Benzo[ a]pyrene-Environmental Occurrence, Human Exposure, and Mechanisms of Toxicity

Abstract

Benzo[a]pyrene (B[a]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments. It is present in cigarette smoke as well as in food products, especially when smoked and grilled. Human exposure to B[a]P is therefore common. Research shows growing evidence concerning toxic effects induced by this substance. This xenobiotic is metabolized by cytochrome P450 (CYP P450) to carcinogenic metabolite: 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), which creates DNA adducts, causing mutations and malignant transformations. Moreover, B[a]P is epigenotoxic, neurotoxic, and teratogenic, and exhibits pro-oxidative potential and causes impairment of animals' fertility. CYP P450 is strongly involved in B[a]P metabolism, and it is simultaneously expressed as a result of the association of B[a]P with aromatic hydrocarbon receptor (AhR), playing an essential role in the cancerogenic potential of various xenobiotics. In turn, polymorphism of CYP P450 genes determines the sensitivity of the organism to B[a]P. It was also observed that B[a]P facilitates the multiplication of viruses, which may be an additional problem with the widespread COVID-19 pandemic. Based on publications mainly from 2017 to 2022, this paper presents the occurrence of B[a]P in various environmental compartments and human surroundings, shows the exposure of humans to this substance, and describes the mechanisms of its toxicity.

Keywords: benzo[a]pyrene; carcinogenicity; genotoxicity; metabolism; polycyclic aromatic hydrocarbons.

Figure 1

Chemical structures of benzopyrene. Created with BioRender.com (accessed on 12 April 2022).

Figure 2

Steps in the biotransformation of B[a]P. Detoxification of B[a]P predominantly occurs with the participation of several cytochrome P450 (CYPs) isoforms. During phase I, xenobiotic is oxidized to reactive metabolites that may exhibit biological activity. In phase II, metabolites are conjugated with transferases (GSH, reduced glutathione; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; UDPGA, uridine diphosphate-glucuronic acid) and converted to more hydrophilic and biologically inactive forms. Then, metabolites are eliminated from the cell via specialized transporters (ABC, ATP-binding cassette transporter; SLC, solute carrier). NTCP, sodium/taurocholate cotransporting polypeptide; OATPs, organic anion transporting polypeptides—biological systems enabling the transport of xenobiotics to the cell [74,75]. Created with BioRender.com (accessed on 12 April 2022).

Figure 3

Biotransformation of B[a]P into mutagen. B[a]P in the I phase of detoxification goes through several stages, giving various derivatives, including B[a]P-7,8-diol-9,10-epoxide, that are able to react with DNA guanine. The reaction results in the formation of adducts with DNA (mtDNA, mitochondrial DNA; nDNA, nuclear DNA) and mutations [80,81]. Created with BioRender.com (accessed on 12 April 2022).

Figure 4

Mechanisms of B[a]P toxicity. Created with BioRender.com (accessed on 12 April 2022).

Figure 5

Environmental pollutants, such as B[a]P, affect the balance between the production of reactive intermediates and the biological system of ROS detoxification. The presence of B[a]P in the cell environment induces various molecular changes, such as lipid peroxidation or protein oxidation. B[a]P^·−, anion B[a]P radical; O^·−₂, superoxide anion; H₂O₂, hydrogen peroxide; OH^•, hydroxyl radical; HOCl, hypochlorous acid; NO, nitric oxide; ONOO, peroxynitrite; GS-B[a]P, glutathione-B[a]P conjugate; GSSG, glutathione disulfide (oxidized glutathione dimers); GR, glutathione reductase; GST, glutathione-S-transferase; CAT, catalase; SOD, superoxide dismutase; GSH, glutathione (reduced state); MPO, myeloperoxidase; TBARS, thiobarbituric acid reactive substances [107,108,109,110]. Created with BioRender.com (accessed on 12 April 2022).

Figure 6

Pro-oxidative mechanisms of B[a]P action. Created with BioRender.com (accessed on 12 April 2022).

Figure 7

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor located in the cytosol. Inactive AhR occurs as a complex bonded with protein HSP90 (heat shock protein 90), p23 co-chaperone, and protein XAP2 (aryl hydrocarbon receptor-interacting protein, known also as AIP) or arachidonic acid (ARA). Binding AhR with ligand (B[a]P) leads to translocation of the active form of receptor to the nucleus and binds it with AhR receptor nuclear translocator (ARNT). Attachment of specific transcription factors (xenobiotic response element, XRE; histone acetyltransferase p300, steroid receptor coactivator-1, SRC-1) triggers gene machinery leading to activation of detoxification pathways (mainly by cytochrome P450 activation, CYPs). Intensification of ROS production can be correlated with DNA damage, mutation (mainly via PBDE), and carcinogenesis [122]. Created with BioRender.com (accessed on 12 April 2022).

Figure 8

Mechanism of epigenetic changes induced by B[a]P. Created with BioRender.com (accessed on 12 April 2022).