Methods and concepts in detecting abnormal reproductive outcomes of paternal origin

There is conclusive evidence that exposures of human males to ionizing radiation or certain chemicals can diminish sperm production and reduce fertility. Of approximately 100 chemical agents and mixtures that have been evaluated in men by semen analysis, about half (mostly drugs and a few occupational exposures) reduced sperm quantity and quality; several of these agents also affected the fertility of exposed men. It is now well recognized that the importance of the father in reproduction goes beyond fertilization. Abnormalities in paternal chromosomes (structural and numeric) have been found in various abnormal reproductive outcomes, including chromosomal abnormality syndromes among newborns. In rodent systems, exposure of males to mutagens before mating induces transmissible cytogenetic and genetic abnormalities as well as morphologic defects and cancer among offspring. Consistent with animal findings, there is growing epidemiologic evidence of associations between male exposures to exogenous agents and abnormal reproductive outcomes (fetal loss, birth defects, childhood cancer, etc.). However, no clear links have been established between exposure, mechanism of transmission, and abnormal reproductive outcomes. It is not known to what extent male-mediated birth defects and childhood cancer are due to genetic, epigenetic, or nongenetic causes. Viewed in a multigenerational context, the role of the father in abnormal reproductive outcomes is dependent on his exposure history and susceptibilities as well as those of his mate. Relevant exposures may occur any time between conception of the parents and production of their fertilizing gametes, including their development in utero, childhood, and adolescence. Efficient measurements (including biomarkers) of relevant exposure, early biologic effects, and susceptibility in human males are under development. An integrated approach is recommended for assessing male reproductive and genetic toxicity that utilizes biomarkers in (a) epidemiologic studies of exposed human populations, (b) risk characterization in sensitive laboratory species, and (c) in vivo and in vitro studies of the molecular mechanisms of action of toxicants. A special category of "bridging" biomarkers is needed for evaluating animal data for risk assessment and for discriminating among genetic, epigenetic, and nongenetic mechanisms of abnormal reproductive outcomes of paternal origin.