The incidence of the XRCC1 rs25487 and PON1 rs662 polymorphisms in a population from Central Brazil: patterns in an area with a high level of agricultural activity

doi:10.21203/rs.3.rs-1612292/v1

In Brazil, high levels of agricultural activity are reflected in the consumption of enormous amounts of pesticide. The production of grain in Brazil has been estimated to reach 289.8 million tons in the 2022 harvest, an increase of 14.7% in comparison with 2021, with an even greater increase being predicted for Goiás, one of the country’s principal grain producing states. These advances are likely associated with a progressive increase in the occupational exposure of rural workers to pesticides. The PON1 gene activates the enzymes involved in phase I of liver detoxification. The rs662 variant of this gene is known to modify the activity of the PON1 enzyme, which can increase the susceptibility of an individual to pesticides, leading to more severe symptoms or the development of diseases. The present study describes the frequencies of the rs25487 (of the XRCC gene) and rs662 variants and their haplotypes in a sample population from Goiás, Brazil, and compares the frequencies with other populations from around the world to verify the variation in the distribution of these Single Nucleotide Polymorphisms (SNPs). The study analyzed samples taken from 494 unrelated individuals resident in the state of Goiás. The A allele of the rs25487 variant had a frequency of 26% in the Goiás study population, and the modified rs662 G allele had a frequency of 42.8%. Four haplotypes were recorded for the rs25487 (G > A) and rs662 (A > G) markers, with a frequency of 11.9% being recorded for the A/G haplotype (both modified alleles), 30.8% for the G/G haplotype, 14.3% for the A/A haplotype, and 42.8% for the G/A haplotype (both wild-type alleles). In conclusion, we demonstrated the distribution of important SNPs associated with pesticide exposure in an area that presents a high level of agricultural activity.

populations

polymorphisms

pesticides

susceptibility

1000 genomes

rural workers

Brazil is a major consumer of pesticides due to the intense agricultural activity (Abreu & Alonzo, 2014). The National Provisions Company (Conab, 2021) estimates that total grain production in the Brazilian state of Goiás will reach 28.8 million tons in the 2022 harvest, a record for the state, and an increase of 21.1% in comparison with 2021.

Exposure to agricultural pesticides can lead to the impairment of a set of essential functions, such as the inhibition of carboxyl ester hydrolases, chymotrypsin, acetylcholinesterase (AchE), butyrylcholinesterase, liver carboxylases, and paraoxonases (Abdollahi et al., 2004; Kampire et al., 2011; Sifuentes Dos Santos et al., 2015). Exposure may also cause, directly or indirectly, damage to the single- or double-stranded DNA by producing Reactive Oxygen Species, or ROS (Ceja Galvez et al., 2021; Franco et al., 2016; Godoy et al., 2014; Rohr et al., 2011; Singh et al., 2011). Base Excision Repair (BER) is a fundamental pathway of repairing single-stranded DNA breaks, which may help to minimize this type of impact caused by pesticides (Ceja Galvez et al., 2021; de Oliveira et al., 2019).

The XRCC1 gene (X-Ray Repair Cross-Complementing Group 1), which is located on chromosome 19 (q13.2-13.3), consists of 33 kb, 17 exons, 16 introns, and encodes a protein of 633 amino acids with a molecular weight of 70KDa (Batar et al., 2016; Li et al., 2012a). The XRCC1 gene is an essential component of the BER pathway, coordinating other components, such as the poly ADP-ribose, DNA polymerase H, and DNA ligase III, which are all involved in the repair of single strands damaged by ROS (de Oliveira et al., 2019; Fujihara; et al., 2016; Mahmoud et al., 2019; Sobiahe et al., 2020; Xu et al., 2019). A single nucleotide polymorphism (SNP) in the XRCC1 gene results in increased susceptibility to DNA damage (Chang et al., 2009; de Oliveira et al., 2019). The rs25487 G > A SNP of the XRCC1 gene causes a change in codon 399 in the C-terminal domain of the protein, which shifts from arginine to glutamine (Arg399Gln), with the wild-type G allele producing arginine, and the A allele producing glutamine (Bukowski & Woźniak, 2017; Huang et al., 2011; Mahmoud et al., 2019). This shift (Arg399Gln) is associated with a decreased level of DNA repair (Batar et al., 2016), the development of skin cancer (Sobiahe et al., 2020) and lung cancer (Wang et al., 2015), and increased susceptibility to viral hepatitis C (Leite et al., 2013; Mahmoud et al., 2019).

