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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- Chromosomes and Gene Expression
- Microbiology and Infectious Disease
Candida glabrata can thrive inside macrophages and tolerate high levels of azole antifungals. These innate abilities render infections by this human pathogen a clinical challenge. How C. glabrata reacts inside macrophages and what is the molecular basis of its drug tolerance are not well understood. Here, we mapped genome-wide RNA polymerase II (RNAPII) occupancy in C. glabrata to delineate its transcriptional responses during macrophage infection in high temporal resolution. RNAPII profiles revealed dynamic C. glabrata responses to macrophages with genes of specialized pathways activated chronologically at different times of infection. We identified an uncharacterized transcription factor (CgXbp1) important for the chronological macrophage response, survival in macrophages, and virulence. Genome-wide mapping of CgXbp1 direct targets further revealed its multi-faceted functions, regulating not only virulence-related genes but also genes associated with drug resistance. Finally, we showed that CgXbp1 indeed also affects fluconazole resistance. Overall, this work presents a powerful approach for examining host-pathogen interaction and uncovers a novel transcription factor important for C. glabrata’s survival in macrophages and drug tolerance.
