NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure

Autoři: Patrick J. Murphy aff001;  Jingtao Guo aff002;  Timothy G. Jenkins aff003;  Emma R. James aff003;  John R. Hoidal aff005;  Thomas Huecksteadt aff005;  Dallin S. Broberg aff003;  James M. Hotaling aff003;  David F. Alonso aff006;  Douglas T. Carrell aff003;  Bradley R. Cairns aff002;  Kenneth I. Aston aff003
Působiště autorů: Department of Biomedical Genetics, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America aff001;  Howard Hughes Medical Institute, Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America aff002;  Andrology and IVF Laboratories, Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah, United States of America aff003;  Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America aff004;  Department of Internal Medicine, University of Utah School of Medicine and Salt Lake VA Medical Center, Salt Lake City, Utah, United States of America aff005;  Department of Psychology, University of Utah, Salt Lake City, Utah, United States of America aff006;  Department of Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America aff007
Vyšlo v časopise: NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008756
Kategorie: Research Article


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.

Klíčová slova:

DNA methylation – Epigenetics – Gene expression – Mouse models – Oxidative stress – Prefrontal cortex – Smoking habits – Sperm


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