Fetal ethanol exposure and zinc homeostasis in the newborn alveolar macrophage Open Access

Abstract

Alcohol exposure increases risk of extreme premature birth (<32 weeks gestational age) by over 34 fold. One of the major complications of pre-term birth is lung immaturity which contributes up to 75% of early mortality and morbidity in the pre-term infant. Alcohol further exacerbates an already dysfunctional lung through alteration of lung development and induction of oxidative stress which results in arrested alveolarization and vascular development, increasing risk of pulmonary infections in animal models of fetal ethanol exposure. Zinc is essential for the immune system and its deficiency increases susceptibility to infection and exacerbates existing infections. Alcohol may also affect maternal-placental-fetal transfer of zinc by altering zinc transporter expression in the placental surface or by inducing an inflammatory state in the placenta that impairs zinc transport to the fetus. Using a mouse model of chronic ethanol exposure in utero, we investigated whether zinc homeostasis was disturbed in the ethanol-exposed alveolar macrophage (AM) and whether these effects could be reversed with zinc treatments. In exploring mechanisms by which ethanol altered zinc homeostasis in the newborn AM, we focused in characterization of cytokine profiles in placental tissues from a pre-term population that was exposed to alcohol in utero. In utero ethanol exposure was associated with decreased expression of zinc transporters, intracellular zinc levels, and bacterial clearance in the AM when compared to no ethanol exposure. In vitro zinc treatments increased expression of zinc transporters and this was concomitant with restored intracellular zinc levels and AM bacterial clearance in the ethanol-exposed pups. Additionally, fetal alcohol exposure was associated with an increase in pro-inflammatory cytokines in the placenta. These studies suggest that zinc insufficiency is a critical component in the impaired AM immune functions associated with fetal alcohol exposure. Furthermore, it supports zinc supplements as a novel therapeutic approach for attenuating the derangements in AM bacterial clearance and risk for respiratory infections in the newborn with fetal alcohol exposure.

Table of Contents

CHAPTER 1: INTRODUCTION 1

CHAPTER 2: LITERATURE REVIEW 5

ALCOHOL

Alcohol and zinc deficiency 5

Alcohol metabolism 6

Alcohol biomarkers 7

Alcohol and disease 11

ZINC

Zinc sources and bioavailability 17

Zinc metabolism 19

Zinc functions 20

Zinc deficiency 21

Zinc excess 22

Zinc biomarkers 23

Zinc transporters 25

Zinc transporters in the lung 33

MATERNAL OUTCOMES

Zinc requirements during pregnancy 34

Zinc deficiency and supplementation in pregnancy outcomes 34

Zinc biomarkers in pregnancy 35

Zinc transporters in pregnancy 36

Alcohol and pregnancy 37

Alcohol biomarkers during pregnancy 38

FETAL OUTCOMES

Alcohol exposure in utero 40

Lung development 41

Fetal alcohol exposure and lung immune response 42

Zinc deficiency and neonatal outcomes 43

Zinc deficiency and neonatal immunity 45

Zinc supplementation and neonatal outcomes 46

Alcohol, zinc and FASD 47

Animal models of alcohol exposure 48

Our model of fetal alcohol exposure 49

Newborn biomarkers of fetal alcohol exposure 49

INFLAMMATION AND PREGNANCY

Placental development and the effect of alcohol 51

Cytokines and pregnancy 53

Alcohol and cytokines during pregnancy 54

CHAPTER 3: ZINC INSUFFICIENCY MEDIATES ETHANOL-INDUCED ALVEOLAR

MACROPHAGE DYSFUNCTION IN THE PREGNANT FEMALE MOUSE

Abstract 56

Introduction 57

Materials and Methods 59

Results 62

Discussion65

CHAPTER 4: ZINC INSUFFICIENCY MEDIATES THE FETAL ALVEOLAR MACROPHAGE

DYSFUNCTION ASSOCIATED WITH FETAL ETHANOL EXPOSURE

Abstract 79

Introduction 80

Materials and Methods 82

Results 85

Discussion 87

CHAPTER 5: FETAL ALCOHOL EXPOSURE IS ASSOCIATED WITH INCREASED

CYTOKINE PRODUCTION IN THE PLACENTA OF THE PREMATURE NEWBORN

Abstract 102

Introduction 103

Materials and Methods 105

Results 108

Discussion 109

CHAPTER 6: CONCLUSIONS, LIMITATIONS, FUTURE DIRECTIONS, PUBLIC

HEALTH IMPLICATIONS

CONCLUSIONS

Experimental studies 116

Clinical study 118

LIMITATIONS

Experimental studies 119

Clinical study 120

FUTURE DIRECTIONS 121

IMPLICATIONS FOR PUBLIC HEALTH 124

REFERENCES 126

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition
Keyword	alveolar macrophage phagocytic index fetal ethanol exposure zinc transporters zinc insufficiency
Committee Chair / Thesis Advisor	Brown, Lou Ann, Emory University
Committee Members	Venkat Narayan, K.M., Emory University Gauthier, Theresa, Emory University Ziegler, Thomas R, Emory University Ramakrishnan, Usha, Emory University Tangpricha, Vin, Emory University

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