ORCID ID

0000-0002-1072-6222

Publication Date

2017-08-07

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Biochemistry and Molecular Pharmacology

First Thesis Advisor

Oliver J. Rando

Keywords

chromosomes, epigenetics, genes, mouse, paternal effects, substance abuse, neuroscience

Abstract

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends on short-term environmental challenges with low doses of nicotine prior to the LD50 application. The observed survival phenotype is not restricted to nicotine as drug of abuse, but also presents itself, when NIC offspring is challenged with a cocaine LD50 after acclimatization to low doses of either nicotine or cocaine. Functionally, NIC offspring metabolizes nicotine faster than control. Mechanistically, NIC offspring livers show global up-regulation of xenobiotic processing genes (XPG), an effect that is even more pronounced in primary hepatocyte cultures. Being known targets of Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR), these XPGs show higher baseline expression in naïve NIC offspring livers. Nicotine’s action on the brain’s reward circuitry does not appear to be of biological significance in our model system. Taken together, paternal nicotine exposure leads to a non-specific and conditional phenotype in male NIC offspring that may provide a general survival advantage against xenobiotic challenges.

DOI

10.13028/M2W388

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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