Phthalates may promote female puberty by increasing kisspeptin activity

Abstract

Is there an association between exposure to phthalates and the timing of female puberty? Our study suggests that the early onset of puberty is related to increased kisspeptin secretion. Girls are maturing earlier than in past decades and the quantity of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may increase kisspeptin secretion and thereby cause early-onset puberty is unexplored. This case-control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan; prepubescent controls were recruited from local elementary schools and all were categorized based on a pediatrician's diagnosis. The physical characteristics of puberty were assessed and levels of LH, FSH estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography-tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Non-parametric analyses, trend tests and linear regressions were performed on the data. All seven urinary phthalate metabolites in the CPP group were significantly (P < 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (P = 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (P = 0.03). There was a significant increasing trend (P(trend) = 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with leuprorelin acetate. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (ng/ml: R(2) = 0.251, P < 0.001; μg/g-creatinine: R(2) = 0.109, P = 0.024). The study duration was short and the sample size relatively small; therefore, we were unable to collect sufficient evidence to support the temporality between exposure to phthalates and the subsequent occurrence of PP. Kisspeptin may promote the onset of puberty in girls who are exposed to a high level of phthalates, especially di-n-butyl phthalate. These data suggest that developing a kisspeptin antagonist might be an alternative strategy for treating PP. This work was supported by grants NSC 96-2621-Z-006-013 and NSC 97-2621-M-006-001 from the Taiwan National Science Council. The authors have no conflicts of interest to disclose.