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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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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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Sheep scab is a highly contagious ectoparasitic disease caused by the mite, Psoroptes ovis, which causes intensely pruritic lesions with severe dermatitis and is a major welfare and production issue in the UK national flock. In an attempt to improve disease control, sheep scab was recently made notifiable in Scotland indicating that early diagnostic tests will be crucial to the success of this legislation. A sensitive and specific antibody based assay has been developed which can diagnose early infestation, but which does not indicate current disease status post-treatment due to residual circulating antibody levels. However, studies into host biology and response to disease have illustrated the potential use of biomarkers (BMs) in diagnostics as indicators of disease progression and the effectiveness of treatment regimes, including a recent microarray analysis which identified over 600 host genes differentially expressed in circulating leukocytes following P. ovis infestation. As many of these genes encoded proteins known to be involved in inflammatory responses, this data was used in the search for potential BMs. Initially the genes were filtered and ranked, using bioinformatic analysis, to identify the most promising BM candidates and then evaluated using Western blot analysis against a range of sera from P. ovis infested and naïve sheep. Promising results were obtained for a complement binding protein, C4BPB, showing it was rapidly up-regulated following infestation and correlated with disease progression as determined by lesion size development. The ovine C4BPB gene was successfully sequenced for the first time and a recombinant form of this protein expressed in E. coli. Antibodies, raised in rabbits against ovine rC4BPB, were used to develop a sandwich ELISA, results from which suggested the potential of C4BPB as a BM for sheep scab as it indicated current disease status postinfestation and post-treatment. The major ruminant acute phase proteins (APPs) serum amyloid A (SAA) and haptoglobin (Hp) were then investigated using commercially available assays, as previous studies indicated they were effective markers of inflammatory disease in ruminants. Results from these analyses indicated that both APPs responded positively to infestation with P. ovis but this was not statistically significant until 4 weeks post-infestation. After treatment, the APPs declined rapidly, as described by their short half life of less than 3 days following successful treatment, compared with 56 days for the estimated half life of the host antibody against the mite antigen Pso o 2. Further statistical analysis of the APP response suggested that SAA was the more discriminatory marker, with lower pre-infestation levels and higher sensitivity at the estimated optimum cut-off values. The possibility of using a signature of BMs, as an alternative to a single BM, was discussed as a method of increasing the sensitivity and specificity of the improved test, along with the potential of combining the BM diagnostic with the existing antibody assay. It was concluded that this would provide a highly sensitive and specific test for sheep scab which would diagnose early infestation as well as indicating current disease status post-treatment, providing a highly beneficial tool to the sheep industry to aid the control of this disease.