Sex Steroid Hormone Single-Nucleotide Polymorphisms, Pesticide Use, and the Risk of Prostate Cancer: A Nested Case-Control Study within the Agricultural Health Study.

Carol H Christensen,Sonja I Berndt,Gabriella Andreotti,Scott P Kelly,Stella Koutros,Laurie A Burdett,Kathryn Hughes Barry,Michael B Cook,Laura E Beane Freeman,Meredith Yeager,Michael C R Alavanja

doi:10.3389/fonc.2016.00237

Abstract

Experimental and epidemiologic investigations suggest that certain pesticides may alter sex steroid hormone synthesis, metabolism or regulation, and the risk of hormone-related cancers. Here, we evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. We evaluated pesticide–SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions, we included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP–pesticide interactions were calculated using a likelihood ratio test. We translated p-values for interaction into q-values, which reflected the false discovery rate, to account for multiple comparisons. We observed a significant interaction, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 × 10−5; q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk.

Highlights

Farmers have a greater risk of prostate cancer than the general population or other occupational groups [1,2,3]
In the present hypothesis-generating study, we investigated genetic variation along the sex steroid hormone candidate pathway, as well as single-nucleotide polymorphism (SNP) that have been associated with circulating sex steroid concentrations in genome-wide association studies (GWAS) as potential modifying factors of the relationship between pesticide exposure and prostate cancer risk
In the second approach for SNP selection, we selected SNPs that were associated with circulating sex steroid hormone concentrations in GWAS [28,29,30,31,32]. To identify these SNPs, we queried the GWAS Catalog1 for SNPs that influenced circulating steroid hormone concentration using the terms such as “androgens,” “estrogens,” “sex hormone-binding globulin (SHBG),” “testosterone,” and “estradiol.” We identified 17 SNPs at a threshold of p < 10−5 that were related to circulating hormone levels,2 of which 4 were genotyped on the iSelect platform

Summary

Introduction

Farmers have a greater risk of prostate cancer than the general population or other occupational groups [1,2,3]. Investigations within the Agricultural Health Study (AHS), a large prospective cohort of pesticide applicators, have identified links between prostate cancer, including aggressive forms of the disease, and pesticide exposure [4]. Previous studies within the AHS have suggested that pesticides may interact with single-nucleotide polymorphisms (SNPs) along several different biological pathways to influence the risk of prostate cancer [5,6,7,8,9]; additional biological pathways, including those involving hormones, have yet to be examined. It is possible that variants in genes along this pathway may alter or amplify pesticide effects on hormone homeostasis and alter prostate cancer disease risk

Methods

Results

Conclusion