title: Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring.
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.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Vallaster
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Shweta
authors.initials: S
authors.lastname: Kukreja
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Xin Y
authors.initials: XY
authors.lastname: Bing
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.|Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ngolab
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.|Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Rubing
authors.initials: R
authors.lastname: Zhao-Shea
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.|Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Oliver J
authors.identifier: 0000-0003-1516-9397
authors.initials: OJ
authors.lastname: Rando
mesh_terms: D000818:Animals; D004351:Drug Resistance; D004781:Environmental Exposure; D005260:Female; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009538:Nicotine / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000378:metabolism*; D018812:Paternal Exposure; D000072740:Paternal Inheritance; D016019:Survival Analysis; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D018722:Nicotinic Agonists; D015262:Xenobiotics; D009538:Nicotine
keywords: chromosomes; epigenetics; genes; mouse; paternal effects; substance abuse