The identification of biomarkers of genetic risk and susceptibility of individuals to exposure to xenobiotic substances, such as the rs25487 and rs662 SNPs, can be valuable for the monitoring of individuals exposed to carcinogenic and genotoxic compounds (Kvitko et al., 2012; Lima Sombra et al., 2011; Manel et al., 2003; Leite et al., 2013).
The A allele of the rs25487 of the XRCC1 gene was recorded in 26% of the individuals sampled from Goiás state. The A/A genotype has been associated with skin cancer in individuals with sunburn (Nelson et al., 2002), squamous cell skin cancer (Kang et al., 2007), and Hodgkin’s disease (El-Zein et al., 2009). It is also related to an inadequate response to esophageal cancer and an increased risk of side effects to the treatment of head and neck cancer (Gong et al., 2021), in addition to an increased risk of radiation-induced lymphopenia in patients who have been treated for lung cancer (Xie et al., 2021).
A significantly higher frequency (p = 0.001) of this allele was recorded in the EXP (IND) population (49%) in comparison with the Goiás study population. Kaur & Kaur (2020) associated high frequencies of the altered genotypes of the OGG1 rs1052133 (Ser326Cys; 1245CA), XRCC1 rs1799782 (Arg194Trp; 26304CT), and XRCC1 rs25487 (Arg399Gln; 2815GA) genes with the DNA damage observed in agricultural workers exposed to organophosphates in the Punjab, India. These alterations can be linked to the use of pesticides, which can be genotoxic, cytotoxic, and cause reproductive hormone disorders. These toxic compounds can induce DNA damage and cytotoxic effects in both humans and animals through oxidative pathways (Singh et al., 2011a; Kim et al., 2010; Miranda-Contreras et al., 2013).
The rs25487 (Agr399Gln) SNP is related to a reduction in the capacity of the organism to repair DNA, due to the down-regulation of the interaction of the XRCC1 enzyme with the poly-ADP-ribose polymerase, which causes mutagenic damage (Mahmoud et al., 2019; Floris et al., 2020; Sobiahe et al., 2020). Interestingly, the wild-type rs25487 G allele, which produces arginine, has been associated with an increased risk of late fibrosis of the subcutaneous and deep tissues, in people who have been treated with radiotherapy (Andreassen, 2005).
Some patients with the wild G/G rs25487 genotype may experience severe neutropenia during the treatment of ovarian cancer with chemotherapy (Khrunin et al., 2010). This genotype may also be associated with an increase in hematological toxicity following radiotherapy in breast cancer patients (Petty et al., 2007) and an increase in skin cell toxicity (Gossage & Madhusudan, 2007). Alsbeih et al. (2010) suggested that the A allele may confer a degree of resistance to high doses of radiation, which would be advantageous in normal tissue during radiotherapy treatment, given the apparent increased risk of skin reactions in individuals with the G allele following radiotherapy. The toxicity induced by radiotherapy may provoke a number of effects, including certain responses in normal tissues, primarily in the mucosa and blood, leading to apoptosis, with the loss of the capacity for reproduction and cell replacement (Gossage & Madhusudan, 2007).
The evidence from these studies indicate that the G and A alleles of the rs25487 polymorphism may be associated with different outcomes, depending on the exposure scenario, i.e., radiotherapy or exposure to pesticides. The frequency of the G allele in the Goiás study population was 74%, while that of the A allele was 26%. Few previous study in the Brazilian state of Goiás have evaluated systematically the association between the rs25487 polymorphism and the outcome of exposure to pesticides, in particular the development of cancer, or radiotherapy in the inhabitants of this region of intense agricultural activity.
The distribution of the G allele of the rs662 polymorphism in the Pakistani and Thai populations exposed to pesticides (EXP [PAK] and EXP [THA]) was significantly different from that of the Goiás population. The authors of these studies (Leonel Javeres et al., 2020; Sridon et al., 2020) relate the incidence of this allele in these populations to an increase in DNA damage when exposed to pesticides.
By contrast, the frequencies recorded in the Cameroonian, Colombian, and Egyptian (EXP-WS and EXP-NS) populations exposed to pesticides did not vary significantly in comparison with the Goiás study population. It is nevertheless interesting to note that the authors of those studies found a significant relationship between the G allele of rs662 and increased DNA damage (Leonel Javeres et al., 2020; Siller-López et al., 2017; Zayed et al., 2015).
