Phthalate exposure and pubertal development in a longitudinal study of US girls.

study questionDoes phthalate exposure during early childhood alter the timing of pubertal development in girls? SUMMARY ANSWER: Urinary concentrations of high-molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. WHAT IS KNOWN ALREADY: Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. STUDY DESIGN, SIZE, AND DURATION: This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6-8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 µg/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age-specific body mass-index percentile, one of the strongest predictors of pubertal onset. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (ΣDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary ΣDEHP (medians: 510 and 59 µg/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. LIMITATIONS, REASONS FOR CAUTION: While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. WIDER IMPLICATIONS OF THE

findingsPhthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests.