The Birds, the Bees, and Cigarettes: Leveraging Interdisciplinary Methodologies in Computational Toxicology and Reproductive Epidemiology to Elucidate Mechanisms of Ovarian Follicle Maturation and Aging via Environmental Exposures Restricted; Files Only
Moyd, Sarahna Azaria (Spring 2024)
Published
Abstract
Introduction: Infertility burdens sizeable proportions of the U.S. population. Approximately 15-25% of women between 15 to 44 years in the U.S experience infertility—the inability to conceive after one year of intentional attempts in those under age 35 and within 6 months for those 35 and older. While reproductive senescence is a normal process during chronological aging, it can be influenced by environmental factors such as reproductive toxins and toxicants. However, there is limited understanding of the mechanisms underpinning how environmental exposures may cause infertility through premature ovarian aging and follicle maturation. This dissertation integrates approaches of computational toxicology and reproductive epidemiology to examine environmental impacts on adverse outcome pathways of ovarian dominant follicle selection and associations with the ovarian reserve, a hallmark that determines the female reproductive life span.
Methods: In Aim 1, a mathematical model of FSH-stimulated biochemical events essential to dominant follicle selection was developed and numerically simulated. In Aim 2, a mathematical model was developed and numerically simulated to describe the depletion of ovarian nongrowing follicles (NGF) through apoptosis and activation into growing follicles (GF), which is regulated by an inhibitory factor-mediated incoherent feedforward loop and by an AMH-mediated negative feedback loop. In Aim 3, multivariable adjusted Poisson regression models were tested for association between parental smoking and adult AFC, adjusting for confounders identified a priori and with DAG diagrams.
Results: Aim 1’s model demonstrated disruption of key FSH-driven event may result in ovulation failure or lengthening of the follicular phase of a menstrual cycle. Aim 2’s model recapitulated the nonlinear NGF depletion and a menopause age distribution of 50.3±4.3 years (mean ± SD) that is comparable to several large studies in literature, as well as smoking dose-dependent reduction in menopause age. Aim 3 results suggest paternal smoking outside of pregnancy may be associated with reduced ovarian reserve of female offspring, implicating pre-conceptional exposure during folliculogenesis and oogenesis, or childhood through adolescence as sensitive windows.
Conclusion: Overall, this dissertation demonstrates the value of pairing mechanistically based modeling with epidemiological analysis to test hypotheses on the effects of environmental exposures on ovarian reserve, menopause, and fertility.
Table of Contents
Table of Contents
Chapter 1: Summary of Significance and Innovation. 1
Synopsis. 2
Introduction. 3
Rationale for integrating methodologies. 3
Overview of female reproduction biology and physiology. 4
Mechanisms of Cigarette Smoke Toxicity. 6
Smoking and ovary maturation/follicle maturation in humans. 7
Dissertation Aims. 9
Chapter 2: Computational Modeling of Endocrine Disruption of Gonadotrophin-Dependent Ovarian Follicle Maturation. 11
Abstract 12
Introduction. 14
Overview of ovarian folliculogenesis. 14
FSH threshold for FSH-dependent dominant follicle selection. 14
Intrafollicular positive feedback pathways underpinning FSH threshold. 15
Environmental chemical exposures and follicle maturation toward ovulation. 17
Adverse outcome pathway (AOP) and computational modeling. 19
Hypothesis. 20
Methods. 20
Structure and construction of the qAOP Model 20
Model ODEs, parameters, tools, and sharing. 22
Results. 22
Characterization of the bistable behavior of the intrafollicular PFL in response to FSH.. 22
