Mesoamerican nephropathy (MeN) is a leading cause of morbidity and mortality in Central America, yet its aetiology remains unclear. Environmental exposures including heat stress, pesticides, and heavy metals have all been suggested as possible causes or exacerbating factors of the disease, but intermittent and cumulative exposures are difficult to capture using conventional biomonitoring. Locus-specific differential DNA-methylation (DNAm) which is known to occur in association with these environmental exposures can be readily measured in peripheral blood leucocytes, and therefore have the potential to be used as biomarkers of these exposures. In this study, we aimed first to perform a hypothesis-free epigenome-wide association study of MeN to identify disease-specific methylation signatures, and second to explore the association of DNAm changes associated with potentially relevant environmental exposures and MeN onset. Whole-blood epigenome-wide DNAm was analysed from a total of 312 blood samples: 53 incident cases (pre- and post-evidence of disease onset), 61 matched controls and 16 established cases, collected over a 5-year period. Mixed-effect models identified three unique differentially methylated regions that associated with incident kidney injury, two of which lie within the intron of genes (Amphiphysin on chromosome 7, and SLC29A3 chromosome 10), none of which have been previously reported with any other kidney disease. Next, we conducted a hypothesis-driven analysis examining the coefficients of CpG sites reported to be associated with ambient temperature, pesticides, arsenic, cadmium, and chromium. However, none showed an association with MeN disease onset. Therefore, we did not observe previously reported patterns of DNA methylation that might support a role of pesticides, temperature, or the examined metals in causing MeN.