The PON1 (Paraoxonase 1) gene is located on chromosome 7 in the q21.3. This gene consists of 26.8 kb, nine exons, eight introns, and encodes a protein of 354 amino acids with a molecular weight of 43KDa (Shunmoogam et al., 2018). Paraoxonase 1 is synthesized by the liver and is found on the surface of high-density lipoproteins (HDL). It is an enzyme involved in phase I detoxification, and plays a role in protecting the low-density lipoproteins (LDL). Paraoxonase 1 is also involved in the oxidation pathway of the reverse transport of cholesterol, generating anti-atherogenic effects, as well as hydrolyzing and catalyzing organophosphates before they phosphorylate AchE (Durrington et al., 2001; Hofer et al., 2006; Medina-Díaz et al., 2017).

A number of different polymorphisms of the PON1 gene affect the concentration and activity of the paraoxonase 1 enzyme. These polymorphisms have been associated with an increased risk of developing cardiac and autoimmune diseases, and osteonecrosis (Durrington et al., 2001; Hadjigeorgiou et al., 2007; Zayed et al., 2015; Sunay et al., 2015; Sridon et al., 2020; Hernández-Collazo et al., 2021). The PON1 rs662 A > G mutation is responsible for changing amino acid 192 from glutamine to arginine (Gln192Arg). The former paraoxonase isoform (allele A), which contains glutamine, has been shown to have more efficient catalytic properties for the detoxification of the liver and lipoprotein oxidation reactions in comparison with the latter isoform (allele G), which contains arginine (Rossignol et al., 2014; Siller-López et al. al., 2017; Sridon et al., 2020). The Gln192Arg mutation is associated with the development of atherosclerosis, hypertension, and coronary heart disease (Dardiotis et al., 2019; Han et al., 2015; Siller-López et al., 2017), changes in the action of AchE, and DNA damage resulting from exposure to pesticides (Bukowski & Woźniak, 2017; Dardiotis et al., 2019; Leonel Javeres et al., 2020).

As the economy of Goiás state is dominated by its agricultural sector, occupational exposure to pesticides may be widespread, leading to the frequent intoxication of farm workers (de Araújo Nascimento et al., 2020; IBAMA, 2019). This emphasizes the need to determine the distribution of the rs25487 and rs662 polymorphisms, given their association with susceptibility to intoxication and DNA damage. Understanding the susceptibility of the population of Goiás to pesticide exposure will be essential to the development of adequate preventive measures by government agencies. In this context, the present study describes the frequencies of the rs25487 and rs662 SNPs and their haplotypes in a sample of the population of Goiás, compares the frequencies with other groups from Brazil, and around the world to have better understand the distribution pattern in this Brazilian state.

2.1. Study population

The study population included 494 unrelated individuals resident in Goiás state, with ages of between 20 and 65 years that were sampled randomly. All the participants were informed of the objective of the study and the procedures used to collect data. Once each participant had filled out a questionnaire with their personal details and signed the Informed Consent Term. A 10-ml sample of peripheral blood was collected. The study population from Goiás state was designated "SAMPLE (GO)" for the comparative analyses.

It was obtained approval for this study from the Research Ethics Committee of the Federal University of Goias (reference number 2.648.494). All research procedures were according to the principles of the regulatory guidelines and standards described in Resolution No. 466/12 of the National Health Council, which approves the regulatory

guidelines and standards for research involving human beings in Brazil.

2.2. Extraction of the DNA and SNP Genotyping by real-time quantitative PCR

The genomic DNA was isolated from the blood samples using the ReliaPrep™ Blood gDNA Miniprep System kit (Promega, USA), following the manufacturer`s protocol. The DNA was diluted to a final concentration of 20 ng/µL for quantification using a NanoVue Plus™ spectrometer, also following the manufacturer’s protocol.

