RESUMEN
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.
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Envejecimiento/fisiología , Metilación de ADN/efectos de los fármacos , Retardadores de Llama/efectos adversos , Espermatozoides/efectos de los fármacos , Animales , Desarrollo Embrionario/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Epigenoma/efectos de los fármacos , Epigenómica/métodos , Femenino , Masculino , Parto/efectos de los fármacos , Edad Paterna , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ratas WistarRESUMEN
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.
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Contaminantes Ambientales/efectos adversos , Epigénesis Genética/efectos de los fármacos , Epigenoma , Éteres Difenilos Halogenados/efectos adversos , Hígado/efectos de los fármacos , Hígado/metabolismo , Animales , Biomarcadores , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Metilación de ADN , Susceptibilidad a Enfermedades , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/patología , MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , RatasRESUMEN
BACKGROUND: The association of exposure to endocrine disrupting chemicals in the peripubertal period with subsequent sperm DNA methylation is unknown. OBJECTIVE: We examined the association of peripubertal serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations with whole-genome bisulfite sequencing (WGBS) of sperm collected in young adulthood. METHODS: 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. WGBS of sperm was conducted to identify differentially methylated regions (DMR) between highest (nâ¯=â¯4) and lowest (nâ¯=â¯4) peripubertal TCDD groups. RESULTS: We found 52 DMRs that distinguished lowest and highest peripubertal serum TCDD concentrations. One of the top scoring networks, "Cellular Assembly and Organization, Cellular Function and Maintenance, Carbohydrate Metabolism", identified estrogen receptor alpha as its central regulator. CONCLUSION: Findings from our limited sample size suggest that peripubertal environmental exposures are associated with sperm DNA methylation in young adults.
Asunto(s)
Metilación de ADN , Disruptores Endocrinos/sangre , Contaminantes Ambientales/sangre , Dibenzodioxinas Policloradas/sangre , Espermatozoides/metabolismo , Adolescente , Adulto , Niño , Monitoreo del Ambiente , Humanos , Masculino , Pubertad , Federación de Rusia , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
Polybrominated diphenyl ethers (PBDEs) are a group of ubiquitous reproductive toxins. Given that spermatogenesis requires extensive epigenetic changes, we hypothesize that PBDEs impact sperm DNA methylation. Pregnant Wistar rats were exposed perinatally to 0.2mg/kg 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and caudal epididymal sperm were collected from offspring on postnatal days (PNDs) 65 and 120. Libraries were prepared from sperm DNA and sequenced with an average of 18.0 million unique reads per sample. Differential methylated regions (DMRs) were identified via MethPipe package. BDE-47 exposure increased DNA methylation of epididymal sperm on PND 65 in genes, promoters and intergenic regions; however, on PND120 methylation decreased in these genomic elements. We identified 21 and 9 exposure-related DMRs in sperm collected on PND65 and PND120, respectively. Two DMRs overlapped between the two time-points. This is the first study to demonstrate that environmentally-relevant perinatal exposure to PBDE results in long-lasting changes in sperm DNA methylation.