Environmental Light and Circadian Disruption Impact Visual, Metabolic, and Developmental Programming Open Access

Abstract

Circadian disruption, commonly caused by light exposure out of sync with the body’s internal clock system, is a significant stressor affecting human health. This exposure is relevant not only for working adults, but also for infants, children, and adolescents. However, little is known about how circadian disruption at the earliest points of life, including during in utero, affects development across the life course. Using data from both a human cohort and a mouse model, this body of work investigated the influence of light and circadian disruption on developmental programming.

Utilizing both a differential expression analysis and cosinor analysis, we uncovered seasonal gene expression in full-term human placenta and characterized placental processes demonstrating season rhythmicity. To examine if shift work, which can lead to circadian disruption, was related to epigenetic variation in the placenta, we conducted an epigenome-wide association study (EWAS) of maternal night shift work and placental DNA methylation. The EWAS revealed differential methylation of genes related to immune system function and neurodevelopment in the placenta of night shift workers.

To examine the developmental impacts of environmental circadian disruption, we utilized a mouse model of developmental chronodisruption and measured placental signaling (embryonic day 15.5) as well as longitudinal visual and metabolic outcomes in adulthood. Embryo count, fetal sex ratio and placental weight did not differ, but developmental chronodisruption caused higher expression of immune markers CD11b and Iba1 and lower gene expression of Serpinf1, which encodes a protein that regulates macrophage inflammatory signaling and neuronal differentiation, in the placenta. Likewise, adult offspring developmentally exposed to chronodisruption developed impaired visual function and had increased retinal expression of immune markers.

These findings suggest that circadian disruption can contribute to developmental programming of adult disease, with the placenta as a potential regulator. Furthermore, our results suggest that developmental circadian disruption and light environment are relevant exposures for human health and should be integrated in more studies of environmental public health and Developmental Origins of Health and Disease (DOHaD) research. These results warrant further research to characterize the placental clock system and the mechanisms by which circadian disruption affects placental and fetal development.

Table of Contents

Chapter 1: Introduction 1

Telling time: the core circadian clock 2

Entrainment to zeitgebers 4

The eye as part of the visual system 4

Suprachiasmatic nucleus (SCN), the central clock 6

Night shift work as a “Probable Human Carcinogen” 8

Light as an endocrine disruptor 10

Rhythms and development 15

Figure 1-1 17

Developmental origins of health and disease (DOHaD) 17

Dissertation overview 19

Figure 1-2 20

Chapter 2: Seasonally Variant Gene Expression in Full-Term Human Placenta 23

Abstract 24

Introduction 24

Materials and methods 26

Figure 2-1 28

Results 31

Table 2-1 32

Figure 2-2 34

Figure 2-3 35

Table 2-2 36

Figure 2-4 37

Figure 2-5 38

Discussion 39

Chapter 2 Supplemental Material 44

Chapter 3: Maternal Circadian Disruption is Associated with Variation in Placental DNA Methylation 51

Abstract 52

Introduction 53

Materials and methods 54

Results 59

Table 3-1 60

Table 3-2 61

Figure 3-1 64

Table 3-3 65

Discussion 67

Chapter 3 Supplemental Material 71

Chapter 4: Impacts of High Fat Diet on Ocular Outcomes in Rodent Models of Visual Disease 76

Abstract 77

Introduction 78

Methods 80

Figure 4-1 81

HFD treatment 81

Systemic and metabolic effects of HFD 83

Table 4-1 83

HFD models of diet-induced obesity and diabetes 86

STZ with HFD models of Type 1 and Type 2 Diabetes and DR 87

Table 4-2 89

HFD and genetic models of AMD 90

Figure 4-2 91

Table 4-3 92

Effects of HFD on ocular tissues and possible mechanisms 95

Table 4-4 97

Figure 4-3 98

Table 4-5 100

Table 4-6 106

Table 4-7 108

Important considerations in experimental design 112

Summary of findings 115

Chapter 4 Supplemental Material 116

Chapter 5: Light Environment Influences Developmental Programming of the Metabolic and Visual Systems in Mice 118

Abstract 119

Introduction 119

Methods 121

Figure 5-1 122

Figure 5-2 124

Results 129

Figure 5-3 130

Figure 5-4 132

Figure 5-5 134

Figure 5-6 136

Figure 5-7 138

Figure 5-8 140

Discussion 142

Figure 5-9 143

Chapter 5 Supplemental Material 147

Chapter 6: Developmental Circadian Disruption Alters Placental Signaling in Mice 155

Abstract 156

Introduction 156

Materials and methods 158

Results and discussion 163

Figure 6-1 164

Figure 6-2 167

Figure 6-3 171

Chapter 6 Supplemental Material 172

Chapter 7: Summary and conclusions 176

Figure 7-1 181

References 182

 

About this Dissertation

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School	Laney Graduate School
Department	Environmental Health
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Environmental Sciences Health Sciences, General
Keyword	Circadian Seasonal
Committee Chair / Thesis Advisor	Pardue, Machelle, Emory University Marsit, Carmen, Emory University
Committee Members	Zhang, Qiang , Emory University Iuvone, Michael, Emory University Qin, Zhaohui, Emory University Smarr, Melissa, Emory University Caudle, William Michael , Emory University

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