The PON1 gene encodes the paraoxonase 1 enzyme, which plays an essential role in the inactivation of organophosphate pesticides (Rossignol et al., 2014). In the first phase of liver detoxification, bioactivation reactions convert the pesticides into more polar metabolites (Lieber et al., 2004; Li et al., 2012b). These intermediates are electrophilic, genotoxic, and highly carcinogenic metabolites that are biotransformed by the phase II inactivating enzymes, glutathione-S-transferases (GST) and N-acetyltransferases (NAT), into more water-soluble compounds that are easier to eliminate (Tanaka, 1999; Hatagima et al., 2000; Liu, 2006; Moura, 2005; Singh et al., 2011a; Alves et al., 2019).
The G/G rs662 genotype codifies a less active isoform of the protein, in terms of both its capacity to oxidize lipids and to inactivate pesticides. This isoform has also been associated with increased DNA damage and decreased activity in the acetylcholinesterase enzymes of rural workers exposed to pesticides, in a number of different studies (Hernández et al., 2013; Leonel Javeres et al., 2020; Singh et al., 2011bc; Han et al., 2015; Sridon et al., 2020; Zayed et al., 2015). This genotype is also associated with the development of autism (D'Amelio et al., 2005; Rossignol et al., 2014; Siller-López et al., 2017; Sridon et al., 2020), depression, and bipolar disorder (Yildiz et al., 2017). Overall, then, the G/G genotype appears to represent a significant risk factor for individuals that come into contact with pesticides, due to the sample variation in the PON1 enzyme produced by the rs662 polymorphism
However, the A allele of the rs662, which produces glutamine, has also been associated with an increased risk of hypertension and cardiovascular disease in rural workers exposed to pesticides (Siller-López et al., 2017). In a study of South African farmers (Lee et al., 2003), the A allele was identified as a predictor of chronic poisoning, and the genotypes with this allele had a higher incidence of chronic symptoms. Ji et al. (2012) also found an association between the A allele and increased DNA damage in the sperm in a Chinese study of 1,657 men suffering from infertility.
These associations may reflect the fact that the A allele produces isoforms with more intense activity (Rossignol et al., 2014; Siller-López et al., 2017; Sridon et al., 2020). The more active isoform generates more genotoxic and carcinogenic metabolites which, in turn, may not be biotransformed entirely in the second stage of liver detoxification. Ramos et al. (2016), for example, found that the alleles that cause the over-expression of CYP2E1 lead to an increase in enzyme activity by forming more genotoxic metabolites and increasing DNA damage, as indicated by the evaluation polymorphisms of the CPY2E1 gene in alcoholics from Goiás state.
However, Sunay et al. (2015) obtained contrasting results from the analysis of a Turkish population exposed to pesticides, in terms of the influence of the rs662 polymorphism on the enzymatic activity of the PON1. In this study, the G/G allele was responsible for an increase in PON1 activity, in both the exposed and control groups. The A/G mutant haplotype has low frequencies in most other populations, reaching a maximum of 20% in the Japanese population (EAS), while that of the Goiás study population was 11.9%.
The high G/G haplotype frequencies recorded in AFR and EAS populations highlight the intrinsic variability of these loci. In fact, a high proportion of the individuals in the African and East Asian populations had haplotypes with at least one mutant allele (i.e., A/G, G/G, and A/A), with mean frequencies of 78% (AFR) and 75% (EAS). These haplotypes were recorded in 57% of the individuals sampled in the Goiás study population. The high frequencies of these haplotypes in the AFR and EAS populations may make them more vulnerable to intoxication by pesticides (Kvitko et al., 2012; Lima Sombra et al., 2011; Manel et al., 2003; Leite et al., 2013).
In addition, the principal factor determining intoxication by pesticides is the use and distribution of these substances. In Goiás, at least 43,000 tons of active pesticide compounds may be applied to the local plantations per year (IBAMA, 2019), and the state’s population may be at relatively high risk, given the large proportion (57%) of haplotypes that have at least one mutant allele (A/G, G/G or A/A). Goiás is a major agricultural region, and Araújo Nascimento et al. (2020) have already observed a direct relationship between the increase in the area cultivated in the state and the frequency of intoxication by pesticides