Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan 704, Taiwan.
Hum Reprod. 2013 Oct;28(10):2765-73. doi: 10.1093/humrep/det325. Epub 2013 Aug 14.
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.
STUDY DESIGN, SIZE, DURATION: 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.
PARTICIPANTS/MATERIALS, SETTING, METHODS: 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).
LIMITATIONS, REASONS FOR CAUTION: 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.
STUDY FUNDING/COMPETING INTEREST(S): 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.
接触邻苯二甲酸酯与女性青春期开始时间之间是否存在关联？
我们的研究表明，青春期提前与 kisspeptin 分泌增加有关。
与过去几十年相比，女孩的成熟时间更早，而用于消费产品的邻苯二甲酸酯的数量也同时增加。接触邻苯二甲酸酯可能会增加 kisspeptin 分泌并导致青春期提前的假说尚未得到探索。
研究设计、大小和持续时间：本病例对照研究于 2006 年至 2009 年进行。我们招募了 104 名女孩。台湾儿科内分泌门诊招募中枢性性早熟（CPP）（病例）组的女孩；青春期前对照组从当地小学招募，所有组均根据儿科医生的诊断进行分类。
参与者/材料、地点、方法：使用放射免疫分析法评估青春期的身体特征，并评估血液样本中 LH、FSH、雌二醇和 kisspeptin-54 的水平。使用反相高效液相色谱-串联质谱法分析七种尿邻苯二甲酸酯代谢物。对数据进行非参数分析、趋势检验和线性回归。
CPP 组的所有七种尿邻苯二甲酸酯代谢物均显著高于青春期前对照组（P<0.05）。CPP 组的血清 kisspeptin-54 水平高于对照组（P=0.022），并且在调整年龄后仍显着升高（P=0.03）。 kisspeptin 水平与青春期阶段之间存在显著的递增趋势（P（趋势）=0.005）。接受醋酸亮丙瑞林治疗的女孩 kisspeptin-54 浓度没有变化。 kisspeptin-54 与尿单正丁基邻苯二甲酸（ng/ml：R（2）=0.251，P<0.001；μg/g-肌酐：R（2）=0.109，P=0.024）之间存在显著正相关。
局限性、谨慎的原因：研究持续时间短，样本量相对较小；因此，我们无法收集足够的证据支持接触邻苯二甲酸酯与随后发生的 CPP 之间的时间关系。
kisspeptin 可能会促进暴露于高水平邻苯二甲酸酯的女孩青春期的开始，特别是二正丁基邻苯二甲酸酯。这些数据表明，开发 kisspeptin 拮抗剂可能是治疗 CPP 的另一种策略。
研究资金/利益冲突：这项工作得到了台湾国家科学委员会 NSC 96-2621-Z-006-013 和 NSC 97-2621-M-006-001 的资助。作者没有利益冲突需要披露。