The DNA samples were used to genotype the rs25487 SNP of the XRCC1 gene and the rs662 SNP of the PON1 gene, using the 5'-GGGTTGGCGTGTGAGGCCTTACCTC[A/G]GGGAGGGCAGCCGCCGACGCATGCG-3' and 5’-ACTTTTCCCCCTAGTTG’TGCATTCCGT-3’ regions, respectively, to detect the alleles. In addition, 1 µl of the DNA was used for real-time PCR amplification using the TaqMan SNP Genotyping Assays system (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

For this, 5 µl of TaqMan™ Master MIX, 0.25 µL of the TaqMan™ SNP Genotyping Probe, and 3.75 µL of milli-Q H2O were added to the diluted DNA. The plates were then inserted in a One Step Plus Real-Time PCR system thermocycler (Applied Biosystems Inc., Foster City, CA, USA) for processing. The plate was exposed to a temperature of 95°C for 10 minutes for initial denaturation, 15 seconds at 95°C for DNA strand denaturation, and 1 minute at 60°C for primer annealing, with 45 repetition cycles and a final 5 minutes at 72°C for extension and the emission and detection of the fluorescence. Following the manufacturer’s protocol (Thermo Fisher Scientific Inc., Waltham, MA, USA), the reactions being run in duplicate, with a positive control for each genotype and a negative control, which ensured the absence of contamination.

2.3 Populations included in the study for comparison

The data collected in the present study were compared with those from other studies, in both Brazil and other parts of the world. For this comparison, studies of the rs25487 and rs662 polymorphisms – from the period between 2007 and 2021 – were surveyed in the Web of Science and Google Scholar platforms using the search terms “rs25487”, “rs662”, “pesticide”, “rs25487 and pesticide”, and “rs662 and pesticide”. The papers identified in this search contained data appropriate for comparison with the parameters recorded in the present study, in particular, the frequencies of the alleles and genotypes of the rs25487 and rs662 SNPs.

Data on the rs25487 and rs662 polymorphisms were also compiled from 26 populations (2,504 individuals) representing five different ethnic groups sampled by the 1000 Genomes Project. These data were obtained in .vcf files, which were downloaded from the project’s online database (www.1000genomes.org). These data were used for comparison with the sequences of the Goiás study population.

2.4. Statistical analysis

The genotype and allele frequencies of the rs662 (PON1) and rs25487 (XRCC1) polymorphisms were calculated using GENEPOP 4, while Arlequin 3.5.2.2 was used to calculate the haplotype frequencies and Hardy-Weinberg equilibrium. Fisher’s Exact Test was run in the RStudio software to compare the distribution of the allele and haplotype frequencies between populations.

Overall, the 494 unrelated individuals sampled in the present study from the state of Goiás had a mean age of 48.18 ± 15.56 years, 129 (26%) were female and 365 (74%) were male. For comparative purposes, studies of rs25487 and/or rs662 were compiled from 56 other populations, including 26 from the 1000 Genomes Project database (Table 1), 15 other rs25487 studies (Table 2) and 15 rs662 studies (Table 3).

Table 1

The populations of the third phase of the 1000 Genomes project used for comparison in the present study. Ethnicity: AFR = African, AMR = American, EAS = East Asian, EUR = European, SAS = South Asian. (Available at: http://www.internationalgenome.org/faq/which-populations-are-part-your-study/)
Code	Population	Ethnicity
ACB	Descendants of Africans from Barbados	AFR
ASW	Descendants of Africans from the southwestern USA
ESN	Esan from Nigria
GWD	Gambians from the Gambia
LWK	Ludhiana from Webuye, Kenya
MSL	Mendes from Serra Leoa
YRI	Yorubas from Ibadan, Nigeria
CLM	Colombians from Mendelim, Colombia	AMR
MXL	Descendants of Mexicans from Los Angeles, USA
PEL	Peruvians from Lima, Peru
PUR	Puerto Ricans from Puerto Rico
CDX	Dai Chinese from Xishuangbanna, China	EAS
CHB	Han Chinese from Beijing, China
CHS	Han Chinese from South China
JPT	Japanese from Tokyo, Japan
KHV	Vietnamese from Ho Chi Minh City, Vietnam
CEU	Descendants of Europeans from Utah, USA	EUR
FIN	Finns from Finland
GBR	English from England and Scotland
IBS	Iberians from Spain
TSI	Tuscans from Italy
BEB	Bangladeshi from Bangladesh	SAS
GIH	Gujarati Indians from Houston, Texas
ITU	Telugu Indians from the UK
PJL	Panjabi from Lahore, Pakistan
STU	Tamil Sri Lankans from the UK

