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
-
Hepatocyte RNA-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE94059).
-
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.
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.
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
-
- 3,502
- views
-
- 728
- downloads
-
- 55
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring
eLife 6:e24771.
https://doi.org/10.7554/eLife.24771
Further reading
-
Exposing male mice to nicotine can make their sons more resistant to nicotine and other drugs.
-
- Chromosomes and Gene Expression
- Structural Biology and Molecular Biophysics
Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
