Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson's disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity

Abstract

Background: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases.

Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n = 20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (p < 0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGCs, identified 8 and 18 DML in brain and blood DNA, respectively (p < 0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases.

Conclusions: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

Keywords: Genome-wide DNA methylation; Glia; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Organochlorines; Parkinson’s disease; Plantation work.

Fig. 1

PCA and hierarchical clustering for plantation work DML (10+ years vs 0 years). a, b Principal component graphs as coordinates in 3-D Euclidian space, depicting the clear separation of the high and low exposure groups. DML loci with p < 0.0001 were used, 7 for brain (a) and 123 for blood (b). c, d Hierarchical clustering of the DML for high and low exposure to plantation work in brain and blood. For brain (c), 94 DML loci with p < 0.001 were used, for blood (d), 123 DML loci with p < 0.0001 were used

Fig. 2

PCA and hierarchical clustering for OGC exposure DML (4+ years vs 0 years). a, b Principal component graphs as coordinates in 3-D Euclidian space, depicting the clear separation of the high and low exposure groups. DML loci with p < 0.0001 were used, 8 for brain (a) and 18 for blood (b). c, d Hierarchical clustering of the DML for high and low detectable OGCs in brain and blood. DML loci with p < 0.001 were used, 69 for brain (c) and 176 for blood (d)