Impact of exposures to persistent endocrine disrupting compounds on the sperm methylome in regions associated with neurodevelopmental disorders

Although autism spectrum disorder (ASD) is among the most heritable of neurodevelopmental disorders, the rapidly rising prevalence of ASD suggests that environmental factors may interact with genetic risk for ASD. Environmental factors may impact both gene expression and phenotypes in ASD through epigenetic modifications that, in turn, could lead to intergenerational effects influencing risk for ASDs. Endocrine disrupting compounds (EDCs), such as the long-lived organochlorines, are of particular interest with respect to risk for autism because of their ability to interfere with sex hormones that have been implicated in the regulation of RORA, a dysregulated gene in ASD that is a master regulator of many other ASD risk genes. The specific aims of this study are to: 1) investigate whether high versus low exposures to the persistent organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are associated with differentially methylated regions (DMRs) in sperm from a Faroese cohort whose natural diet of pilot whale meat and blubber exposes them to higher than average levels of organic pollutants; 2) determine if genes associated with DDE DMRs are enriched for ASD risk genes; 3) identify pathways and functions over-represented among genes associated with DMRs. Whole genome bisulfite sequencing (WGBS) was used to identify genome-wide DMRs in sperm from individuals divided by high and low exposure levels. Gene ontology and pathway analyses were used to determine enrichment in functional relationships to ASD. Genes in DMRs not only could discriminate between high and low exposures to DDE, but also were enriched in autism risk genes. Gene ontology and pathway analyses of these genes show significant enrichment for neurodevelopmental processes frequently impacted by ASD. Results of this study show that elevated exposure to certain organochlorines is associated with genome-wide DNA methylation patterns in sperm affecting genes involved in neurological functions and developmental disorders, including ASD. DNA methylation in sperm from a cohort of men from the Faroe Islands (Denmark) was investigated using whole genome bisulfite sequencing. This cohort was selected based on their higher than average exposure to persistent organochlorine compounds based on their diet of pilot whale meat and blubber. Semen samples from 52 men were divided into two exposure groups for comparison of methylation profiles; these were the high (26 samples] and low (26 samples) exposure groups based on the highest and lowest tertiles of serum levels of the organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), which correlated well with the levels of several other organochlorines (e.g., PCBs) in the respective sera.