Background: Brazil has been the world's largest pesticide consumer, driven by permissive legislation allowing use of active ingredients banned globally. This widespread exposure encompasses probable human carcinogens classified by IARC, including glyphosate (Group 2A). Rural workers face particularly severe exposure through direct occupational contact and environmental contamination, representing a critical understudied population for cancer risk assessment. Chronic pesticide exposure triggers carcinogenic mechanisms primarily through oxidative stress-mediated DNA damage. Reactive oxygen species generated during pesticide metabolism induce 8-oxoguanine lesions—highly mutagenic base modifications—alongside DNA strand breaks and chromosomal instability, recognized hallmarks of carcinogenesis. These genotoxic effects are not uniform across populations; individual susceptibility is profoundly modulated by genetic variants in DNA repair pathways, particularly the base excision repair (BER) system responsible for correcting oxidative damage. Two functionally relevant polymorphisms warrant investigation: OGG1Ser326Cys (rs1052133), affecting the enzyme that excises 8-oxoguanine lesions, and XRCC1Arg194Trp (rs1799782), encoding a scaffold protein coordinating BER complex assembly. The OGG1326Cys variant demonstrates reduced glycosylase activity and impaired repair capacity, whereas XRCC1194Trp may compromise protein-protein interactions critical for efficient DNA repair. Carriers of variant genotypes theoretically face amplified genotoxic responses to pesticide exposure, yet population-specific genetic architecture remains largely unexplored in Brazilian agricultural communities. Critically, genetic epidemiology in isolated rural populations may reveal unique risk profiles. Small founding populations with limited gene flow—characteristic of many Brazilian agricultural settlements—can exhibit genetic drift, inbreeding, and Hardy-Weinberg deviations, potentially concentrating deleterious repair variants. This "genetic bottleneck" phenomenon could create populations with inherently compromised DNA repair capacity, rendering them exceptionally vulnerable to environmental carcinogens. Understanding this gene-environment interaction is essential for targeted cancer prevention strategies.
Objectives: To evaluate genotoxic effects and DNA repair gene polymorphisms in rural workers occupationally/environmentally exposed to pesticides in Casimiro de Abreu, Rio de Janeiro, through assess genotoxicity by micronucleus and comet assays;  investigate OGG1 and XRCC1 polymorphisms via Sanger sequencing; compare exposed individuals with unexposed urban controls; integrate polymorphism and genotoxicity data to identify cancer risk modulation patterns.
Methods: This cross-sectional study, coordinated by Brazil's National Cancer Institute since 2016 with Public Ministry of Labor funding, evaluated 102 occupationally/environmentally exposed rural residents and 33 urban controls. Genomic instability was assessed via cytokinesis-block micronucleus (MNcitB) and comet assays; polymorphisms via Sanger sequencing. Allelic/genotypic frequencies and Hardy-Weinberg equilibrium were analyzed.
Results: Exposed individuals showed elevated genomic instability: 1.8-fold increase in micronucleated binucleated cells (p<0.001), higher %Tail DNA (p=0.0067), and Olive Tail Moment (p=0.0026). OGG1 heterozygotes were absent in exposed individuals (0/9) versus 60% in controls (6/10), with 22.2% G/G variant homozygotes in the rural group. XRCC1 showed wild-type G fixation (100%). Genotypic patterns indicated Hardy-Weinberg deviation, suggesting inbreeding/genetic drift.
Conclusions: Occupational pesticide exposure drives significant genotoxic damage, amplified by population-specific DNA repair deficits, heightening cancer risk. The complete absence of OGG1 heterozygotes suggests potential consanguinity, creating a "genetic bottleneck" that compounds chemical carcinogen effects. Findings underscore urgent needs for rural worker surveillance, toxicogenetic monitoring, and public policy action—translating cancer research into public health impact.