Abstract

Large epidemiological and animal studies have revealed a clear association of adverse intrauterine environment with the increased risk of metabolic, cardiovascular and neurological diseases. Maternal smoking is the single most widespread perinatal insult in the world and has been associated with adverse pregnancy outcomes for mother, fetus and the newborn. Our study aims to test the hypothesis that perinatal nicotine exposure induces reprogramming of susceptibility to hypoxic ischemic brain injury in the immature brain, focusing on the roles of AT1R and/or AT2R and trying to reveal the underlying epigenetic mechanisms. Therefore, we established two rat models: perinatal nicotine exposure model in time-dated pregnant rats; hypoxic-ischemic encephalopathy (HIE) in 10-day-old rat pups. In the first part of our study, we demonstrated that nicotine exposure induces aberrant brain development in P10 pups, downregulating AT2R expression in male but upregulating AT2R in female pup brain, enhancing brain vulnerability to HIE in a sex-specific manner. In addition, we observed both AT1R and AT2R are implicated in the pathogenesis of neonatal HIE and confers neuroprotective property; AT2R plays the pivotal and causal role in nicotine induced sex-dependent alteration of vulnerability to HIE in the developing rat brain. Our further study focused on the epigenetic mechanisms involved in nicotine exposure mediated pathological effects in HIE. We demonstrated that perinatal nicotine exposure causes heightened methylation status of a single CpG adjacent to TATA-box at AT2R promoter, inhibiting TBP and recruiting MeCP2 binding, repressing AT2R gene expression, contributing to the enhanced vulnerability to HIE brain injury in male rat pups. All of pathological effects are reversed by administration of 5-Aza, a well-known DNA methylase inhibitor. These findings provide new insights in understanding of the pathogenesis of HIE in newborns and may suggest potential targets for the prevention and treatment of HIE, one of the most common causes of brain damage with severe mortality and long-lasing morbidity in infants and children.

LLU Discipline

Pharmacology

Department

Basic Sciences

School

School of Medicine

First Advisor

Zhang, Lubo

Second Advisor

Blood, Arlin B.

Third Advisor

Buchholz, John N.

Fourth Advisor

Ducsay, Charles A.

Fifth Advisor

Xiao, Daliao

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2013

Date (Title Page)

6-1-2013

Language

English

Library of Congress/MESH Subject Headings

Cardiovascular Diseases; Neurological Diseases; Metabolic Diseases; Fetal Development; Nicotine;

Subject - Local

Nicotine Exposure; Adverse Intrauterine Environment; Maternal Smoking; Pregnancy; Infant mortality; Morbidity in Infants and Children

Type

Dissertation

Page Count

135 p.

Digital Format

Application/PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses & Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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