Identification of Systemic Biomarkers in Serum, Urine, and Deoxyribonucleic Acid as Indictors for Environmental Exposures and the Development of Metabolic Outcomes Among Women in the United States
Type 2 diabetes (T2D) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and β-cell dysfunction. Excessive body weight is associated with an increased risk of T2D and other major chronic diseases including cardiovascular disease and certain cancers. The current work focuses on the identification of systemic biomarkers in various biological samples, including serum, urine, and DNA, as indicators for environmental risk factors and the development of T2D and obesity in different human populations. Environmental endocrine-disrupting chemicals (EDCs) have been shown to affect the biosynthesis, secretion, transport, binding action, and metabolism of endogenous sex hormones, and were suggested to be associated with increased risk of developing T2D and obesity. In Chapter 1, we conducted a meta-analysis study to comprehensively assess the role of EDCs in affecting risk of T2D and related metabolic traits. We found that both persistent (including dioxin, polychlorinated biphenyls, and chlorinated pesticides) and non-persistent EDCs (including bisphenol A and phthalates) may affect the risk of developing T2D. To evaluate urinary concentrations of BPA and major phthalate metabolites in relation to prospective weight change, we conducted a prospective analysis in the Nurses' Health Study (NHS) and NHSII in Chapter 2. Our data suggest urinary concentrations of BPA and certain individual phthalate metabolites were associated with modestly greater weight gain in a dose-response fashion. These data are consistent with a potential role of BPA and phthalates in weight gain, although more prospective data are needed to corroborate these observations.
In previous studies, T2D was associated with biomarkers on different molecular pathways. Earlier prospective studies have shown that low birth weight (LBW), an indicator of intrauterine growth restriction, was predictive of higher risk of T2D in adulthood, but the pathways that lead LBW individuals to the onset of T2D are still unclear. In Chapter 3, we assessed the effect of LBW on T2D risk that is explained by potential mediators on different biological pathways using mediation modeling in a case-control study of T2D in the Women's Health Initiative (WHI). We found that the effect of LBW on T2D risk seems mainly mediated by insulin resistance, which is further explained by circulating levels of sex hormone-binding globulin (SHBG), E-selectin, and systolic blood pressure. These prospective data provide quantifiable mechanistic evidence linking LBW to increased risk of T2D whilst presenting risk stratification and intervention in a population at greater risk of developing T2D later in life.
The process of biological aging involves in the pathogenesis process of metabolic disorders including T2D and obesity. It is also necessary to examine the potential predictors and determinants of biological aging. Despite the consistent observations that women outlive men, the mechanisms underlying the relation between sex and longevity have not been fully elucidated. In Chapter 4, we examined the associations of circulating estradiol and testosterone with leukocyte TL in WHI. We found that serum concentration of estradiol was not associated with leukocyte TL in this large sample of postmenopausal women. Total and free testosterone levels were inversely associated with TL in Asian/Pacific Islander women but not in black and Hispanic women. Future studies to replicate our observations are warranted to address potential ethnicity-specific relations.