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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
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. doi:10.1289/ehp.8100 available via http://dx.doi.org/[Online 27 May 2005]
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Diesters of phthalic acid, commonly referred to as phthalates, are widely used in industry and commerce; they are used in personal care products (e.g., makeup, shampoo, and soaps), plastics, paints, and some pesticide formulations. Consistent toxicologic evidence indicates association between several of these phthalate esters and reproductive effects. In particular, dibutyl phthalate (DBP), benzylbutyl phthalate (BzBP), di-2-ethylhexyl phthalate (DEHP), and di-isononyl phthalate have been shown to disrupt reproductive tract development in male rodents in an antiandrogenic manner (Parks et al. 2000). Recent studies have reported significant reductions in anogenital distance (AGD) in Sprague-Dawley rats after prenatal exposure at high doses to BzBP (Nagao et al. 2000; Tyl et al. 2004), DBP (Barlow and Foster 2003; Foster et al. 2000), and DEHP (Gray et al. 2000; Parks et al. 2000).
Despite the growing body of literature on phthalate reproductive toxicity and data demonstrating extensive human exposure (Silva et al. 2004a), few studies have examined the effects of these chemicals on human reproductive development. Colon et al. (2000) reported elevated levels of several phthalates [including diethyl phthalate (DEP), DBP, and DEHP] in serum samples from young girls with premature breast development. However, the timing of exposure was unknown and high exposure levels may have reflected phthalate contamination of serum samples (McKee and Toxicology Research Task Group 2004). Until recently, the only study of humans to evaluate phthalate exposure and male reproductive toxicity measured phthalate diesters in semen. As with the Colon et al. study, contamination from diesters in laboratory equipment could not be excluded (Murature et al. 1987).
More recent studies have examined phthalate monoester metabolites in urine. Because urinary metabolites are not likely to be present as the result of contamination, these studies avoid this potential source of measurement error. Duty et al. (2003a) reported dose-response relationships between tertiles of monobutyl phthalate and sperm motility and sperm concentration, and between tertiles of monobenzyl phthalate (MBzP) and sperm concentration. They also reported inverse dose-response relationships between monoethyl phthalate (MEP) and sperm DNA damage measured using the neutral single-cell gel electrophoresis (comet) assay (Duty et al. 2003b). In this population of men attending an infertility clinic, increased urinary concentration of MBzP was also associated with decreased follicle stimulating hormone, whereas increases in monobutyl phthalate were marginally associated with increased inhibin-B (Duty et al. 2005).
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