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.
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.
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Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring
eLife 6:e24771.
https://doi.org/10.7554/eLife.24771
Further reading
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Exposing male mice to nicotine can make their sons more resistant to nicotine and other drugs.
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- Cell Biology
- Chromosomes and Gene Expression
We investigated the role of the nucleolar protein Treacle in organizing and regulating the nucleolus in human cells. Our results support Treacle’s ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation of these biomolecular condensates is crucial for segregating nucleolar fibrillar centers from the dense fibrillar component and ensuring high levels of ribosomal RNA (rRNA) gene transcription and accurate rRNA processing. Both the central and C-terminal domains of Treacle are required to form liquid-like condensates. The initiation of phase separation is attributed to the C-terminal domain. The central domain is characterized by repeated stretches of alternatively charged amino acid residues and is vital for condensate stability. Overexpression of mutant forms of Treacle that cannot form liquid-like phase condensates compromises the assembly of fibrillar centers, suppressing rRNA gene transcription and disrupting rRNA processing. These mutant forms also fail to recruit DNA topoisomerase II binding protein 1 (TOPBP1), suppressing the DNA damage response in the nucleolus.
