Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pharmacology and Toxicology

Supervisor(s)

Dr. Daniel B. Hardy

Abstract

While nicotine replacement therapy (NRT) is presumed to be a safer alternative to smoking in pregnancy, the long-term consequences in offspring are still largely unknown. Animal studies now suggest that maternal nicotine exposure during pregnancy and lactation (MNE-PL) leads to a wide variety of adverse outcomes for the offspring, including increased adiposity. The focus of this study was to investigate how MNE-PL in rats may lead to liver dysfunction long-term in offspring through alterations in gene expression and epigenetic modifications. Postnatal day 180 (PND180) offspring exposed to nicotine during pregnancy and lactation (1mg/kg/day) exhibited increased circulating and hepatic triglycerides concomitant with increased expression of fatty acid synthase (FAS), an enzyme involved in hepatic de novo fatty acid synthesis. Furthermore, we demonstrate that MNE-PL offspring displayed increased protein expression of the Liver X Receptor a (LXRa), a key regulator of FAS. Chromatin immunoprecipitation revealed enriched binding of LXRa to the putative LXRE element on the FAS promoter in PND180 male offspring. This was associated with 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 increased circulating and hepatic triglyceride levels long-term via changes in transcriptional and epigenetic regulation of the hepatic lipogenic pathway.



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