Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring
- 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
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Hepatocyte RNA-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE94059).
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Hepatocyte ATAC-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE92240).
Article and author information
Author details
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.
Reviewing Editor
- Detlef Weigel, Max Planck Institute for Developmental Biology, Germany
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.
Version history
- Received: December 30, 2016
- Accepted: January 31, 2017
- Accepted Manuscript published: February 14, 2017 (version 1)
- 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.
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Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring
eLife 6:e24771.
https://doi.org/10.7554/eLife.24771
