UCLA

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.