| Heterocyclic aromatic amines (HAAs) |
HAAs are activation-dependent, heat-induced mutagenic agents predominantly present in foodstuffs containing nitrogenous and creatine components. Molecular structure of HAAs is dependent on the temperature and level of heat transferred to the food. Can generate SSBs, chromosomal aberrations and DNA adducts in guanine-rich regions. Activated metabolites can attack N2-position of guanine (most common) or C8-atom of guanine (occurs less frequently). |
[13–15] |
| Polycyclic aromatic hydrocarbons (PAHs) |
Combustion of organic matter results in the generation of PAHs. These are the most abundant indirect-acting carcinogens to which humans are exposed to on a daily basis. Exposure has been associated with the development of breast, skin or lung cancer. Bioactivation of PAHs is required in order for these agents to exhibit mutagenic properties, which is primarily mediated by cytochrome P450 enzymes. Bioactivated metabolites target multiple genomic sites, including guanine and adenine bases via PAH diol epoxides. This results in the generation of bulky BPdG chemical DNA adducts; examples include quinone-mediated cross-linking of N7 position of guanine and N3 of adenine. |
[11,16] |
| Ultraviolet (UV) |
Direct- and indirect-acting genotoxic cancer-causing agent, primarily absorbed by epidermal components, such as DNA bases (thymine and cytosine) and proteins. This agent is implicated in the causation of skin tumours by targeting pyrimidine bases. Exposure to the epidermis and dermis induces both the up-regulation of cell proliferation and photoproduct generation, including CPDs and (6–4) pyrimidine pyrimidines. |
[5,17–19] |
| Aristolochic acid (AA) |
Naturally derived acids from Aristolochiaceae plants. Ingestion of these carcinogens shown to be largely associated with nephrotoxicity of the renal cortex and further damage to the bladder and liver; very likely due to the development of bulky chemical DNA adducts. Most abundant and mutagenic form of DNA adduct associated with AA is dA-AA. In exons 2–11 of TP53, bulky chemical DNA adducts result in mutations, primarily of A:T base pairs. |
[20–24] |
| Nitrosamines |
Metabolism of nitrosamines subsequently induces alkylating DNA damage via the formation of DNA adducts such as O6-alkylguanine, oxidative stress and production of diazonium ions. Humans are exposed to these agents through various foods and tobacco smoke. |
[25,26] |
| Mycotoxins |
Mycotoxins are fungal-derived metabolites, which primarily contaminate food. The most commonly found mycotoxin is aflatoxin B1, discovered in the early 1960s. These are indirect carcinogens, which require bioactivation via CYP to generate DNA adducts. Adduct formation targeting guanine bases, which induces G → T transversions at codon 249 in TP53. |
[27–29] |
| Ionising radiation (IR) |
Exposure to ionising radiation induces DNA damage in an indirect or direct manner. The indirect carcinogenic effect is mediated via water radiolysis, which promotes the production of ROS resulting in oxidative damage, which can result in SSBs. The direct effect involves direct interaction of electrons with DNA resulting in molecular distortion and DSBs. |
[5,6] |
| Asbestos |
Asbestos is highly carcinogenic and used historically in industry and household applications. Exposure to fibres is directly linked to asbestosis, pleural plaques and mesothelioma. Dimension, shape and chemical composition are factors in asbestos pathogenicity. Damage occurs through oxidative stress (may give rise to DNA strand breaks), fibrosis and interaction with the mitotic apparatus of dividing cells. Synergism in the causation of lung cancer is seen with other mutagens, including PAHs, due to asbestos' insoluble core via which adsorbed carcinogens are delivered to target sites where they exert their genotoxic effects. |
[30,31] |
| Nanoparticles (NPs) |
Nanotechnology engineering has seen increasing usage of nanoparticles in medical, cosmetics and electronic industries. NPs have one dimension <100 nm, aiding cell penetration following inhalation, dermal or oral exposure with consequent ability to cause DNA damage. Damage can be direct and genotoxic effects include DNA adducts resulting from oxidative damage, epigenetic changes and DNA strand breaks. |
[32–34] |
