Date of Graduation

2002

Document Type

Dissertation/Thesis

Abstract

Integrated biomarkers of physiologic and genetic damage in sperm are needed to identify factors that affect male fertility and influence a father's risk of producing abnormal progeny. Offspring studies show a preferential paternal origin for heritable structural chromosomal abnormalities, presenting the need for methods to efficiently detect structural chromosomal abnormalities in human sperm. This dissertation breaks new conceptual ground toward the understanding of paternally transmitted genetic disease by adapting FISH technology to detect human sperm that carry chromosomal breaks and partial chromosomal duplications and deletions and by integrating state-of-the-art biomarkers of semen quality including computer-assisted sperm analysis (CASA). These sperm biomarkers of genetic and physiologic damage were applied in a large-scale epidemiological study that investigated the effects of age in a population of about 100 healthy men, 22 to 80 years of age. The results revealed age-related increases in the frequency of sperm carrying de novo breaks and partial chromosomal duplications and deletions and a continuous decline in the kinetics of sperm motion. The paternal-age effect on motility has important implications for men who choose to delay fatherhood, since age may reduce their chance for success. The paternal-age effect on sperm chromosomal abnormalities is important because changes in the number of sperm carrying structural chromosomal abnormalities would be expected to have a corresponding effect on the number of affected newborns. Understanding the effects of host factors, such as age, on baseline frequencies of abnormal sperm will be extremely important for identifying potential confounders or effect modifiers in future epidemiological studies evaluating the effects of chemicals and genotoxic agents on male reproductive health. The CASA and FISH technologies applied in this research promise to provide an efficient approach for identifying paternal factors that affect male fertility and increase the risk of producing a chromosomally abnormal baby.

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