Overuse of antibiotics and increases in antibiotic-resistant strains are a global health problem. To address this, the Ministry of Health, Welfare and Labour in Japan introduced several health policies: the National Action Plan on Antimicrobial Resistance in 2016; the financial incentives for not prescribing antibiotics in 2018; and the financial incentives for creating antimicrobial stewardship teams. This dissertation assessed the effects of the newly introduced health policies and current healthcare insurance systems on antibiotic and non-antibiotic prescription patterns and healthcare resource utilization using a nationally representative administrative database from 2012–2019. The quasi-experimental designs allowed to compare the changes in outcomes between the eligible and ineligible medical facilities or areas for the health policies. The studies found that the introduction of the National Action Plan and financial incentives for non-prescribing of antibiotics substantially reduced total and broad-spectrum antibiotics in outpatient settings. In contrast, the introduction of financial incentives for creating antimicrobial stewardship teams did not affect antibiotic use in inpatient settings. The free medical certificates and free prescription policy did not influence the outpatient antibiotic prescriptions but had effects on increases in non-antibiotic prescriptions and outpatient healthcare expenditures.The findings suggest that the National Action Plan and financial incentives for not prescribing antibiotics have successfully reduced antibiotic prescriptions, supporting the recent expansion of the age ranges for the financial incentives. Also, the findings infer the need for modifying the current health policies (incentives for creating antimicrobial stewardship teams and free medical certificates for children) to improve inpatient antibiotic prescriptions and outpatient non-antibiotic prescriptions.

Introduction: Breast cancer is the most common invasive cancer among women. Percent breast density is a strong breast cancer risk factor in adult women. Few studies have assessed breast composition in adolescents. Yet, breast development begins during puberty, and adolescent breast composition may influence later-life breast cancer risk. Breast tissue density during puberty, a critical period of growth, may be particularly susceptible to the influence of endocrine-disrupting chemicals (EDCs), which interfere with hormonal pathways in the body. However, the mechanisms through which EDCs may influence breast density are not well understood. The microbiome has emerged as a potential regulator underlying the associations between environmental exposures and human health, including growth and development, metabolic disease, and cancer. The influence of EDCs on composition of the gut microbiome and the relation of the gut microbiome to breast composition remain unclear. The objective of this dissertation was to evaluate the associations of EDCs, the gut microbiome, and breast density in a cohort of adolescent Chilean girls. We hypothesize that: 1) EDCs are associated with adolescent breast density; 2) EDCs influence the composition of the gut microbiome in adolescence; and 3) the gut microbiome composition and function is associated with breast composition during adolescence.Methods: This dissertation includes biomarker, anthropometric, demographic, dietary, and breast composition data from 530 girls participating in the longitudinal Growth and Obesity Cohort Study in Santiago, Chile. EDC biomarker concentrations of 16 phenols, phthalates, and parabens were assessed by liquid chromatography mass spectrometry in urine samples. Microbiome composition was assessed by targeted sequencing of the V3-V4 hypervariable region of the 16S rRNA gene in self-collected stool samples. Breast composition was measured using dual-energy x-ray absorptiometry and evaluated as percent fibroglandular volume (%FGV), absolute fibroglandular volume (aFGV), and total breast volume (tBV). In Chapter 2, we evaluated the relation between urinary concentrations of suspected EDC biomarkers across three peripubertal time points (Tanner breast stage 1 [B1], Tanner breast stage 4 [B4], and 1-year post menarche [1YPM]) and breast composition (%FGV, aFGV, and tBV) measured at 2-years post-menarche in a longitudinal study design using generalized estimating equations. In Chapter 3, we assessed whether EDC biomarker concentrations were associated with composition of the gut microbiome in both single-chemical and chemical mixture analyses. In Chapter 4, we examined the relation between composition and predicted function of the gut microbiome and breast density measured at 2-years post-menarche using a cross-sectional study design. All three chapters identified potential confounding factors a priori using directed acyclic graphs and controlled for confounding in statistical analyses. Where appropriate, the Benjamini-Hochberg method was used to control for multiple hypothesis testing. Results: There was high variability in EDC concentration across peripubertal time points. Select EDCs were associated with %FGV and aFGV; the association was modified by time point at which the urine sample was measured. When evaluated as single chemicals, select phenols and phthalates were marginally associated with differences in gut microbial alpha diversity and beta diversity. Only a minor association was found for the relation of an EDC mixture to gut microbial alpha diversity. There were no differences in gut microbial composition nor were there differentially abundant microbial genera across categories of breast density (%FGV, aFGV). Conclusions: Understanding the influence of environmental exposures during puberty, a critical period of growth and development, on adolescent breast composition is important for developing opportunities to reduce risks for breast cancer. Overall, these results suggest that there are pubertal windows of susceptibility to select EDCs for an association with gut microbial composition and breast density, though we cannot rule out significant findings by chance. We did not find evidence to suggest that breast density associated with composition and predicted function of the gut microbiome. Future research might consider the role of the gut microbiome in understanding how environmental chemicals may modify pubertal growth and development.

