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Shanna H. Swan,¹ Katharina M. Main,² Fan Liu,³ Sara L. Stewart,³ Robin L. Kruse,³ Antonia M. Calafat,⁴ Catherine S. Mao,⁵ J. Bruce Redmon,⁶ Christine L. Ternand,⁷ Shannon Sullivan,⁸ J. Lynn Teague,⁹ and the Study for Future Families Research Team*

¹Department of Obstetrics and Gynecology, University of Rochester, Rochester, New York, USA; ²Department of Growth and Reproduction, University of Copenhagen, Copenhagen, Denmark; ³Department of Family and Community Medicine, University of Missouri-Columbia, Columbia, Missouri, USA; ⁴National Center for Environmental Health, Centers for Disease Control and Prevention, Division of Laboratory Sciences, Atlanta, Georgia, USA; ⁵Department of Pediatrics, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA; Departments of ⁶Pediatrics and ⁷Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA; ⁸Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA; ⁹Departments of Surgery (Urology) and Child Health, University of Missouri-Columbia, Columbia, Missouri, USA

Abstract
Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02) . We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg) ] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85) . Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP) , mono-n-butyl phthalate (MBP) , monobenzyl phthalate (MBzP) , and monoisobutyl phthalate (MiBP) ] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2) . The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05) . We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009) . The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans. Key words: anogenital distance, benzylbutyl phthalate, dibutyl phthalate, diethyl phthalate, monobenzyl phthalate, monoethyl phthalate, monoisobutyl phthalate, mono-n-butyl phthalate, phthalates, prenatal exposure. Environ Health Perspect 113: 1056-1061 (2005) . doi:10.1289/ehp.8100 available via http://dx.doi.org/ [Online 27 May 2005]

Address correspondence to S.H. Swan, University of Rochester, Department of Obstetrics and Gynecology, School of Medicine and Dentistry, 601 Elmwood Ave., Box 668, Rochester, NY 14642-8668 USA. Telephone: (585) 273-3521. Fax: (585) 275-7366. E-mail: shanna_swan@urmc.rochester.edu

*The Study for Future Families Research Team included, from the University of Missouri-Columbia: E.Z. Drobnis, B.S. Carter, D. Kelly, and T.M. Simmons. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center: C. Wang, L. Lumbreras, S. Villanueva, M. Diaz-Romero, M.B. Lomeli, and E. Otero-Salazar. Cedars-Sinai Medical Center: C. Hobel and B. Brock. University of Minnesota: C. Kwong and A. Muehlen. University of Iowa: A. Sparks, A. Wolf, J. Whitham, M. Hatterman-Zogg, and M. Maifeld.

We thank the health care providers and study participants at University Physicians Clinic (Columbia, MO) , Fairview Riverside Women's Clinic (Minneapolis, MN) , Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (Los Angeles, CA) , Cedars-Sinai Medical Center (Los Angeles, CA) , and University of Iowa Hospitals and Clinics (Iowa City, IA) . We also thank M. Silva, J. Reidy, E. Samandar, and J. Preau for phthalate analyses and E. Gray, P. Foster, and D. Barr for their guidance.

This work was supported by grants from the U.S. Environmental Protection Agency and the National Institutes of Health (R01-ES09916 to the University of Missouri, MO1-RR00400 to the University of Minnesota, MO1-RR0425 to Harbor-UCLA Medical Center) and by grant 18018278 from the State of Iowa to the University of Iowa.

The authors declare they have no competing financial interests.

Received 7 March 2005 ; accepted 25 May 2005.

An erratum was published in Environ Health Perspect 113:A583 (2005) .