Table 2

Populations from other studies that genotyped the rs25487 polymorphism of the XRCC1 gene included in the present study for the comparison of allele frequencies.
rs25487 (XRCC1)
Code	Population	Description	Reference
CONT (MT)	Cuiabá, Mato Grosso (MT), Brazil	Control	(Leite et al., 2013)
CIR (MT)	Cuiabá, Mato Grosso (MT), Brazil	Individuals with cirrhosis	(Leite et al., 2013)
ORC (PR)	Paraná (PR), Brazil	Individuals with buccal cancer	(Reis et al., 2013)
CONT (PR)	Paraná (PR), Brazil	Control	(Reis et al., 2013)
CONT (RN)	Natal, Rio Grande do Norte (RN), Brazil	Control	(Lopes Pinheiro et al., 2016)
EXP-UMA (PA)	Monte Alegre, Pará (PA), Brazil	Miners exposed to uranium	(Lima Sombra et al., 2011)
EXP-UP (PA)	Prainha, PA, Brazil
EXP-UA (PA)	Alenquer, PA, Brazil
GIC (IND)	India	Individuals with gastrointestinal cancer	(Patil et al., 2020)
CONT (IND)		Control	(Patil et al., 2020)
EXP (IND)		Individuals exposed to organophosphates	(Kaur et al., 2020)
LC (CHN)	China	Individuals with lung cancer	(Wang et al., 2015)
CONT (KOR)	South Korea	Control	(Kim et al., 2014)
LNH (KOR)	South Korea	Patients with Hodgkin’s Lymphoma	(Kim et al., 2014)
QT (BAN)	Bangladesh	Patients undergoing chemotherapy	(Bushra et al., 2020)

Table 3

Populations from other studies that genotyped the rs662 polymorphism of the PON1 gene included in the present study for the comparison of allele frequencies.
rs662 (PON1)
Acronym	Country		Description	Reference
CAML (BRA)	Brazil		Children with acute amyotrophic leukemia	(Gonçalves et al., 2012)
CONT (BRA)	Brazil		Control	(Gonçalves et al., 2012)
ONFH (GRE)	Greece		Individuals with osteonecrosis of the head of the femur	(Hadjigeorgiou et al., 2007)
EXP (CAM)	Cameroon		Exposure to organophosphates	(Leonel Javeres et al., 2020)
CONT (CAM)	Cameroon		Control
EXP (PAK)	Pakistan		Exposure to organophosphates
CONT (PAK)	Pakistan		Control
EXP (COL)	Colombia		Exposure to organophosphates	(Siller-López et al., 2017)
EXP (THA)	Thailand			(Sridon et al., 2020)
CONT (THA)	Thailand		Control	(Sridon et al., 2020)
CONT (EGT)	Egypt		Control	(Zayed et al., 2015)
EXP-NS (EGT)			Exposure to organophosphates with symptoms
EXP-WS (EGT)			Exposure to organophosphates (no symptoms)
PSM (MEX)	Mexico		Individuals with psoriasis	(Hernández-Collazo et al., 2021)
CONT (MEX)		Control

In the Goiás study population, the mutant A allele of the rs25487 polymorphism has a frequency of 26% (Table 4), while the frequency of the mutant G allele of the rs662 polymorphism was 42.8% (Table 4). In the case of the rs25487 polymorphism, the highest frequency (49.0%) of the mutant A allele was recorded in Indian farmers (SAS) exposed to pesticides (EXP [IND]). For the rs662 polymorphism, the highest frequency of the mutant G allele was 80.8% in Ludhiana from Kenya, representing the African ethnicity in the 1000 Genomes project (Table 4).

