Environmental Light and Circadian Disruption Impact Visual, Metabolic, and Developmental Programming Open Access
Clarkson-Townsend, Danielle (Spring 2021)
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
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