UCLA

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.