Table 4

Allele frequencies of the rs25487 polymorphism of the XRCC1 gene and the rs662 polymorphism of the PON 1 gene recorded in the populations included in the present study
Population	Allele frequency rs25487		Population	Allele frequency rs662
Population	G	A	Population	A	G
SAMPLE (GO)	0.740	0.260	SAMPLE (GO)	0.572	0.428
CONT (MT)	0.750	0.250	CAML (BRA)	0.615	0.385
CIR (MT)	0.590	0.410	CONT (BRA)	0.535	0.465
ORC (PR)	0.630	0.370	ONFH (GRE)	0.810	0.13
CONT (PR)	0.590	0.410	EXP (CAM)	0.605	0.395
CONT (RN)	0.700	0.300	CONT (CAM)	0.716	0.284
EXP-UMA (PA)	0.720	0.280	EXP (PAK)	0.530	0.470
EXP-UP (PA)	0.700	0.300	CONT (PAK)	0.630	0.370
EXP-UA (PA)	0.680	0.320	EXP (COL)	0.600	0.400
GIC (IND)	0.640	0.360	EXP (THA)	0.370	0.630
CONT (IND)	0.690	0.310	CONT (THA)	0.670	0.330
EXP (IND)	0.510	0.490	CONT (EGT)	0.810	0.190
LC (CHN)	0.735	0.270	EXP-NS (EGT)	0.700	0.300
CONT (KOR)	0.740	0.260	EXP-WS (EGT)	0.525	0.475
LNH (KOR)	0.770	0.230	PSM (MEX)	0.572	0.428
QT (BAN)	0.750	0.250	CONT (MEX)	0.706	0.294
ACB	0.849	0.151	ACB	0.255	0.745
ASW	0.811	0.189	ASW	0.377	0.623
ESN	0.914	0.086	ESN	0.227	0.773
GWD	0.907	0.093	GWD	0.265	0.735
LWK	0.904	0.096	LWK	0.192	0.808
MSL	0.924	0.076	MSL	0.247	0.753
YRI	0.889	0.111	YRI	0.218	0.782
CLM	0.628	0.372	CLM	0.58	0.42
MXL	0.727	0.273	MXL	0.477	0.523
PEL	0.694	0.306	PEL	0.388	0.612
PUR	0.712	0.288	PUR	0.538	0.462
CDX	0.801	0.199	CDX	0.290	0.710
CHB	0.748	0.252	CHB	0.408	0.592
CHS	0.790	0.210	CHS	0.352	0.648
JPT	0.721	0.279	JPT	0.303	0.697
KHV	0.768	0.232	KHV	0.313	0.687
CEU	0.646	0.354	CEU	0.687	0.313
FIN	0.667	0.333	FIN	0.747	0.253
GBR	0.659	0.341	GBR	0.659	0.341
IBS	0.579	0.421	IBS	0.706	0.294
TSI	0.626	0.374	TSI	0.743	0.257
BEB	0.657	0.343	BEB	0.570	0.430
GIH	0.607	0.393	GIH	0.621	0.379
ITU	0.711	0.289	ITU	0.574	0.426
PJL	0.635	0.365	PJL	0.578	0.422
STU	0.672	0.328	STU	0.534	0.466

The frequencies of the rs662 polymorphism of the Goiás study deviated significantly (p = 0.03) from the values expected under the Hardy-Weinberg equilibrium, while those of the rs25487 polymorphism were in equilibrium. All the 26 populations of the 1000 Genomes database were in equilibrium for both polymorphisms. In the Goiás study population, the mutant (A/G) haplotype had a frequency of 11.9%, while the wild type G/A haplotype was the most common, with a frequency of 42.8% (Table 5).

Table 5

Haplotype frequencies of the SNPs (rs25487 polymorphism of the XRCC1 gene and the rs662 of the PON1 gene) in the Goiás study population.
Alleles	rs25487 (G > A)	rs662 (A > G)
Haplotype	Frequency
A/G	0.119
G/G	0.308
A/A	0.143
G/A	0.428

The highest frequency (20.1%) of the mutant (A/G) haplotype was recorded in the Japanese (JPT) population of the EAS group, in which the frequencies ranged from 11–20%, while in the SAS group, the frequencies of the mutant haplotype ranged between 8% and 13% (Fig. 1). The G/G haplotype was relatively common in the African (AFR) populations, with frequencies of between 40% and 74%, which were higher than those of the wild (G/A) haplotype, although the mutant (A/G) haplotype was the least common haplotype in this group.

The rs25487 allele frequencies recorded in the Goiás study population were significantly different (p < 0.05) from those of seven populations (Table 6: CONT [MT], EXP [IND], ESN, MSL, YRI, CLM, and TSI). In the case of the rs662 polymorphism, the allele frequencies of the Goiás population were significantly different (p < 0.05) from almost half the other populations, i.e., EXP (PAK), EXP (THA), CONT (MEX), ACB, ASW, ESN, LWK, MSL, YRI, CLM, MXL, PUR, CHB, CHS, JPT, KHV, CEU, GBR, and BEB (Table 6).

