Aging-Induced Changes in Sperm DNA Methylation are Modified by Low Dose of Perinatal Flame Retardants

Abstract

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.

Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

“…The copyright holder for this preprint this version posted September 11, 2021. ; https://doi.org/10.1101/2021.09.09.459659 doi: bioRxiv preprint genomic information is organized and regulated through epigenetic processes to control gene expression and cell functions in the next generation is still in a nascent stage. We and others have shown that errors in epigenomic profiles in sperm can be induced by environmental exposure to toxicants such as those in insecticides and plastics, obesity, and poor diet (Lambrot et al, 2013;Radford et al, 2014;Donkin et al, 2016;Wu et al, 2017;Lismer, Dumeaux, et al, 2021;Pilsner et al, 2021). We recently demonstrated that these epigenome changes at the level of chromatin can be transmitted via sperm to alter embryonic gene expression, development, and offspring health (Lismer, Dumeaux, et al, 2021).…”

“…We and others have shown that errors in epigenomic profiles in sperm can be induced by environmental exposure to toxicants such as those in insecticides and plastics, obesity, and poor diet (Lambrot et al, 2013;Radford et al, 2014;Donkin et al, 2016;Wu et al, 2017;Lismer, Dumeaux, et al, 2021;Pilsner et al, 2021). We recently demonstrated that these epigenome changes at the level of chromatin can be transmitted via sperm to alter embryonic gene expression, development, and offspring health (Lismer, Dumeaux, et al, 2021).…”

“…Uncovering how genomic information is organized and regulated through epigenetic processes to control gene expression and cell functions in the next generation is still in a nascent stage. We and others have shown that errors in epigenomic profiles in sperm can be induced by environmental exposure to toxicants such as those in insecticides and plastics, obesity, and poor diet [5][6][7][8][9][10]. We recently demonstrated that these epigenome changes at the level of chromatin can be transmitted via sperm to alter embryonic gene expression, development, and offspring health [9].…”

Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers

“…In total 21 and 9 exposure-related differentially methylated regions (DMRs) were identified in sperm collected on PND65 and PND120, respectively, with two differentially methylated regions (DMRs) overlapped between the two time-points. Further, the authors focused on age-dependent changes in sperm epigenome, namely profiles of DNA methylation [36] and small non-coding RNA (sncRNA) [37]. They demonstrated that both profiles change significantly with age: 5,319 age-dependent DMRs and 1,384 sncRNA with age-dependent expression were identified.…”

“…Perinatal BDE-47 modified the normal dynamics of age-dependent changes in both DNAmethylation and sncRNA in sperm. For both epigenetic marks, these changes may be interpreted as an acceleration of age-dependent changes in younger animals and their deceleration in older animals [36,37]. Genes associated with age-dependent DMRs as well as genes-targets of age-dependent sncRNA were highly enriched with categories relevant to embryonic development.…”