Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring

  1. Markus P Vallaster
  2. Shweta Kukreja
  3. Xinyang Y Bing
  4. Jennifer Ngolab
  5. Rubing Zhao-Shea
  6. Paul D Gardner
  7. Andrew R Tapper  Is a corresponding author
  8. Oliver J Rando  Is a corresponding author
  1. University of Massachusetts Medical School, United States

Abstract

Paternal environmental conditions can influence phenotypes in future generations, but it is unclear whether offspring phenotypes represent specific responses to particular aspects of the paternal exposure history, or a generic response to paternal 'quality of life'. Here, we establish a paternal effect model based on nicotine exposure in mice, enabling pharmacological interrogation of the specificity of the offspring response. Paternal exposure to nicotine prior to reproduction induced a broad protective response to multiple xenobiotics in male offspring. This effect manifested as increased survival following injection of toxic levels of either nicotine or cocaine, accompanied by hepatic upregulation of xenobiotic processing genes, and enhanced drug clearance. Surprisingly, this protective effect could also be induced by a nicotinic receptor antagonist, suggesting that xenobiotic exposure, rather than nicotinic receptor signaling, is responsible for programming offspring drug resistance. Thus, paternal drug exposure induces a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics.

Data availability

The following data sets were generated
    1. Vallaster MP
    2. Kukreja S
    3. Rando OJ
    (2017) Hepatocyte RNA-Seq
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE94059).
    1. Vallaster MP
    2. Kukreja S
    3. Rando OJ
    (2017) Hepatocyte ATAC-Seq
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE92240).

Article and author information

Author details

  1. Markus P Vallaster

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shweta Kukreja

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xinyang Y Bing

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jennifer Ngolab

    Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rubing Zhao-Shea

    Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Paul D Gardner

    Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Andrew R Tapper

    Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Andrew.Tapper@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Oliver J Rando

    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Oliver.Rando@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1516-9397

Funding

National Institute on Drug Abuse

  • Markus P Vallaster
  • Jennifer Ngolab
  • Rubing Zhao-Shea
  • Paul D Gardner
  • Andrew R Tapper
  • Oliver J Rando

Eunice Kennedy Shriver National Institute of Child Health and Human Development

  • Shweta Kukreja
  • Xinyang Y Bing
  • Oliver J Rando

National Institutes of Health (F32DA034414)

  • Markus P Vallaster

National Institutes of Health (R01DA033664)

  • Paul D Gardner
  • Andrew R Tapper
  • Oliver J Rando

National Institutes of Health (R01HD080224)

  • Oliver J Rando

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol (A-1788) of the University of Massachusetts.

Reviewing Editor

  1. Detlef Weigel, Max Planck Institute for Developmental Biology, Germany

Publication history

  1. Received: December 30, 2016
  2. Accepted: January 31, 2017
  3. Accepted Manuscript published: February 14, 2017 (version 1)
  4. Version of Record published: March 7, 2017 (version 2)

Copyright

© 2017, Vallaster et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,002
    Page views
  • 629
    Downloads
  • 35
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Markus P Vallaster
  2. Shweta Kukreja
  3. Xinyang Y Bing
  4. Jennifer Ngolab
  5. Rubing Zhao-Shea
  6. Paul D Gardner
  7. Andrew R Tapper
  8. Oliver J Rando
(2017)
Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring
eLife 6:e24771.
https://doi.org/10.7554/eLife.24771
  1. Further reading

Further reading

  1. Exposing male mice to nicotine can make their sons more resistant to nicotine and other drugs.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Bethany Sump et al.
    Research Article Updated

    For some inducible genes, the rate and molecular mechanism of transcriptional activation depend on the prior experiences of the cell. This phenomenon, called epigenetic transcriptional memory, accelerates reactivation, and requires both changes in chromatin structure and recruitment of poised RNA polymerase II (RNAPII) to the promoter. Memory of inositol starvation in budding yeast involves a positive feedback loop between transcription factor-dependent interaction with the nuclear pore complex and histone H3 lysine 4 dimethylation (H3K4me2). While H3K4me2 is essential for recruitment of RNAPII and faster reactivation, RNAPII is not required for H3K4me2. Unlike RNAPII-dependent H3K4me2 associated with transcription, RNAPII-independent H3K4me2 requires Nup100, SET3C, the Leo1 subunit of the Paf1 complex and, upon degradation of an essential transcription factor, is inherited through multiple cell cycles. The writer of this mark (COMPASS) physically interacts with the potential reader (SET3C), suggesting a molecular mechanism for the spreading and re-incorporation of H3K4me2 following DNA replication.