The association between glyphosate use and mosaic loss of chromosome Y in buccal samples among male pesticide applicators in the Agricultural Health Study

Glyphosate-based herbicides are the most widely applied pesticides worldwide and have been implicated in the development of certain hematologic malignancies; however, the underlying biological mechanisms are not well-understood. High lifetime use of glyphosate-based herbicides, hereafter referred to as glyphosate, was previously associated with mosaic loss of chromosome Y (mLOY), a biomarker of genomic instability potentially linked to cancer and immune dysregulation, in circulating blood of male farmers from a subcohort of the Agricultural Health Study (AHS). Here, we further investigated the association between glyphosate use and mLOY using buccal-derived DNA among 1,868 male pesticide applicators in an independent AHS study. We detected mLOY using genotyping array intensity data in the male-specific region of the Y chromosome. Information on cumulative lifetime use of glyphosate was derived from questionnaires. Logistic regression analyses were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations of glyphosate use with overall mLOY and mLOY affecting a high cell fraction (≥ median), adjusted for potential confounders. Overall, mLOY was detected in buccal samples of 298 (16 %) pesticide applicators. High intensity-weighted lifetime days of glyphosate use was associated with overall mLOY (OR_{highest vs. lowest quartile of glyphosate use} = 1.54; 95 % CI: 1.01, 2.37), although the exposure-response trend was not statistically significant (P_trend = 0.40). For mLOY affecting a high fraction of cells, positive associations were observed for both high lifetime days (OR_{highest vs. lowest quartile of glyphosate use} = 1.76; 95 % CI: 1.04, 2.99; P_trend = 0.06) and high intensity-weighted lifetime days (OR_{highest vs. lowest quartile of glyphosate use} = 2.02; 95 % CI: 1.12, 3.64; P_trend = 0.16). Together, these findings support previous evidence linking glyphosate and mLOY and help inform our understanding of the biological impact of glyphosate on human health and its potential role in carcinogenesis.