Glyphosate Use and Mosaic Loss of Chromosome Y among Male Farmers in the Agricultural Health Study

BACKGROUND: Glyphosatc is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce. OBJECTIVES: We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers. METHODS: We analyzed blood -derived DNA from 1,606 farmers > 50 years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (Cts) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or rnLOY affecting > 10% of cells (expanded mLOY). RESULTS: Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; OR = 1.75 (95% CI: 1.00, 3.07), P-acrid = 0.03] but not with overall MLOY, the associations with expanded mLOY were most apparent among older (>= 70 years of age) men [OR = 2.30 (95% CI: 1.13, 4.67), = 0.01], never smokers [OR = 2.32 (95% CI: 1.04, 5.21), p(ared) = 0.04], and nonobese men [OR = 2.04 (95% CI: 0.99, 4.19), = 0.03]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use. DISCUSSION: High lifetime glyphosate use could be associated with mLOY '' affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies.