Lead (Pb) is one of the most widely used heavy metals in several industries for the manufacturing process of Pb-based products due to its physical and chemical properties, such as high density, softness, malleability, and poor conductibility. Thus, Pb can be found in workplaces and other contaminated environments. Pb toxicity can occur via both nonoccupational and occupational exposure through inhalation, ingestion, and dermal absorption. Absorbed Pb enters the plasma and then moves rapidly to various body areas Pb is exchanged primarily among three areas, including the blood, mineralizing tissues (teeth and bones), and soft tissues (liver, kidneys, lungs, brain, spleen, muscles, and heart), contributing to Pb accumulation and the induction of its mechanisms of action in several organ systems, such as the nervous, hematological, digestive, cardiovascular, skeletal, reproductive, and excretory systems [1]. Thus, Pb is a highly poisonous heavy metal affecting almost every organ in the body. Moreover, the genotoxic effects of lead have been studied for a long time. The genotoxic endpoints induced by Pb have been well demonstrated in different test systems. Pb was found to produce positive responses in several biological and biochemical tests for DNA breaks and lesions, mutation, and DNA oxidative damage [2,3,4,5]. However, the exact mechanisms are still largely unknown. Previous studies suggested that the mechanics of its genotoxicity could be involved with indirect mechanisms, such as the inhibition of DNA repair systems [2,3,4,5,6].

DNA molecules are continuously damaged by both endogenous and exogenous genotoxic factors. These genotoxic factors contribute to DNA damage and genome instability, affecting transcription and replication, and they can be inherited by daughter cells. However, cells have a repair process known as the DNA damage response (DDR) for the recognition and repair of this DNA damage. The DNA repair mechanisms include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), translesion synthesis, and DNA interstrand crosslink repair [1]. In DNA repair systems, several DNA repair genes and their encoded proteins are responsible for monitoring chromosomes by correcting the damaged nucleotide residues in specific repair pathways, for example 8-oxoguanine DNA glycosylase 1 (hOGG1), X-ray repair cross-complementing protein 1 (XRCC1), and Excision Repair 1(ERCC1), which play a crucial role in ROS-induced DNA repair pathways. Importantly, the inactivation of DNA repair genes contributes to a deficiency in DNA repair and the accumulation of DNA damage that promotes tumorigenesis [7]. In addition, epigenetics involves gene expression and regulation without DNA sequence changes. Transcriptional regulation is administered through important epigenetic pathways, dictated primarily by DNA methylation, RNA regulation, and the posttranslational modification (PTM) of histones [8]. Several previous studies demonstrated an interaction between heavy metals and the aberrant expression of DNA repair genes via epigenetic mechanisms, such as aberrant DNA methylation, modified histone modification, and the altered expression profiles of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) [9,10,11]. Moreover, some studies have shown that heavy metal-impaired DNA repair was mediated by aberrant expression through mutation in the exon of DNA repair genes.

Heavy metals can interfere with the activities of several proteins and alters the expression pattern of numerous genes [12,13]. Recent studies also reported a role of Pb toxicity in the impairment of DNA repair systems. This review gathered evidence of the impact of Pb toxicity on the altered expression of DNA repair genes. Although the results are conflicting, these findings reinforce the need for the investigation of the mechanism of genotoxic effects of Pb related to the inhibition of DNA repair systems that promote cancer development.

The International Agency for Research on Cancer (IARC) has classified Pb as a possible human carcinogen (group 2B) and its inorganic compounds as probable human carcinogens (group 2A). The genotoxic effects of Pb have been investigated for many years and include chromosome aberration (CA), mutation, DNA breakage, and DNA synthesis inhibition [14,15]. According to previous studies, the end-points of the genotoxic effects of Pb have been well-demonstrated in different in vitro, in vivo, and epidemiological studies. Pb has been tested and found to exhibit positive responses in biological and biochemical tests for DNA lesions, such as structural and numerical CA, sister chromatid exchanges (SCE), micronucleus (MN) tests, and DNA strand breaks using the single-cell gel electrophoresis (comet) assay [2]. Moreover, hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene and T-cell receptor (TCR) mutation assays, most frequently used to determine the mutations caused by mutagenic agents in somatic cells, also indicated the genotoxic effect of Pb [2].

The genotoxic endpoints induced by Pb have been well-known for a long time. However, the genotoxic properties and mechanisms underlying the genotoxic effects of Pb are still unclear. It has been suggested that the mechanisms of the genotoxic effects of Pb could be involved with indirect mechanisms, such as the induction of oxidative stress contributing to DNA damage, the inhibition of DNA repair, the formation of DNA and/or protein crosslinks, and the regulation of tumor suppressor and promoter genes [6,16,17,18,19].

The major mechanism of Pb toxicity is primarily involved in oxidative stress, described as an imbalance between the generation of reactive oxygen species (ROS) and the ability of antioxidants [20]. Pb is capable of inhibiting the activities of antioxidant enzymes by interacting with a functional sulfhydryl (SH) group in antioxidant enzymes, such as δ-aminolaevulinic acid dehydrase (δ-ALAD), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glucose-6-phosphate dehydrogenase (G6PD) [21,22,23]. Inhibition of δ-ALAD, which catalyzes the condensation of delta-aminolaevulinic acid (δ-ALA) to porphobilinogen (PBG) in the pathway for heme synthesis, leads to accumulation of δ-ALA [24]. This eventually stimulates ROS production and the generation of 4,5-dioxovaleric acid, which is an efficient alkylating agent of the guanine moieties within both nucleoside and isolated DNA [25]. As a consequence of alkylation, single-strand breaks and quinine oxidation were produced with an increase in the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) [25]. 8-OHdG is one of the predominant forms of oxidative lesions and has been widely used as a biomarker for oxidative stress [26]. Several studies demonstrated a positive relation between 8-OHdG and Pb [15,27,28]. The DNA repair machinery plays the crucial role of protecting the cells from DNA damage generated by exposure to carcinogens and cytotoxic agents, as well as heavy metals. A previous study suggested that Pb substitutes calcium and zinc in enzymes involved in DNA processing and repair, resulting in an enhancement in genotoxicity when combined with other DNA-damaging agents such as tobacco smoke or UVA [2]. Interestingly, an abnormal DNA repair capacity was reported in lead-exposed workers [29,30].