Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants

Version 1 : Received: 29 October 2020 / Approved: 30 October 2020 / Online: 30 October 2020 (13:37:14 CET)

How to cite: Pilsner, J.; Shershebnev, A.; Wu, H.; Marcho, C.; Dribnokhodova, O.; Shtratnikova, V.; Sergeyev, O.; Suvorov, A. Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants. Preprints 2020, 2020100641 (doi: 10.20944/preprints202010.0641.v1). Pilsner, J.; Shershebnev, A.; Wu, H.; Marcho, C.; Dribnokhodova, O.; Shtratnikova, V.; Sergeyev, O.; Suvorov, A. Aging-induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame retardants. Preprints 2020, 2020100641 (doi: 10.20944/preprints202010.0641.v1).

Abstract

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.

Subject Areas

aging; paternal exposure; sperm; advanced paternal age; epigenetics; DNA methylation; RRBS, 2,2′,4,4′-tetrabromodiphenyl ether; PBDE; BDE-47; perinatal; environment

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