Date on Master's Thesis/Doctoral Dissertation

12-2019

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Environmental and Occupational Health Sciences

Degree Program

Public Health Sciences with a specialization in Environmental Health, PhD

Committee Chair

Neal, Rachel

Committee Co-Chair (if applicable)

Hoyle, Gary

Committee Member

Hoyle, Gary

Committee Member

Greene, Robert

Committee Member

Pisano, Michele

Committee Member

Zheng, Qi

Committee Member

Corbitt, Cynthia

Author's Keywords

cigarette smoke; liver; SIRT1; barker hypothesis

Abstract

In the U.S., 7.2% of women still report having smoked at some point during pregnancy despite known risks to fetal health. Prenatal cigarette smoke exposure (CSE) in children puts them at risk for low birth weight, premature birth, and other adverse impacts on developmental and postnatal health. Children subjected to prenatal CSE have a higher risk of adulthood metabolic disease predicted by the Barker Hypothesis. The hepatic molecular phenotype associated with this risk is unknown. This dissertation characterizes the prenatal CSE-induced hepatic molecular phenotype during three key life stages. We used a murine model of prenatal CSE utilizing a Teague TE-10C cigarette smoking apparatus that induces low birth weight with catch-up growth. This model was used in a preliminary study to observe the hepatic metabolic phenotype of prenatal (gestational day 6-18) CSE offspring during adulthood in conjunction with a high-fat diet (HFD) or control low-fat diet (CD) feeding for three months. The hepatic molecular phenotype was characterized by the expression of SIRT1, a Class III deacetylase NAD+ sensor, and associated genes and proteins. Female CSE offspring maintained on a HFD exhibited exacerbated weight gain and body fat accumulation while male CSE offspring exhibited decreased SIRT1-related protein expression. Follow up studies subjected offspring to prenatal (GD1-18) CSE and measured their hepatic molecular phenotype at the neonatal and post-weaning periods. Male CSE offspring at 1.5 weeks of age exhibited signs of elevated SIRT1 signaling independent of the main SIRT1 regulatory loop. Female CSE 1.5-week old offspring exhibited signs of delayed functional liver ontogeny via depressed expression of Sirt1, related enzymes, and serum glucose levels. Weaned fed male CSE offspring exhibited mixed expression in SIRT1-regulatory pathways. Fasted male CSE offspring exhibited signs of an exacerbated fasting response via increased SIRT1-related gluconeogenic mRNA expression. Fed female CSE offspring exhibited an exacerbated fed response and untimely gluconeogenic mRNA expression. Fasted female CSE offspring exhibited signs of an exacerbated fasting response via SIRT1-related mRNA and protein expression and untimely lipogenic mRNA expression. This work attempted to extend the Barker Hypothesis by characterizing the hepatic molecular phenotype at key life stages in offspring subjected to prenatal CSE.

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