolism. They play several physiological roles, such as cell signalling, but at high levels, they can cause harm to important cellular structures like proteins, lipids, and nucleic acids.

ROS can be produced by mitochondria, during both physiological and pathological conditions. Mitochondria have an intrinsic ROS scavenging capacity, but this is not enough to address the cellular need to clear the amount of ROS produced. Cells deploy an antioxidant defensive system based mainly on enzymatic components, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), to protect themselves from ROS-induced cellular damage.

Heavy metals can induce the production of ROS through several mechanisms. They can generate free radicals, which can cause DNA damage, alteration of sulphydryl homeostasis, and lipid peroxidation. They can also activate signalling pathways and induce the production of free radicals, which can cause a variety of DNA base modifications. Heavy metals can also directly damage DNA, causing site-specific damage. They can cause both "direct" and "indirect" damage. In the "direct" damage, conformational changes occur to the biomolecules due to the metal. In the "indirect" damage, the heavy metal causes "indirect" damage, which is a result of the production of reactive oxygen and nitrogen species, which comprise the hydroxyl and superoxide radicals, hydrogen peroxide, nitric oxide, and other endogenous oxidants.

Heavy metals inhibit DNA damage repair or cause inefficient lesion repair, leading to genomic instability and abnormal mitosis

Heavy metals such as cadmium, arsenic, and nickel are classified as carcinogens. Although the precise mechanism of carcinogenesis is undefined, heavy metal exposure can contribute to genetic damage by inducing double-strand breaks (DSBs) as well as inhibiting critical proteins from different DNA repair pathways.

Heavy metals can disrupt the gastric mucosal barrier by decreasing mucosal thickness, mucus content, and basal acid output, thereby affecting the function of E-cadherin and inducing reactive oxygen species (ROS) damage. Heavy metals can also directly or indirectly induce ROS generation, causing gastric mucosal and DNA lesions, which subsequently alter gene regulation, signal transduction, and cell growth, ultimately leading to carcinogenesis. Heavy metal exposure also enhances gastric cancer cell invasion and metastasis.

Heavy metals may inhibit DNA damage repair or cause inefficient lesion repair. Heavy metals can induce the expression of proinflammatory chemokine interleukin-8 (IL-8) and microRNAs, which promotes tumorigenesis.

Heavy metals may induce other gene abnormalities, such as epigenetic and structural alterations that can lead to changes in gene transcription and critical cell cycle regulatory genes

Heavy metals can induce other gene abnormalities, such as epigenetic and structural alterations, which can lead to changes in gene transcription and critical cell cycle regulatory genes.

Epigenetic alterations

Epigenetics is the study of mitotically and meiotically heritable changes in gene expression without mutating the DNA sequence. Heavy metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression.

DNA methylation

DNA methylation is the most well-studied epigenetic alteration and plays a key role in development, such as genomic imprinting and X chromosome inactivation. DNA methylation is associated with cancer, Alzheimer’s disease, diabetes, atherosclerosis, Friedrich’s ataxia, immunodeficiency, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

Heavy metals can cause both hypo- and hypermethylation of DNA. For example, inorganic arsenic (As) compounds can deplete intracellular methyl group stores, which may result in hypomethylation of genes. However, arsenic exposure has also been linked to hypermethylation of promoters of tumour suppressor genes.

Histone modifications

Histones package and order DNA into basic structural units called nucleosomes. Histones can undergo various post-translational modifications (PTMs) including acetylation, methylation, phosphorylation, ubiquitylation and sumoylation. Histone modifications provide another important mechanism of epigenetic regulation.

Heavy metals can induce histone modifications, including phosphorylation, acetylation, and methylation. For example, arsenic can induce histone phosphorylation, while cadmium can decrease histone phosphorylation.

Non-coding RNA expression

Non-coding RNA (ncRNA) is another epigenetic modulator of gene expression. Small ncRNAs regulate gene expression by translational repression (by microRNA, miRNA) and mRNA degradation (by small interfering RNA, siRNA). Aberrant expression of miRNAs has been associated with various human diseases such as cancer, cardiovascular disease, and genetic disorders.

Structural alterations

Heavy metals may also cause structural alterations in DNA. Heavy metals can generate free radicals, which can lead to DNA damage, including base modification, crosslinking, strand scission, and depurination. Heavy metals can also cause DNA-protein crosslinking.

Heavy metals can induce the expression of pro-inflammatory chemokines and microRNAs, which can promote tumorigenesis and cancer development

Heavy metals are defined as those with a density higher than 5.0 g/cm3, a low solubility of their hydrates, a typical behaviour like cations, a strong ability to form complexes, and an affinity towards sulphides. They are transition metals, which form ions with incompletely filled electron shells. Heavy metals include iron, chromium, mercury, nickel, lead, copper, aluminium, cadmium, and metalloids with similar properties, such as arsenic, bismuth, and selenium.

Heavy metals can induce the expression of pro-inflammatory chemokine interleukin-8 (IL-8) and microRNAs, which promotes tumorigenesis. They can also induce other gene abnormalities.

Heavy metals can induce the expression of microRNAs, which can cause epigenetic anomalies.

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