Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk

Environ Health Perspect. 2011 Dec;119(12):1726-32. doi: 10.1289/ehp.1103454. Epub 2011 Aug 2.

Abstract

Background: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage.

Objectives: Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators.

Methods: We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach.

Results: The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10-6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2.

Conclusions: Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Case-Control Studies
  • DNA Repair / genetics*
  • Fonofos / adverse effects*
  • Genetic Variation*
  • Genotype
  • Humans
  • Likelihood Functions
  • Logistic Models
  • Male
  • N-Glycosyl Hydrolases / genetics
  • North Carolina / epidemiology
  • Occupational Exposure / adverse effects*
  • Odds Ratio
  • Pesticides / adverse effects*
  • Polymorphism, Single Nucleotide / genetics
  • Prostatic Neoplasms / chemically induced*
  • Prostatic Neoplasms / epidemiology*
  • Prostatic Neoplasms / genetics
  • Risk Assessment

Substances

  • Pesticides
  • FLJ10858 protein, human
  • N-Glycosyl Hydrolases
  • Fonofos