Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Public Health

First Advisor

Johnson, Caroline

Abstract

Phenols are endocrine-disrupting chemicals that have been used in everyday consumer products for decades. Exposure is widespread, with detectable levels in populations worldwide. Studies suggest phenols can influence reproductive function through endocrine-disrupting mechanisms. This dissertation focuses on seven less-studied phenols: methyl paraben (MPB), propyl paraben (PPB), butyl paraben (BPB), triclosan (TCS), benzophenone-3 (BP-3), 2,4-dichlorophenol (DCP-24), and 2,5-dichlorophenol (DCP-25). These chemicals are found in a range of products including foods, personal care products, cosmetics, soaps, sunscreens, herbicides, and mothballs. Despite plausible mechanisms by which phenols could impact reproductive function, there are inconsistent results across limited epidemiologic studies. Though metabolomics is a sensitive tool for characterizing metabolite changes associated with endocrine disruption, few studies have used untargeted metabolomics to examine the effect of exposure to parabens in humans, and none during the periconceptional period. If phenols contribute to diminished reproductive function and subfertility, then minimizing the preconception use of common phenol-containing consumer products through individual consumer choices and regulation of product ingredients could have substantial public health benefits. The overarching objectives of this dissertation are 1) to examine the relationship between periconceptional exposure to seven phenols (MPB, PPB, BPB, TCS, BP-3, DCP-24, DCP-25) and fecundability and early pregnancy loss in women without a history of infertility, and 2) to investigate the potential underlying mechanisms of possible associations by examining changes in the periconceptional urinary metabolome associated with paraben exposure. Before undertaking the epidemiologic analyses of Objective 1 and metabolomics data analyses of Objective 2, it was necessary to address three methodological issues related to accounting for urinary dilution in periconceptional urine samples to ensure a sound analysis. First, although kidney function and creatinine excretion are recognized to change with normal pregnancy by the end of the first trimester, we found that creatinine excretion declines substantially in very early pregnancy soon after implantation (Objective 1, Chapter 2). This could bias biomarker measurement and interpretation when creatinine is used to account for urinary dilution in periconceptional urine samples. Second, we assessed whether creatinine adjustment was biased when using pooled, within-person samples rather than averaging individually-adjusted results. We found that although adjustment using pooled samples introduced a small underestimation of analyte concentration, there was a very strong agreement between the two approaches (Objective 1, Chapter 2). Third, we compared three common approaches to adjusting periconceptional untargeted metabolomics data for urinary dilution, and found that creatinine adjustment was not an accurate approach, while either specific gravity adjustment or probabilistic quotient normalization were more reliable methods (Objective 2, Chapter 4). The results from these methodological studies were used to investigate the impact of phenol exposure on time to pregnancy, early pregnancy loss, and the urinary metabolome. We found an increased risk of early pregnancy loss associated with DCP-25 exposure (5th vs. 1st quintile odds ratio [OR]: 4.79; 95% CI: 1.06, 21.59), and that the per-cycle odds of conception increased at higher concentrations of BPB (OR: 1.62; 95% CI: 1.08, 2.44) and TCS (OR: 1.49; 95% CI: 0.99, 2.26) (Objective 1, Chapter 3). There were no associations between these endpoints and the other phenols examined in this study. We then investigated whether exposure to the parabens MPB, PPB, or BPB altered the periconceptional urinary metabolome in a subgroup of the same cohort (Objective 2, Chapter 5). We found seven metabolites were associated with paraben exposure, four of which we identified as food-related, including smoke flavoring, grapes, and olive oil, suggesting the importance of diet to paraben exposure. We did not find evidence that paraben exposure impacted metabolites in steroid hormone classes or pathways associated with endocrine-disruption, emphasizing the value of untargeted metabolomics research to reveal novel associations. This dissertation contributes to an emerging area of research on phenol exposure and reproductive function and the metabolome. It is the first study to use repeated measures to assess impact of exposure to MPB, PPB, BPB, TCS, BP-3, DCP-24, and DCP-25 on fecundity, the only study to examine DCP-24 and DCP-25 exposure in relation to fecundity, and the only study of the effects of phenol exposure on early pregnancy loss. It is also the first study to probe associations between paraben exposure and the periconceptional metabolome. Given rising rates of subfertility, investigating the effects of phenols and other endocrine-disrupting chemicals on time to pregnancy, pregnancy loss, other reproductive function indicators, and the metabolome remains of clear public health importance.

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