Environmental Factors and Male Sexual Development

A recent and sharp decline in human male reproductive health has been widely reported. This includes a range of problems such as a high incidence of undescended testes and ambiguities of the male genitalia, low semen quality and quantity, and an increasing incidence of testicular cancer. Approximately 20 per cent of young men in many European countries have low sperm counts that could negatively influence fertility. These phenotypes may be interrelated, leading to the proposition of the unifying term of 'testicular dysgenesis syndrome' to describe these problems (1).

The influence of genetic and environmental factors is the subject of an ongoing debate. However, reports of declining semen quality in industrialised countries during the last 60 years, particularly in western Europe, suggest major environmental influences and identifying these factors and their mechanism of action has been the subject of major research drives in recent years.

A considerable body of data suggests that exposure of a developing male fetus in vivo to a number of environmental factors can negatively influence sexual development and testicular function. Much of this data come from well-documented studies of wildlife and experimental laboratory animals exposed at critical periods in their life stage to synthetic chemicals that alter hormone activity in the body (endocrine disruptors).

These include a broad range of substances such as phthalates or Bisphenol A that are used as plasticisers or solvents. These products are found everywhere in the environment and particularly in consumer products such as cosmetics, medical tubing and toys. Young infants exposed to lotion, powder, and shampoos are significantly associated with increased urinary concentrations of phthalate metabolites. Human exposure is therefore variable but widespread, and it is at doses predicted to have a negative impact on reproductive health (2).

Increasing public concern to these reports has eventually lead to at least some regulation of their use, particularly in the European Union. One reason for the general lethargy in adequately addressing this problem is the lack of evidence showing a direct causal effect of these products on the reproductive system of the human male. Extrapolation from animal studies suggests that the human male fetus may be susceptible to maternal exposure to these factors at a sensitive window of development at around 5-6 weeks of pregnancy. The effects of such exposure could manifest 20-30 years later in the form of infertility or germ cell testicular cancer.

Such a potentially long latency period renders retrospective maternal exposure difficult, if not impossible. However, recent prospective epidemiological studies together with improved biomonitoring procedures, have attempted to tackle this problem. In one, a statistical correlation was demonstrated between primary metabolites of phthalates in the urine of expectant mothers and boys born with reduced anogenital distance (a sensitive measure of testosterone activity; (3). This subtle difference in genital formation could influence future fertility. Second, a correlation with phthalate metabolites in breast milk and reduced testosterone levels in infants has been noted (4). These suggest a causal link between phthalates and anomalies of the male reproductive system but like all association studies other factors could be involved and the interpretation of statistical trends remains controversial. Associations can be fortuitous and other lifestyle factors could be involved

A move away from trend analyses can be seen in an increasing number of studies that are directly evaluating the effects of these chemicals on the synthesis or activity of proteins known to be involved in testicular descent or spermatogenesis (5). In the longer term, data from functional studies may provide a more persuasive argument demonstrating the negative impact of these chemicals on male reproductive development and function.

This approach will also help to address an important outstanding issue - what are the effects of various combinations of chemicals? All of us are exposed to a broad range of chemicals that may have dose-additive effects. There is an urgent need to understand how these factors interact and influence the endocrine system and put in place appropriate control measures to limit exposure.