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Maternal exposure to genotoxic chemicals may produce a variety of adverse birth outcomes. Depending on the dose and duration of exposure, adverse birth outcomes can range from premature or low-birth weight, to congenital abnormalities including neural tube defects (NTDs). The research described in this dissertation focused on several rural counties in Shanxi province, China. Shanxi has one of the highest rates of NTDs in the world. In 2005, the incidence of NTDs in the study counties ranged from 8 to 24 cases per 1,000 births. While some of these birth defects are likely to be related to nutrition, it is also suggested that environmental factors play a significant role. One such factor includes polycyclic aromatic hydrocarbon (PAH) exposure as a result of combustion of coal for indoor heating and cooking. Human populations in Shanxi depend heavily on coal as their main source of energy. This study determined the concentrations of PAHs in house dust, venous blood and placenta of study participants. Dust was collected from homes in the study site. Carcinogenic PAH levels in dust collected from kitchen floors ranged from 12 to 2,000 µg/m2. The genotoxic potential of dust was confirmed by shortterm bioassays. Median concentrations of total PAHs in placenta from children born with NTDs were elevated compared to matched controls and appeared to be associated with the risk of having a child with a NTD. Tobacco smoking was not associated with elevated levels of PAH biomarkers in this study population. Levels of bulky DNA adducts in placenta have also been quantified using 32P-postlabeling. Adduct levels do not appear to be significantly different between cases and controls and were not associated with deletions in enzymes GSTM1 or GSTT1. These data suggest that children born with NTDs may be at increased risk due to exposure to genotoxic PAHs. Studies with a larger number of subjects are needed to further elucidate the relationship between PAH exposure and adverse birth outcomes.

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Biomarkers are used in clinical and research settings to enable prevention, subtype disease, quantify severity, guide treatment, and prioritize therapeutic targets. Large scale high throughput platforms have allowed for measurement of high quantities of proteins in large epidemiologic samples. By combining proteomic assays with results from genomic platforms, biological insights can be gleaned to facilitate clinical relevance of emerging markers. In Study 1, we used the Prospective Urban Rural Epidemiology (PURE) study analyzed in a case-cohort fashion to evaluate the importance of angiotensin-converting enzyme 2 (ACE2) as a cardiometabolic risk marker. Using long-run prospective data, we showed ACE2 predicted incident diabetes, cardiovascular disease, and death beyond traditional cardiac risk factors. In Study 2, we evaluate M-CSF as a causal driver of vascular disease using a similar case-cohort design. We find M-CSF is a strong predictor of stroke, myocardial infarction, heart failure, and death. Using Mendelian randomization, an approach that leverages genetic variants as instrumental variables, we find M-CSF is not only associated with cardiovascular disease and death, but is also a causal driver of the development of vascular disease. In a subsequent Mendelian randomization analysis, we find that body-mass index correlates with increased plasma M-CSF, indicating that M-CSF may play a mediating role between BMI and cardiovascular disease. Finally, in Study 3, we use polygenic risk scores to agnostically prioritize among a set of 539 plasma proteins which ones are dysregulated early in the heart failure disease course. We identify 7 proteins representing a diverse set of pathways including IL6 (Interleukin 6), HGF (Hepatocyte growth factor), and CPM (Carboxypeptidase M) as markers associated with both incident heart failure as well as genetic predisposition to heart failure. Of the 7 identified proteins, 3 maintained prognostic significance for death and hospitalization in those with heart failure (IL6, KIM1, HGF). / Thesis / Doctor of Philosophy (PhD) / Finding risk factors for heart disease can assist in efforts to prevent disease and prioritize targets for treatment. Advances in the ability to measure entities like proteins and genetic markers at scale allow researchers to evaluate these new risk factors in large databases. We take advantage of these advances in technology to uncover new insights in global studies with participants representing 5 continents. In Study 1, we performed a comprehensive evaluation of the emerging biomarker angiotensin-converting enzyme 2 (ACE2) wherein we evaluated the association of ACE2 with future risk of cardiometabolic events, but also gained insights into possible drivers of plasma protein concentration. In Study 2, we employ a similar analytic profiling of the biomarker macrophage-colony stimulating factor (M-CSF). Available evidence is conflicting as it relates to whether M-CSF serves a harmful or beneficial role in the development of cardiovascular disease. We perform an analysis examining the upstream determinants and downstream consequences of M-CSF levels. In Study 3, we adopt an approach to identify early markers of heart failure by using genetic predisposition to heart failure as an additional filter for biomarker relevance. Overall, this work relies on complementary approaches to better understand risk factors evaluated in large global databases including the Prospective Urban Rural Epidemiology study and Global Congestive Heart Failure study.

Background: Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue).  Methods: In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting.  Results: Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis.  Conclusions: Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients.

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