Selection of a single dominant follicle among a cohort of antral follicles. 23
Monte Carlo (MC) simulation of multiple cycles of dominant follicle selection. 24
Simulations of chemical disruption of dominant follicle selection. 25
Discussion. 26
Menstrual cycle length and dominant follicle selection. 27
Twinning rate and co-dominant follicle selection. 28
Implications for ecotoxicity in polyovulatory species. 29
Limitations and future improvements. 29
Potential applications. 31
Conclusion. 32
Figures and legends. 33
Figure 1. AOP, Conceptual Model, and Computational model 33
Figure 2. Bistable-switch properties of the intrafollicular IGF-1/IGF-1R/PAPPA/IGFBP PFL underpinning dominant follicle selection. 34
Figure 3. Simulation of dominance selection of a single follicle among a cohort of 10 maturing antral follicles. 36
Figure 4. Monte Carlo simulation of dominant follicle selection. 37
Fig. 5. Simulated effects of inhibiting PP-1 on dominant follicle selection. 38
Fig. 6. Simulated effects of inhibiting CYP19A1 on dominant follicle selection. 39
Appendix. 40
Table 1: ODEs of the computational qAOP model 40
Table 2: Parameter values of the computational qAOP model 42
Chapter 3: Computational Modeling of the Biphasic Depletion of Ovarian Follicle Reserve and the Chemical Effects on Ovarian Aging. 48
Abstract 49
Introduction. 51
Ovarian depletion and aging phenomena. 51
Biphasic depletion of NGF. 52
Uncertainty in mathematical approach describing the depletion curve. 53
Constant supply of GF. 54
Mechanism of regulated follicle recruitment and depletion. 55
Hypothesis. 57
Methods. 57
Model structure and assumptions. 57
Human data and model parameterization and optimization. 58
Sensitivity analysis. 59
Monte Carlo (MC) simulation of a virtual population. 59
Simulation of chemical effects. 60
Results. 60
Linear and exponential depletion (two reference curves) 60
Model-simulated average NGF depletion. 61
Sensitivity analysis. 62
MC population simulation. 62
Simulated generic chemical effects. 62
Effects of cigarette smoke exposure. 63
Discussion. 63
Age-dependent primordial follicle fate outcomes. 64
Age-dependent NGF:GF ratio. 64
Constant supply of GF regulated by intraovarian mechanisms. 65
Mechanisms and effects of cigarette smoke toxicity. 66
Conclusions. 69
Tables. 70
Table 1: Parameter Values. 70
Figures and legends. 71
Figure 1. Model structure of NGF activation and depletion. 71
Figure 2. Reference depletion curves on (A) linear and (B) log scale. 72
Figure 3. Model simulated average NGF depletion. 73
Figure 4. Tornado plots of local parameter sensitivity. 74
Figure 5. MC simulation of NGF depletion. 75
Fig. 6. Simulation results for chemical effects. 76
Fig. 7. Simulation results for cigarette smoke expsure. 77
Chapter 4: Examining maternal and paternal smoking and implications for adulthood antral follicle count in women presenting for infertility evaluation. 79
Abstract 80
Introduction. 81
Tobacco smoke as an Endocrine Disrupting Chemical 82
Smoking and ovary maturation/follicle maturation in humans. 83
Study Design and Methods. 85
Participants. 85
In Utero Exposure Assessment 86
Outcome Assessment 87
Covariate Assessment 87
Statistical analysis. 88
Results. 89
Participant Characteristics 89
Main Analysis Findings. 90
Discussion. 92
On maternal and paternal findings. 92
Potential sources of bias and residual confounding. 96
Conclusion. 97
Figure 1: Study flow chart 99
Tables. 100
Table 1. 100
Table 2. 103
Table 3. 105
Table 4. 106
Supplemental Table 1. 107
Supplemental Table 2. 108
Supplemental Table 3. 109
Supplemental Table 4. 110
Supplemental Table 5. 111
Supplemental Table 6. 112
Supplemental Table 7. 113
Supplemental Figure 1: DAG for maternal smoke and offspring AFC.. 114
Chapter 5: Conclusion & Future Directions. 115
Summary of the Science. 115
Future Directions. 116
Conclusion. 119
References. 121
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