Decrease in anogenital distance among male infants with prenatal phthalate exposure

Environmental Health Perspectives, August, 2005 by Shanna H. Swan, Katharina M. Main, Fan Liu, Sara L. Stewart, Robin L. Kruse, Antonia M. Calafat, Catherine S. Mao, J. Bruce Redmon, Christine L. Ternand, Shannon Sullivan, J. Lynn Teague

Our analysis is based on a single measure of AGD, and the reliability of this measurement in humans has not been established. During two training sessions, three study physicians each measured AGD in four male infants (mean age, 8.1 months). The mean AGD for these measurements was 58.6 mm, SD was (within infant) 4.2 mm, and coefficient of variation of 7.2%, suggesting that AGD can be measured reliably. Use of this measurement in larger studies in a range of diverse populations, with many more such training sessions, will be needed to obtain normative data.

Although it might have been ideal to examine babies shortly after birth, the timing of grant funding did not allow this. Babies were born to SFFI mothers as early as January 2000, and the first baby visits did not occur until April 2002. To maximize the number of children participating, we allowed recruitment over a range of ages. On the other hand, because the use of AGD in humans is new, the optimal timing for this measurement is not known. Our data suggest that measurements are reliable and informative in young children at least until 18 months, when AGD becomes more difficult to obtain reliably. Its value in adolescents and adults has yet to be determined.

We note that phthalate metabolite levels were highly correlated, and most women were exposed to all metabolites at detectable levels. Gray et al. (2000) suggested that risk assessments for phthalate-induced reproductive toxicity should consider phthalates as a group and include exposures from multiple sources. The score we use reflects joint exposure to the four AGI-associated phthalates, and our results suggest that joint exposure may convey greater than additive risk, but larger sample sizes are needed to confirm this.

Gray and Foster (2003) refer to a "phthalate syndrome" characterized by testicular, epididymal, and gubernacular cord agenesis as well as decreased AGD, and stress the importance of evaluating all components of a syndrome so that affected animals are not misidentified. It has recently been suggested (Fisher 2004) that this "phthalate syndrome" shares many features with the human testicular dysgenesis syndrome proposed by Skakkebaek et al. (2001) to follow chemically induced disruption of embryonic programming and gonadal development during fetal life. The present findings, though based on small numbers, provide the first data in humans linking measured levels of prenatal phthalates to outcomes that are consistent with this proposed syndrome.

This is the first study to look at subtle patterns of genital morphology in humans in relation to any prenatal exposure. It was motivated by toxicologic studies showing that genital morphology is altered by antiandrogens, including some phthalates. We report that AGD, the most sensitive marker of antiandrogen action in toxicologic studies, is shortened and testicular descent impaired in boys whose mothers had elevated prenatal phthalate exposure. These changes in male infants, associated with prenatal exposure to some of the same phthalate metabolites that cause similar alterations in male rodents, suggest that commonly used phthalates may undervirilize humans as well as rodents.