Drugs that affect sperm structure or function, male-mediated developmental toxicity, prevention, tests to detect damage to spermatozoa

It is well established that there are dangers to the progeny associated with maternal exposure to a variety of chemicals and drugs. Interest in this area may be traced back to the discovery in the 1960s that women exposed to thalidomide during the first trimester of pregnancy had offspring with severe limb malformations. Can exposure of men to xenobiotics (foreign chemicals) also result in an increased incidence of adverse effects on progeny? Such adverse progeny outcomes might include early or late pregnancy loss, preterm delivery or delivery of a small-for-gestational age infant, malformations, behavioral abnormalities, or cancer. Two major approaches have been taken to identify instances in which paternal exposure to xenobiotics adversely affects progeny outcome, namely epidemiological studies and animal experiments.

Epidemiological studies have focused principally on determining the effects of paternal occupational exposures on fetal development and childhood cancers. Paternal occupation as a motor vehicle mechanic is associated with an increased incidence of spontaneous abortions in the spouse. Fathers employed in occupations associated with solvent exposures are more likely to have offspring with anencephaly, with painters having the highest risk. Other paternal occupations which are associated with an increased risk of having a liveborn child with a birth defect include employment as a fireman, janitor, forestry and logging worker, printer, or plywood mill worker. Further, an increased risk of stillbirth, preterm delivery, or of delivery of a small-for-gestational age infant is associated with paternal employment in the art or textile industries. Although there is no definitive evidence that life style exposures, such as paternal smoking or alcohol consumption, cause birth defects in the offspring, paternal smoking has been associated with low birth weight and increased perinatal mortality. In addition, an increased incidence of childhood cancer has been associated with paternal occupational exposures. The exposure of men to motor vehicle exhaust fumes or the products of combustion engines has been associated with an increase in childhood leukemia. An increased occurrence of Wilm's tumour has been reported in the children of vehicle mechanics, auto body repairmen and welders.

Thus, certain paternal chemical or drug exposures, including exposure to fuel combustion products, organic solvents and metals such as lead and mercury, are consistently associated with an elevated incidence of abnormal progeny outcomes. In various studies, the increased risk of an abnormal progeny outcome associated with a particular paternal occupation has ranged from 1.5 times to as high as 5 times the risk for the control group. However, there are a number of professions which have not been associated with an increased likelihood of abnormal progeny outcome.

Therapeutic drug exposures are also of concern with respect to progeny outcome. After men are treated with anticancer drugs, there is a high incidence of transient or permanent infertility. However, when these men have fathered children, the proportion of malformed children has not been higher than in control groups.

The inherent limitation to most epidemiological and clinical studies is an inability to identify the specific chemicals or to control the exposures. These difficulties can be circumvented using well controlled animal studies. There is convincing evidence from animal studies that paternal exposures to specific environmental or therapeutic agents result in a higher incidence of adverse progeny outcomes. A wide range of environmental chemicals (e.g., lead, dibromochloropropane) and drugs (e.g., the anticancer alkylating agent, cyclophosphamide) produce abnormal progeny outcomes after paternal exposure. Drugs or environmental chemicals to which the male is exposed may be present in his seminal fluid, and thus may have direct effects on the ovulated egg, on the process of fertilization, or on embryo development. Alternatively, drugs or other chemicals may have adverse effects on the fetus by "functionally'' altering male germ cells. The adverse effects on progeny outcome which have been observed include pre- and post-implantation loss (spontaneous abortions), physical malformations evident at birth, behavioral alterations, and a higher incidence of cancer later in life. Furthermore, it is of concern that the germ cell line of the progeny may be affected, thus increasing the risk for subsequent generations. An example of an experimental approach used to demonstrate the risks to progeny due to paternal exposure is treatment with the anticancer drug cyclophosphamide during spermatogenesis.

It is apparent from both epidemiological and animal studies that there are paternal exposures to chemicals that can result in abnormal progeny outcome. Men exposed to certain chemicals as a consequence of their occupation should be made aware that there is concern with respect to an increased risk of adverse progeny outcome.