Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.

Aims: Paternal age is increasing in developed countries. Understanding of aging-related epigenetic changes in sperm is needed as well as factors that modify such changes. Materials & methods: Young pubertal and mature rats were exposed perinatally to vehicle or environmental xenobiotic 2,2′,4,4′-tetrabromodiphenyl ether. Epididymal sperm was reduced representation bisulfite sequenced. Differentially methylated regions (DMRs) were identified via MethPipe. Results: In control animals, 5319 age-dependent DMRs were identified. Age-related DMRs were enriched for embryonic development. In exposed rats, DNA methylation was higher in young and lower in mature animals then in controls. Conclusions: Sperm methylome undergoes significant age-dependent changes, which may represent a causal link between paternal age and offspring phenotype. Environmental xenobiotics can interfere with the natural process of epigenetic aging.

No abstract

Perinatal exposures to polybrominated diphenyl ethers permanently reprogram liver metabolism and induce a nonalcoholic fatty liver disease-like phenotype and insulin resistance in rodents. Aim: To test if these changes are associated with altered liver epigenome. Materials & methods: Expression of small RNA and changes in DNA methylation in livers of adult rats were analyzed following perinatal exposure to 2,2′,4,4′-tetrabromodiphenyl ether, the polybrominated diphenyl ether congener most prevalent in human tissues. Results: We identified 33 differentially methylated DNA regions and 15 differentially expressed miRNAs. These changes were enriched for terms related to lipid and carbohydrate metabolism, insulin signaling, Type-2 diabetes and nonalcoholic fatty liver disease. Conclusion: Changes in the liver epigenome are a likely candidate mechanism of long-term maintenance of an aberrant metabolic phenotype.

Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, Hippo and Wnt pathways. Age-related changes in sncRNA, reported in different study, target similar list of genes and biological categories.In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of epigenetic mechanisms as a likely link betwen paternal age and offspring health and development.

Background: Animal data have demonstrated that the sperm methylome is sensitive to endocrine disrupting compounds (EDCs) at specific windows of development; however, the association of exposure to EDC in the peripubertal period with sperm DNA methylation in human or animals is unknown.Main Questions: Are peripubertal serum dioxin concentrations associated with genome-wide profiles of DNA methylation in sperm collected in young adulthood?Design: The Russian Children's Study is a prospective cohort of 516 boys who were enrolled at 8-9 years of age and provided semen samples at 18-19 years of age. At enrollment, serum dioxins, including the potent dioxin congener, 2,3,7,8-te trachlorodibenzo-p-dioxin (TCDD), were measured. Whole genome bisulfite sequencing of sperm was conducted to identify differentially methylated regions (DMR) between highest (n = 4, median serum TCDD 10.4 pg/g lipid) and lowest (n = 4, median serum TCDD 0.39 pg/g lipid) peripubertal TCDD groups.Main Results: The mean methylation across all CpG sites was significantly lower in the highest peripubertal serum TCDD group compared to the lowest group (49.1 ± 4.9% and 61.9 ± 5.2%, respectively; t-test, p = 0.01). We found 52 DMRs that distinguished two serum TCDD groups. One of the top scoring networks, "Cellular Assembly and Organization, Cellular Function and Maintenance, Carbohydrate Metabolism," identified estrogen receptor alpha (ESR1) as its central regulator.Conclusions: Findings from our limited sample size suggests that peripubertal environmental exposures are associated with sperm DNA methylation in young adults. Funds: RSF #14-45-00065, parental study -US NIH #R01 ES014370