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

Abstract Background: Although autism spectrum disorder (ASD) is among the most heritable of neurodevelopmental disorders, the rapidly rising prevalence of ASD suggests that environmental factors may contribute to epigenetic modifications that can influence risk for ASD. 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 ASD. Methods: Whole genome bisulfite sequencing was used to identify genome-wide differentially methylated regions (DMRs) in a total of 52 sperm samples from a cohort of Faroese men who were equally divided into high and low exposure groups based on their serum levels of the long-lived organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE). Inhabitants of the Faroe Islands, who as a group are considered a genetic isolate, may be exposed to higher than average levels of such persistent EDCs because of their native diet that is enriched in pilot whale meat and blubber. Gene ontology and pathway analyses were used to determine enrichment in ASD-relevant pathways and functions among the DMR-associated genes. Results: DMRs were enriched in autism risk genes and could also discriminate between samples in high and low exposure groups. Functional and pathway analyses of these DMR-associated genes show significant enrichment for neurodevelopmental processes frequently impacted by ASD. Of note, the DMR-associated genes significantly overlap with those previously identified in sperm from fathers of children with ASD versus fathers of neurotypical children, thus suggesting a potential environmental mechanism for introducing ASD-associated epigenetic changes in the sperm methylome. Limitations: A limitation of this study is the relatively low number of samples, although this is somewhat offset by the use of a genetic isolate which reduces the genetic heterogeneity that is often a major challenge in epigenetic studies. Another limitation is the lack of a completely unexposed set of samples for comparisons since persistent EDCs can be detected in a majority of individuals. Conclusion: 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.