1 Department of Systems Biology, Technical University of Denmark2 Center for Biological sequence analysis, Technical University of Denmark
During the past four decades, the incidence rates of testicular cancer and other male reproductive disorders have been increasing at a rapid rate, predominantly in developed and industrialized countries. This increase is considered too great to be explained by genetic factors alone, and thus environmental factors have strongly been suspected to play a major role. There is a large amount of clinical research which has tried to pinpoint the mechanism of action for this trend. Although the exact mechanism of action has not been elucidated, a number of genetic factors as well as environmental chemicals have been found, mostly in animal studies, to act as risk factors for the disorders. The common consensus today is that there exists a common causal mechanism for a number of different male reproductive disorders which takes place before birth, during fetal development, and is termed Testicular Dysgenesis Syndrome (TDS). TDS occurs when certain critical developmental events are disturbed, and has a profound effect that propagates into adulthood, which may lead to lower sperm concentration, cryptorchidism and testicular cancer. The work within this PhD thesis has primarily focused on the environmental aspects of TDS, generating further support for the hypothesis that environmental factors may play a critical role in the observed trends. This thesis is divided into four parts. In the first part I introduce male reproductive disorders and the current state of affairs. In the second part, I focus on studies of environmental chemicals and their possible impact on reproductive health. In the third part, I discuss network biology as a powerful tool for the study of gene-gene and chemical-gene interactions. In the fourth part, I discuss association mining of clinical data as a means to find interesting and unexpected associations between life style factors and disease. The thesis ends with concluding remarks.