title: Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase.
abstract: While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway.
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, Canada; Department of Obstetrics & Gynecology, The University of Western Ontario, Canada; The Lawson Health Research Institute, The University of Western Ontario, Canada.
authors.forename: Noelle
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology, McMaster University, Canada.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Nicholson
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, Canada; Department of Obstetrics & Gynecology, The University of Western Ontario, Canada; The Lawson Health Research Institute, The University of Western Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: Department of Obstetrics and Gynecology, McMaster University, Canada.
authors.forename: Alison C
authors.initials: AC
authors.lastname: Holloway
authors.affiliation: Department of Physiology & Pharmacology, The University of Western Ontario, Canada; Department of Obstetrics & Gynecology, The University of Western Ontario, Canada; The Children's Health Research Institute, The University of Western Ontario, Canada; The Lawson Health Research Institute, The University of Western Ontario, Canada. Electronic address: Daniel.Hardy@schulich.uwo.ca.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000139:chemically induced* / Q000151:congenital / Q000378:metabolism; D007774:Lactation; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020218:Response Elements / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006657:Histones; D000071518:Liver X Receptors; D018722:Nicotinic Agonists; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D009538:Nicotine; D064429:Fatty Acid Synthases
keywords: Fatty acid synthase; Liver; Liver X receptor; Nicotine replacement therapy; Obesity; Triglycerides