Bad news for boys: linking hypospadias and endocrine disruptors. (Science Selections).

Hypospadias, or the arrested development of several parts of the penis, including the urethra, foreskin, and ventral surface, is usually not a topic for public discussion. But a review of research on the condition points to a link between hypospadias and endocrine-disrupting chemicals, one that Laurence Baskin of the University of California at San Francisco and colleagues are working to bring to the attention of the public and the public health community [EHP 109:1175-1183]. In their review article in this issue, the scientists conclude that the link between hypospadias, which occurs in 1 of every 125 live male births in the United States, and exposure to endocrine-disrupting environmental chemicals is a strong one, while environmental estrogens appear to not be involved. They also suggest that an antiandrogen mechanism may cause hypospadias.

Hypospadias can entail a displacement of the urethral opening to points along the shaft, within the scrotum, or even in the perineum. Severe cases result in penile curvature or ambiguous genitalia, making immediate and accurate sex assignment of the newborn difficult. Hypospadias is generally correctable by surgery, but complications from such procedures and psychosocial problems can result.

The condition has increased in prevalence over the past 14 years in the United States, nearly doubling between 1968 and 1993, according to the Centers for Disease Control and Prevention. The authors suggest this increase may be due to environmental chemicals encountered by pregnant women. However, very few of the 15,000 chemicals in the highest-volume production in the United States have been tested for endocrine-disrupting effects during development at any dose. Principal investigator Theo Colborn, who is director of the World Wildlife Fund's Wildlife and Contaminants Program, cautions women who anticipate becoming pregnant or who learn they are pregnant to be exceptionally careful about their diet and environment, at least until they pass childbearing age. More and more, the evidence reveals that the embryonic and fetal stages of development are the most sensitive to endocrine disruption, she says.

Laboratory evidence strongly suggests that endocrine disruptors interfere with development of the male urogenital system, the team reports. So far, the review shows, researchers have found no evidence that environmental estrogens or female hormones impede male urogenital development, despite their feminizing effects on males. Although not all mechanisms are known for some chemicals that cause hypospadias, in the current study the team found solid data pointing to an antiandrogen mechanism, one that hampers the activity of male hormones. But, says Colborn, "In light of the myriad chemicals in the environment today, demonstrating a causal relationship among humans will be difficult, time consuming, and costly." Moreover, other causes are indicated, including genetic or chromosomal damage or defects and possibly other risk factors such as maternal age and low birth weight.

The authors credit not only increased basic research on urogenital development for providing clues to how certain chemicals might cause hypospadias, but also interdisciplinary research where developmental biology and toxicology converged and provided even more insight. These disciplines in turn relied on advances in molecular, cellular, biochemical, morphologic, and functional research for shedding new light on the relation between hypospadias and endocrine disruption--for revealing that an antiandrogen mechanism is involved while environmental estrogens are not. But the authors point out that much remains to be learned about normal development and about what causes hypospadias as well as many other health problems.

The team would like to see more directed basic research that focuses on developing screens and accompanying assays to test chemicals for their endocrine-disrupting effects (currently there are no standardized protocols to determine whether a chemical is a possible endocrine disruptor). But it will take more than a simple battery of tests using receptor binding to reduce exposure. "This lack of screens and assays is the rate-limiting factor that is slowing down the removal of endocrine disruptors from the environment," Colborn says.