Table 6

Results of Fisher’s exact test for the comparison of the allele frequencies of the rs25487 and rs662 polymorphisms of the Goiás study population with those of the other study populations included for comparison (Tables 1–3). The p values in bold script are significant (p < 0.05).
Population	rs25487 (XRCC): p	Population	rs662 (PON): p
CONT (MT)	0.6368	CAML (BRA)	0.6686
CIR (MT)	1.0000	CONT (BRA)	0.6651
ORC (PR)	0.1276	ONFH (GRE)	0.0060
CONT (PR)	0.0355	EXP (CAM)	0.6699
CONT (RN)	0.6368	CONT (CAM)	0.4706
EXP-UMA (PA)	0.8736	EXP (PAK)	0.0003
EXP-UP (PA)	0.6368	CONT (PAK)	0.7742
EXP-UA (PA)	0.4360	EXP (COL)	0.1897
GIC (IND)	0.1686	EXP (THA)	0.0003
CONT (IND)	0.5312	CONT (THA)	0.8885
EXP (IND)	0.0012	CONT (EGT)	0.6664
LC (CHN)	1.0000	EXP-NS (EGT)	0.1048
CONT (KOR)	1.0000	EXP-WS (EGT)	0.4774
LNH (KOR)	0.7425	PSM (MEX)	0.05512
QT (BAN)	1.0000	CONT (MEX)	< 0.001
ACB	0.0790	ACB	< 0.001
ASW	0.3096	ASW	< 0.001
ESN	0.0025	ESN	< 0.001
LWK	0.0025	LWK	< 0.001
MSL	0.0052	MSL	< 0.001
YRI	0.0011	YRI	< 0.001
CLM	0.0101	CLM	< 0.001
MXL	0.1276	MXL	< 0.001
PEL	1.000	PEL	0.2573
PUR	0.5312	PUR	0.0159
CDX	0.7516	CDX	0.7761
CHB	0.4010	CHB	0.0001
CHS	1.0000	CHS	0.0336
JPT	0.5050	JPT	0.0027
KHV	0.8736	KHV	0.0001
CEU	0.7425	CEU	0.0003
FIN	0.2190	FIN	0.1069
GBR	0.3523	GBR	0.0108
IBS	0.2800	IBS	0.2449
TSI	0.0248	TSI	0.05512
BEB	0.1276	BEB	0.017
GIH	0.2800	GIH	1.0000
ITU	0.0696	ITU	0.5646
PJL	0.7516	PJL	1.0000
STU	0.1285	STU	0.6699

The haplotype frequencies (rs25487 + rs662) of the Goiás study population were compared with those of the 1000 Genomes project using Fisher’s exact test (Fig. 2). This analysis indicated significant differences between the haplotype frequencies of the study population and those of all the African (AFR) and East Asian (EAS) populations, whereas none of the American (AMR) or South Asian (SAS) presented any significant variation.

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

Neither of the alleles (A or G) of the rs25487 polymorphism presented any clear association with exposure to pesticides or the incidence of cancer, which reinforces the need for further research, to determine any specific pattern in this marker. In many cases, populations had high frequencies of haplotypes with at least one mutated allele. However, further studies will be needed to determine to what extent the mutant alleles of the rs25487 (A) and rs662 (G) polymorphisms may interact, and whether there is an additive negative effect in individuals exposed to pesticides.

Funding

This work was supported by the Coordination for Higher Education Personnel

Training (CAPES), the Goiás State Research Support Foundation (FAPEG), and

PRONEX/FAPEG/CNPq (Nucleus of Excellence support program – protocol number

20181002600) for financial support.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Alessandro Arruda Alves, Daniela de Melo e Silva, Fernanda Craveiro Franco and Hugo Freire Nunes contributed to the study conception and design.

Alessandro Arruda Alves, Fernanda Craveiro Franco, Kessia Laurinho, Felipe Araujo Nascimento and Hugo Freire Nunes performed material preparation, data collection and analysis.

Alessandro Arruda Alves, Hugo Freire Nunes and Daniela de Melo e Silva wrote the first draft of the manuscript.

All authors read and approved the final manuscript.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author (DMS).

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. The Ethics Committee of Federal University of Goias (reference number 2.648.494) granted approval. All research procedures were according to the principles of the regulatory guidelines and standards described in Resolution No. 466/12 of the National Health Council, which approves the regulatory guidelines and standards for research involving human beings in Brazil.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

Not applicable.

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No competing interests reported.

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The incidence of the XRCC1 rs25487 and PON1 rs662 polymorphisms in a population from Central Brazil: patterns in an area with a high level of agricultural activity

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Abstract

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1. Introduction

2. Materials And Methods

3. Results

4. Discussion

5. Conclusion

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Status:

Journal Publication

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