Authors
Longnecker MP, Klebanoff MA, Brock JW, Zhou H, Gray KA, Needham LL, Wilcox AJ.

Title
Maternal serum level of 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring.

Source
American Journal of Epidemiology; 155: 313-322. 2002.

The use of DDT as an insecticide began around the time of World War II. Its use was first devoted to the protection of military against malaria, typhus and certain vector borne diseases. By 1946 there was widespread use of DDT in agriculture in the US and then later in other countries. Although the use of DDT has been banned in several countries since the 1970's, it is still in use in many developing countries for disease-vector control. Due to its resistance to degradation, DDT and its metabolite DDE have remained ubiquitous in the environment. In rodents, exposure to an antiandrogenic pesticides have induced hypospadias (incomplete development of the urethral, foreskin and ventral aspect of the penis with the urethral anywhere along the shaft of the penis, within the scrotum, or even in the perineum), cryptorchidism (undescended testes) and polythelia (extra nipples) in offspring. In utero, the development of male reproductive system is hormone dependant and the interference of exogenous hormones during critical development periods may potentially alter the male reproductive development.

In the current study the authors hypothesized that in utero exposures to the androgen antagonist DDE may be related to the frequency of cryptorchidism, hypospadias, and polythelia among boys. Subjects were part of the Collaborative Perinatal Project, a prospective study of neurological disorders and other conditions in children. Pregnant women were recruited between 1959 and 1966 from 12 US study centers. The enrolled women (n=42 000) gave non-fasting blood samples every 8 weeks during pregnancy and 6 weeks postpartum. Their offspring were systematically assessed for the presence of birth defects and other outcomes up to the age of 7. Using a nested case-control design subjects were eligible if they were male, liveborn, singleton children and there was a 3-ml aliquot of 3rd trimester serum available. In total there were 219 cryptorchidism, 199 hypospadias, and 167 polythelia cases. Over 550 controls were selected at random making the control to case ratio 2:1. The mother's serum DDE levels were determined from the third trimester because these samples were most complete.

In the analysis, conditional logistic regression was used. Several other factors that may have contributed to the outcome were tested and controlled for in the analysis. Four equally spaced cut-points were used to categorize DDE exposures. The analysis did not find any significant relationships between the DDE exposure categories and cryptorchidism, hypospadias or polythelia. Interesting, the odds of polythelia in the highest exposure group (=85.6 ug/litre) was suggestive of a potential relationship (OR=1.9, 95% CI=0.9-4.0).

This study is an important contribution to the literature because of its precise exposure assessment. It is the first study that has looked at maternal biomarkers of exposure and the risk of birth anomalies in offspring. Biomarkers have been described as indicators that signal an event in biological systems. When trying to establish a causal association between an exposure and an outcome, laboratory-based biomarker measures increase the sensitivity, specificity and power of a study. An earlier study by Hosie et al (2000) measured lipid levels of organochlorines in children undergoing surgery for cryptorchidism but did not account for maternal levels. Few studies have examined the influence of DDT on birth defects. The results of this study may have been limited by the small number of exposed in some of the exposure categories. Yet the results, although insignificant, do suggest a possible relationship with polythelia. Further research into this area would help to elucidate the findings.