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Introduction: Breast cancer is the most common cancer and the leading cause of cancer-related deaths among women in the world. Yet, much of the variation of breast cancer incidence cannot be explained by known or suspected risk factors. Its etiology is comprised of several pathways, some of which point to origins during early life. Specifically, breast development and hormonal changes during puberty contribute to a ‘critical period’ that play an important role in affecting breast cancer risk. The heightened hormonal activity followed by rapid growth in breast tissues presents a window of susceptibility in which environmental exposures can cause significant changes that may or may not be reversible. Environmental exposures, such as endocrine disrupting chemicals (EDCs), have been purported to alter pubertal development, raising concerns about their impact on breast development and subsequently on breast cancer risk. Perfluorooctanoic acid (PFOA), monobenzyl phthalate (MBzP), and trace metals may mimic estrogen behavior and disrupt aspects of endocrine signaling. The central purpose of this research is to use epidemiologic methods to evaluate the effect of EDCs on mammary gland development and circulating hormone levels during puberty. Innovative computational methods (e.g. G-methods) are used to identify and estimate causal effects of real-life exposures of “EDC mixtures” (i.e. accessing multiple EDCs together) and time-specific EDCs on breast density in the presence of time-varying confounders. The main objectives include: 1) to evaluate the impact of serum PFOA and urinary MBzP, individually and in combination, on breast composition during puberty; 2) to evaluate the impact of serum PFOA and urinary MBzP, individually and in combination, on hormonal levels during puberty; and 3) to evaluate the effect of trace metals on breast composition during puberty. Methods: This dissertation uses the longitudinal Growth and Obesity Cohort Study (GOCS) of Latina girls in Santiago, Chile. GOCS prospectively followed children from ages 3-4 and obtained data annually and bi-annually on biomarker, anthropometric, demographic, and breast composition data. Urinary MBzP and trace metals concentrations and serum PFOA concentrations were assessed by liquid chromatography mass spectrometry. Breast composition was measured using dual-energy x-ray absorptiometry and evaluated as percent fibroglandular volume (%FGV) and absolute fibroglandular volume (aFGV). Chapter 2 evaluates the relation between MBzP and PFOA and breast composition across three pubertal time points (Tanner breast stage 1 (B1), Tanner breast stage 4 (B4), and 1-year post menarche (1YPM)) and breast composition (%FGV and aFGV) measured at 2-years post-menarche. Chapter 3 assesses the relation between MBzP and PFOA and hormones at 1YPM. Chapter 4 examines whether trace metals are associated with breast composition. All three chapters utilize parametric G-formula for analysis accounting for covariates that are identified a priori using directed acyclic graphs. Results: In Chapter 2, serum PFOA concentrations corresponded to a marginal increase in absolute FGV and decreased in % FGV, while no effect was observed between MBzP and breast density measures across pubertal WOS. In Chapter 3, MBzP was associated with insulin growth factor-1 (IGF-1) and 17-OH progesterone. PFOA was associated with IGF-1 (IGF-1), 17-OH progesterone and sex hormone binding globulin. Associations between MBzP and PFOA and hormones varied by pubertal time point, suggesting differential effects of EDC exposure by specific window of susceptibility on pubertal hormone levels. In Chapter 4, selected trace metals - barium, copper, lead, antimony, thallium, and vanadium – were associated with absolute breast density. Copper was also associated with percent FGV. Conclusions: Overall, PFOA, MBzP and trace metals were associated with breast density and hormones at varying pubertal windows of susceptibility. By using the framework of life course epidemiology, this dissertation contributes to an understanding of the variation in breast cancer risk associated with environmental exposures in puberty. Findings help identify the most effective and appropriate time period for breast cancer prevention.

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