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NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure
Patrick J Murphy1,2, Jingtao Guo2,3, Timothy G Jenkins3
1Department of Biomedical Genetics, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
Abstract:
Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspring, suggesting the effects are likely not maintained across multiple generations.
Insights
Paternal cigarette smoke exposure causes sperm DNA methylation changes in mice, impacting offspring epigenetics. These effects, linked to oxidative stress, are not directly inherited across generations.
Area of Science:
- Environmental Epigenetics
- Reproductive Toxicology
- Developmental Neurobiology
Background:
- Paternal cigarette smoke (CS) exposure is linked to offspring health risks like behavioral disorders and cancer.
- The underlying mechanisms connecting paternal CS exposure to adverse offspring outcomes remain largely unknown.
- Epigenetic modifications, such as DNA methylation (DNAme), are potential mediators of environmental influences on offspring health.
Purpose of the Study:
- To investigate the mechanisms and impacts of paternal CS exposure on sperm epigenetics and offspring development.
- To determine if CS-induced epigenetic changes in sperm are heritable and if they affect offspring gene expression.
- To explore the role of oxidative stress and Nrf2 in mediating CS-induced epigenetic alterations.
Main Methods:
- Utilized mouse models exposed to CS.
- Analyzed sperm DNA methylation (DNAme) changes following CS exposure and cessation.
- Examined prefrontal cortex DNAme and gene expression patterns in offspring.
- Compared effects in wild-type and Nrf2 knockout (Nrf2-/-) mice.
Main Results:
- CS exposure induced sperm DNAme changes in fathers, partially reversible within 28 days.
- Paternal smoking altered offspring prefrontal cortex DNAme and gene expression.
- Epigenetic and transcriptional effects were partially observed in Nrf2-/- mice, suggesting a role for oxidative stress.
- Sperm DNAme changes in fathers did not directly correlate with offspring DNAme changes, indicating non-direct inheritance.
- CS-associated sperm DNAme changes were absent in unexposed offspring, suggesting limited transgenerational effects.
Conclusions:
- Paternal CS exposure induces reversible sperm epigenetic changes, potentially mediated by oxidative stress via Nrf2.
- Offspring exhibit altered epigenetic and transcriptional profiles in the prefrontal cortex, but direct inheritance of sperm DNAme changes is unlikely.
- These findings highlight the complex interplay between environmental exposures, oxidative stress, and epigenetic inheritance in offspring health.
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