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NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure (RRBS)

ABSTRACT: There is growing evidence that paternal pre-conception cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring. To characterize the effects of CS exposure on the sperm epigenome and offspring neurodevelopment, we investigated the impact of pre-conception paternal CS exposure on mouse sperm DNA methylation and gene expression in offspring. We further investigated the role of oxidative stress on sperm epigenetic changes using a mouse model (Nrf-/-) with impaired antioxidant capacity. Lastly, we evaluated the capacity for sperm DNA methylation to recover following removal of CS for 1-5 spermatogenic cycles (28-171 days). We found that smoking significantly impacts sperm DNA methylation as well as DNA methylation and gene expression in offspring. These changes were largely recapitulated in Nrf-/- mice independent of smoke exposure. Recovery experiments indicated that about half of differentially methylated regions returned to normal within 28 days of removal from smoke, however additional recovery following longer periods was not observed. Thus, we present strong evidence that cigarette smoke exposure induces paternally mediated, heritable epigenetic changes. Parallel studies performed in Nrf-/- mice provide evidence for oxidative stress as the predominant underlying mechanism for smoke-induced epigenetic changes to sperm as well as changes in the offspring of smoke-exposed sires. Lastly, recovery experiments indicate that while many epigenetic changes are corrected following removal from smoke exposure, aberrant methylation persists at a significant number of regions even after five spermatogenic cycles

ORGANISM(S): Mus musculus

PROVIDER: GSE133739 | GEO | 2020/05/06

REPOSITORIES: GEO

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Project description:Purpose: The purpose of this study was to identify cigarette smoke (CS) induced changes in circulatory microRNA (miRNA) in the plasma and ocular fluids of the Rhesus macaque and compare them to normal age-related changes, with the ultimate goal to develop an animal model of early dry age-related macular degeneration (AMD). AMD is a blinding disease having both genetic and environmental components, with cigarette smoke exposure (CS) as the leading environmental risk factor. Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC) at UC Davis. We used 6 animals of the same gender per group: Group 1 (young, 2-4 years old), Group 2 (old, 20-25 years old), Group 3 (middle aged, 9-12 years old) and Group 4 (9-12 years old, exposed to smoke for 1 month). Group 4 macaques were clinically assessed prior to and following CS exposure. Ocular fluids and plasma samples were collected, miRNA isolated, and expression data obtained from Affymetrix miRNA GeneTitan Array Plates 4.0, followed by bioinformatics analysis on Affymetrix Expression Console (EC) and Transcriptome Analysis Software (TAS), and using ANOVA. Results: Statistically significant changes were seen in miRNA populations in ocular fluids and plasma. In the plasma samples, 45 miRNAs were strongly upregulated (Fold Change >+/-1.5, p<0.05) upon CS exposure, while in aging monkeys different miRNAs in plasma were affected, and downregulated. In the vitreous, 3 miRNAs were downregulated in animals exposed to CS, intriguing enough two of them (miR-6794 and miR-6790) were the same ones downregulated with age. Retinal imaging using OCT did not show any significant changes in retinal thickness. Cotinine assays showed that animals received on average dose of 50-60 ng/ml cotinine, a marker for significant CS exposure. Conclusions: One month of CS exposure of Rhesus macaques resulted in significant changes of expression of circulatory miRNAs. We identified several CS related miRNA changes that are plasma or ocular fluid-specific. Healthy aging changes of miRNAs populations were different from the CS exposure induced changes in plasma, while the ones in vitreous were similar. This data will be utilized to develop an animal model of early dry AMD, using a monkey model exposed to CS.

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NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure (RRBS)

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