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DNA methylation markers for glyphosate exposure and mammographic density

Creative Commons 'BY-NC' version 4.0 license

Glyphosate is the most commonly used herbicide in the world. Animal studies and epidemiologic evidence suggest that there may be adverse health effects of exposure to glyphosate. Glyphosate and its primary metabolite aminomethylphosphonic acid (AMPA) are frequently detected in a wide variety of foods, but studies of dietary factors associated with these pesticide residues are limited. Many previous studies have identified epigenetic signatures of environmental exposures and other risk factors for disease. DNA methylation can provide a tool for understanding the molecular impact of exposures and may serve as a biomarker for past exposures. However, no studies to date have examined the relationship between blood DNA methylation and urinary glyphosate and AMPA. Mammographic density, an important risk factor for breast cancer, may also have epigenetic impacts, but previous research on the subject has been uninformative.

Three hundred ninety-two postmenopausal women responded to diet, health, and environmental questionnaires and provided biospecimens including blood and two urine samples. Diet was characterized using up to three 24-hour dietary recalls to capture intake of specific food groups and overall diet quality. Site-specific DNA methylation in blood wasmeasured using the Illumina Infinium MethylationEPIC BeadChip. Urinary glyphosate and AMPA were measured using LC-MS/MS. Mammographic density was obtained from the most recent mammogram report. Using linear mixed-effects models, I explored relationships between dietary characteristics, demographic/behavioral factors, and urinary glyphosate and AMPA concentrations. After standard methylation data filtering and preprocessing, CpG sites throughout the genome were examined for associations with urinary glyphosate and AMPA concentrations and with mammographic density.

Grain consumption was associated with higher urinary glyphosate concentrations, even among women who reported often or always eating organic grains. Soy and alcohol consumption and increased frequency of fast-food dining were associated with greater AMPA, while fruit and corn consumption were associated with lower AMPA. Methylation at 24 CpG sites was associated with urinary glyphosate concentration. These sites were combined into a methylation index which accurately predicted glyphosate concentration in an internal validation cohort. Glyphosate- and AMPA-associated methylation occurred near genes associated with cancer (SF3B2, MSH4, and TRIM31) and endocrine disruption (ESR1), and AMPA was associated with greater epigenetic age acceleration. I identified 250 CpG sites and 37 regions for which DNA methylation was significantly associated with mammographic density. The top sites were located within genes associated with cancer, and were more likely to be located in regulatory regions of the genome.

This is the largest study to date examining paired dietary data and urinary glyphosate and AMPA and identified possible sources of glyphosate and AMPA in the American diet, including grains, soy, and alcoholic beverages. Glyphosate and AMPA exposure are associated with DNA methylation differences that could promote the development of cancer,informing the hypothesis that glyphosate and/or AMPA exposure could elevate the risk for disease. After further validation, these methylation differences may be developed into a biomarker of glyphosate exposure. This research paints a picture of epigenetic dysregulation associated with mammographic density and suggests the potential involvement of several genes in the biological mechanisms behind differences in breast density between women.

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