Elevated exposures to persistent endocrine disrupting compounds impact the sperm methylome in regions associated with autism spectrum disorder

Abstract

Environmental exposures to endocrine disrupting compounds (EDCs) such as the organochlorines have been linked with various diseases including neurodevelopmental disorders. Autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder that is considered strongly genetic in origin due to its high heritability. However, the rapidly rising prevalence of ASD suggests that environmental factors may also influence risk for ASD. In the present study, 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 men from the Faroe Islands (Denmark) 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), a primary breakdown product of the now banned insecticide dichlorodiphenyltrichloroethane (DDT). Aside from being considered a genetic isolate, inhabitants of the Faroe Islands have a native diet that potentially exposes them to a wide range of seafood neurotoxicants in the form of persistent organic pollutants (POPs). The DMRs were mapped to the human genome using Bismark, a 3-letter aligner used for methyl-seq analyses. Gene ontology, functional, and pathway analyses of the DMR-associated genes showed significant enrichment for genes involved in neurological functions and neurodevelopmental processes frequently impacted by ASD. Notably, these genes also significantly overlap with autism risk genes as well as those previously identified in sperm from fathers of children with ASD in comparison to that of fathers of neurotypical children. These results collectively suggest a possible mechanism involving altered methylation of a significant number of neurologically relevant ASD risk genes for introducing epigenetic changes associated with environmental exposures into the sperm methylome. Such changes may provide the potential for transgenerational inheritance of ASD as well as other disorders.

Reproductive toxicity of combined effects of endocrine disruptors on human reproduction

“…EDCs Findings Zhu et al (2022) Triclosan (2,4,4′-trichloro-2′-hydroxy-diphenyl ether, TCS) The association between TCS exposure and male fecundity was investigated in a cohort of couples in Shanghai, China, where elevated TCS concentrations in male urine were found to be associated with diminished fecundability and an increased risk of infertility Holmboe et al (2022) Bisphenol A (BPA), benzophenone-3 (BP-3) High exposure to bisphenol A (BPA) and benzophenone-3 (BP-3) is associated with compensated reduced Leydig cell function, as observed by increased luteinizing hormone (LH) levels, but no other changes in markers of reproductive health Maggio et al (2022) Organochlorine 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) This study examined the effects of environmental exposures to EDCs on the sperm methylome of a cohort of men from the Faroe Islands.…”